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1
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Llorens-Giralt P, Ruiz-Romero M, Nurtdinov R, Herranz-Itúrbide M, Vicent GP, Serras F, Fabregat I, Corominas M. Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers. CELL GENOMICS 2025:100887. [PMID: 40409273 DOI: 10.1016/j.xgen.2025.100887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 03/10/2025] [Accepted: 04/28/2025] [Indexed: 05/25/2025]
Abstract
The mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromatin accessibility and transcriptomic data after partial hepatectomy in mice. We show that the expression of crucial regeneration genes is orchestrated by a diverse array of cis-regulatory elements, including regeneration-specific enhancers and enhancers repurposed from various developmental stages. These enhancers collaborate to activate the transcriptional programs required for hepatocyte priming and proliferation, with their activity initially regulated by the activator protein-1 (AP-1) complex and ATF3, and subsequently by nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) during proliferation. Our results also indicate that hepatic regeneration involves the repression of enhancers regulating liver-specific metabolic functions, particularly those involved in lipid metabolism. This study provides a genome-wide atlas of enhancer-gene interactions, offering new insights into the regulatory mechanisms underlying liver regeneration.
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Affiliation(s)
- Palmira Llorens-Giralt
- Department of Genetics, Microbiology and Statistics, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, Diagonal 643, 08028 Barcelona, Catalonia, Spain
| | - Marina Ruiz-Romero
- Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology (BIST), Dr. Aiguader 88, Barcelona 08003, Spain
| | - Ramil Nurtdinov
- Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology (BIST), Dr. Aiguader 88, Barcelona 08003, Spain
| | - Macarena Herranz-Itúrbide
- TGF-beta and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Av. Granvia de l'Hospitalet 199, 08908 L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Guillermo P Vicent
- Molecular Biology Institute of Barcelona, Consejo Superior de Investigaciones Científicas (IBMB-CSIC), Baldiri Reixac 4-8, 08028 Barcelona, Spain
| | - Florenci Serras
- Department of Genetics, Microbiology and Statistics, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, Diagonal 643, 08028 Barcelona, Catalonia, Spain
| | - Isabel Fabregat
- TGF-beta and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Av. Granvia de l'Hospitalet 199, 08908 L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Montserrat Corominas
- Department of Genetics, Microbiology and Statistics, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, Diagonal 643, 08028 Barcelona, Catalonia, Spain.
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2
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Sanlorenzo M, Novoszel P, Vujic I, Gastaldi T, Hammer M, Fari O, De Sa Fernandes C, Landau AD, Göcen-Oguz BV, Holcmann M, Monshi B, Rappersberger K, Csiszar A, Sibilia M. Systemic IFN-I combined with topical TLR7/8 agonists promotes distant tumor suppression by c-Jun-dependent IL-12 expression in dendritic cells. NATURE CANCER 2025; 6:175-193. [PMID: 39849091 PMCID: PMC11779648 DOI: 10.1038/s43018-024-00889-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 12/04/2024] [Indexed: 01/25/2025]
Abstract
Dendritic cell (DC) activation by pattern recognition receptors like Toll-like-receptors (TLRs) is crucial for cancer immunotherapies. Here, we demonstrate the effectiveness of the TLR7/8 agonist imiquimod (IMQ) in treating both local tumors and distant metastases. Administered orally, IMQ activates plasmacytoid DCs (pDCs) to produce systemic type I interferons (IFN-I) required for TLR7/8 upregulation in DCs and macrophages, sensitizing them to topical IMQ treatment, which is essential for therapeutic efficacy. The mechanism involves c-Jun/AP-1 mediating TLR7/8 signaling in IFN-I-primed DCs, upregulating the pDC-recruiting chemokine CCL2 and the anti-angiogenic cytokine interleukin-12, which suppresses VEGF-A production leading to tumor necrosis and regression. Combining topical and systemic IMQ or IFN-I generates a CD8+ T cell-dependent response at metastatic sites, reinforced by PD-1 blockade, leading to long-lasting memory. Analysis of cohorts of patients with melanoma demonstrates DC-specific TLR7/8 upregulation by IFN-I, supporting the translational potential of combining systemic IFN-I and topical IMQ to improve immunotherapy of topically accessible tumors.
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Affiliation(s)
- Martina Sanlorenzo
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Philipp Novoszel
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Igor Vujic
- Department of Dermatology, Klinik Landstrasse, Vienna, Austria
| | - Tommaso Gastaldi
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Martina Hammer
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Ourania Fari
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Cristiano De Sa Fernandes
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Alina D Landau
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Bilge V Göcen-Oguz
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Martin Holcmann
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Babak Monshi
- Department of Dermatology, Klinik Landstrasse, Vienna, Austria
| | | | - Agnes Csiszar
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
| | - Maria Sibilia
- Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria.
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3
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Carter-Cusack D, Huang S, Keshvari S, Patkar O, Sehgal A, Allavena R, Byrne RAJ, Morgan BP, Bush SJ, Summers KM, Irvine KM, Hume DA. Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation. PLoS Genet 2025; 21:e1011525. [PMID: 39869647 PMCID: PMC11785368 DOI: 10.1371/journal.pgen.1011525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/31/2025] [Accepted: 12/04/2024] [Indexed: 01/29/2025] Open
Abstract
Adaptation to existence outside the womb is a key event in the life of a mammal. The absence of macrophages in rats with a homozygous mutation in the colony-stimulating factor 1 receptor (Csf1r) gene (Csf1rko) severely compromises pre-weaning somatic growth and maturation of organ function. Transfer of wild-type bone marrow cells (BMT) at weaning rescues tissue macrophage populations permitting normal development and long-term survival. To dissect the phenotype and function of macrophages in postnatal development, we generated transcriptomic profiles of all major organs of wild-type and Csf1rko rats at weaning and in selected organs following rescue by BMT. The transcriptomic profiles revealed subtle effects of macrophage deficiency on development of all major organs. Network analysis revealed a common signature of CSF1R-dependent resident tissue macrophages that includes the components of complement C1Q (C1qa/b/c genes). Circulating C1Q was almost undetectable in Csf1rko rats and rapidly restored to normal levels following BMT. Tissue-specific macrophage signatures were also identified, notably including sinus macrophage populations in the lymph nodes. Their loss in Csf1rko rats was confirmed by immunohistochemical localisation of CD209B (SIGNR1). By 6-12 weeks, Csf1rko rats succumb to emphysema-like pathology associated with the selective loss of interstitial macrophages and granulocytosis. This pathology was reversed by BMT. Along with physiological rescue, BMT precisely regenerated the abundance and expression profiles of resident macrophages. The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia. In addition, the transferred BM failed to restore blood monocyte or CSF1R-positive bone marrow progenitors. These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity.
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Affiliation(s)
- Dylan Carter-Cusack
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Stephen Huang
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Sahar Keshvari
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Omkar Patkar
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Anuj Sehgal
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Rachel Allavena
- School of Veterinary Science, The University of Queensland, Gatton, Australia
| | - Robert A. J. Byrne
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - B. Paul Morgan
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Stephen J. Bush
- School of Automation Science and Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Kim M. Summers
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Katharine M. Irvine
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - David A. Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
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4
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Jiang C, Centonze A, Song Y, Chrisnandy A, Tika E, Rezakhani S, Zahedi Z, Bouvencourt G, Dubois C, Van Keymeulen A, Lütolf M, Sifrim A, Blanpain C. Collagen signaling and matrix stiffness regulate multipotency in glandular epithelial stem cells in mice. Nat Commun 2024; 15:10482. [PMID: 39695111 PMCID: PMC11655882 DOI: 10.1038/s41467-024-54843-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 11/21/2024] [Indexed: 12/20/2024] Open
Abstract
Glandular epithelia, including mammary gland (MG) and prostate, are composed of luminal and basal cells. During embryonic development, glandular epithelia arise from multipotent stem cells (SCs) that are replaced after birth by unipotent basal and unipotent luminal SCs. Different conditions, such as basal cell transplantation, luminal cell ablation, and oncogene expression can reinduce adult basal SC (BaSCs) multipotency in different glandular epithelia. The mechanisms regulating the reactivation of multipotency are incompletely understood. Here, we have found that Collagen I expression is commonly upregulated in BaSCs across the different multipotent conditions. Increasing collagen concentration or stiffness of the extracellular matrix (ECM) promotes BaSC multipotency in MG and prostate organoids. Single cell RNA-seq of MG organoids in stiff conditions have uncovered the importance of β1 integrin/FAK/AP-1 axis in the regulation of BaSC multipotency. Altogether our study uncovers the key role of Collagen signaling and ECM stiffness in the regulation of multipotency in glandular epithelia.
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Affiliation(s)
- Chen Jiang
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Alessia Centonze
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Yura Song
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Antonius Chrisnandy
- Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences (SV) and School of Engineering (STI), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Elisavet Tika
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Saba Rezakhani
- Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences (SV) and School of Engineering (STI), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Zahra Zahedi
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Gaëlle Bouvencourt
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Christine Dubois
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | | | - Matthias Lütolf
- Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences (SV) and School of Engineering (STI), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Institute of Chemical Sciences and Engineering, School of Basic Science (SB), EPFL, Lausanne, Switzerland
- Institute of Human Biology (IHB), Pharma Research and Early Development (pRED), F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Alejandro Sifrim
- Laboratory of Multi-Omic Integrative Bioinformatics (LMIB), Department of Human Genetics, University of Leuven, KU Leuven, Leuven, Belgium
| | - Cédric Blanpain
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium.
- WEL Research Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium.
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5
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Wilson ER, Nunes GDF, Shen S, Moore S, Gawron J, Maxwell J, Syed U, Hurley E, Lanka M, Qu J, Désaubry L, Wrabetz L, Poitelon Y, Feltri ML. Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination. Glia 2024; 72:2247-2267. [PMID: 39215540 PMCID: PMC11577967 DOI: 10.1002/glia.24610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/18/2024] [Accepted: 08/13/2024] [Indexed: 09/04/2024]
Abstract
Schwann cells are critical for the proper development and function of the peripheral nervous system (PNS), where they form a collaborative relationship with axons. Past studies highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. Here, we expand on this, showing that drug-mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell-specific ablation of prohibitin 2 (Phb2) in vivo results in severe defects in radial sorting and myelination. We show in vivo that Phb2-null Schwann cells cannot effectively proliferate and the transcription factors EGR2 (KROX20), POU3F1 (OCT6), and POU3F2 (BRN2), necessary for proper Schwann cell maturation, are dysregulated. Schwann cell-specific deletion of Jun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the developmental defect seen in mice lacking Schwann cell Phb2. Finally, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on neuronal signals, and thus are potential mediators of PHB2-associated developmental defects. This work develops our understanding of Schwann cell biology, revealing that Phb2 may modulate the timely expression of transcription factors necessary for proper PNS development, and proposing candidates that may play a role in PHB2-mediated integration of axon signals in the Schwann cell.
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Affiliation(s)
- Emma R Wilson
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, England, UK
| | - Gustavo Della-Flora Nunes
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
- Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Shichen Shen
- Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
| | - Seth Moore
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
| | - Joseph Gawron
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
| | - Jessica Maxwell
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
| | - Umair Syed
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
| | - Edward Hurley
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
| | - Meghana Lanka
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA
| | - Jun Qu
- Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
| | - Laurent Désaubry
- Center of Research in Biomedicine of Strasbourg, Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Strasbourg, France
| | - Lawrence Wrabetz
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
- Department of Neurology, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
| | - Yannick Poitelon
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA
| | - M Laura Feltri
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
- Department of Neurology, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA
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6
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Kluiver TA, Lu Y, Schubert SA, Kraaier LJ, Ringnalda F, Lijnzaad P, DeMartino J, Megchelenbrink WL, Amo-Addae V, Eising S, de Faria FW, Münter D, van de Wetering M, Kerl K, Duiker E, van den Heuvel MC, de Meijer VE, de Kleine RH, Molenaar JJ, Margaritis T, Stunnenberg HG, de Krijger RR, Zsiros J, Clevers H, Peng WC. Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids. Nat Commun 2024; 15:8576. [PMID: 39567475 PMCID: PMC11579375 DOI: 10.1038/s41467-024-52757-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 09/20/2024] [Indexed: 11/22/2024] Open
Abstract
Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic 'fetal' and WNT-high 'embryonal', displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes. Gene regulatory network analysis reveals enrichment of regulons related to hepatic functions such as bile acid, lipid and xenobiotic metabolism in the fetal subtype but not in the embryonal subtype. In addition, the dichotomous expression pattern of the transcription factors HNF4A and LEF1 allows for a clear distinction between the fetal and embryonal tumor cells. We also perform high-throughput drug screening using patient-derived tumor organoids and identify sensitivity to HDAC inhibitors. Intriguingly, embryonal and fetal tumor organoids are sensitive to FGFR and EGFR inhibitors, respectively, indicating a dependency on EGF/FGF signaling in hepatoblastoma tumorigenesis. In summary, our data uncover the molecular and drug sensitivity landscapes of hepatoblastoma and pave the way for the development of targeted therapies.
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Affiliation(s)
- Thomas A Kluiver
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Yuyan Lu
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
- Department of Hepatobiliary Surgery, Xiamen Hospital of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Xiamen, China
| | - Stephanie A Schubert
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Lianne J Kraaier
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Femke Ringnalda
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Philip Lijnzaad
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Jeff DeMartino
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | - Wouter L Megchelenbrink
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Vico L. De Crecchio 7, Naples, Italy
| | - Vicky Amo-Addae
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Selma Eising
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Flavia W de Faria
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, Münster, Germany
| | - Daniel Münter
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, Münster, Germany
| | - Marc van de Wetering
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Kornelius Kerl
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, Münster, Germany
| | - Evelien Duiker
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands
| | - Marius C van den Heuvel
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent E de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ruben H de Kleine
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jan J Molenaar
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Thanasis Margaritis
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Hendrik G Stunnenberg
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Ronald R de Krijger
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, the Netherlands
| | - József Zsiros
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
| | - Hans Clevers
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, the Netherlands
- Pharma, Research and Early Development (pRED) of F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Weng Chuan Peng
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, the Netherlands.
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7
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Zhang C, Xia S, Yan M, Luo F, Zhang B, Zou W, Gong H. Bioinformatics and network pharmacology analysis of DWYG capsule for improving liver regeneration: identification of active compounds and mechanisms. Nat Prod Res 2024; 38:3329-3335. [PMID: 37574795 DOI: 10.1080/14786419.2023.2246630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 07/20/2023] [Accepted: 08/02/2023] [Indexed: 08/15/2023]
Abstract
Aimed to explore the mechanisms and targets of Diwu Yanggan Capsule (DWYG), a traditional Chinese medicine in liver regeneration, we used the TCMSP to obtain the active ingredients and targets of DWYG and the GEO database to obtain the DEGs related to liver regeneration. We also searched for liver regeneration-related genes in disease databases and integrated them with the herbal and GEO data to screen for potential targets of DWYG in liver regeneration. Enrichment analysis using R language and molecular docking of the key targets and active ingredients were constructed. We found 73 potential targets of DWYG in liver regeneration and revealed that DWYG may act through pathways such as MAPK, TNF, and IL-17. We also found that quercetin was a major component of DWYG with low binding energy to three key targets. Our results suggest that DWYG can facilitate liver regeneration and quercetin may be its core ingredient.
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Affiliation(s)
- Chengyi Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Shuang Xia
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Fen Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Wei Zou
- NHC Key Laboratory of Birth Defects Research, Prevention and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, PR China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
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8
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Croushore EE, Stipp CS, Gordon DJ. EWS-FLI1 and Activator Protein-1 (AP-1) Reciprocally Regulate Extracellular-Matrix Proteins in Ewing sarcoma Cells. Int J Mol Sci 2024; 25:8595. [PMID: 39201282 PMCID: PMC11354993 DOI: 10.3390/ijms25168595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/16/2024] [Accepted: 08/03/2024] [Indexed: 09/02/2024] Open
Abstract
Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis of deoxyribonucleotides and the target of multiple chemotherapy drugs, including gemcitabine. We previously identified that inhibition of RNR in Ewing sarcoma tumors upregulates the expression levels of multiple members of the activator protein-1 (AP-1) transcription factor family, including c-Jun and c-Fos, and downregulates the expression of c-Myc. However, the broader functions and downstream targets of AP-1, which are highly context- and cell-dependent, are unknown in Ewing sarcoma tumors. Consequently, in this work, we used genetically defined models, transcriptome profiling, and gene-set -enrichment analysis to identify that AP-1 and EWS-FLI1, the driver oncogene in most Ewing sarcoma tumors, reciprocally regulate the expression of multiple extracellular-matrix proteins, including fibronectins, integrins, and collagens. AP-1 expression in Ewing sarcoma cells also drives, concurrent with these perturbations in gene and protein expression, changes in cell morphology and phenotype. We also identified that EWS-FLI1 dysregulates the expression of multiple AP-1 proteins, aligning with previous reports demonstrating genetic and physical interactions between EWS-FLI1 and AP-1. Overall, these results provide novel insights into the distinct, EWS-FLI1-dependent features of Ewing sarcoma tumors and identify a novel, reciprocal regulation of extracellular-matrix components by EWS-FLI1 and AP-1.
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Affiliation(s)
- Emma E. Croushore
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Iowa, Iowa City, IA 52242, USA;
| | - Christopher S. Stipp
- Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA;
| | - David J. Gordon
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Iowa, Iowa City, IA 52242, USA;
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9
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Andersh KM, MacLean M, Howell GR, Libby RT. IL1A enhances TNF-induced retinal ganglion cell death. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.28.596328. [PMID: 38854045 PMCID: PMC11160597 DOI: 10.1101/2024.05.28.596328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Glaucoma is a neurodegenerative disease that leads to the death of retinal ganglion cells (RGCs). A growing body of literature suggests a role for neuroinflammation in RGC death after glaucoma-relevant insults. For instance, it was shown that deficiency of three proinflammatory cytokines, complement component 1, subcomponent q ( C1q ), interleukin 1 alpha ( Il1a ), and tumor necrosis factor ( Tnf ), resulted in near complete protection of RGCs after two glaucoma-relevant insults, optic nerve injury and ocular hypertension. While TNF and C1Q have been extensively investigated in glaucoma-relevant model systems, the role of IL1A in RGC is not as well defined. Thus, we investigated the direct neurotoxicity of IL1A on RGCs in vivo. Intravitreal injection of IL1A did not result in RGC death at either 14 days or 12 weeks after insult. Consistent with previous studies, TNF injection did not result in significant RGC loss at 14 days but did after 12 weeks. Interestingly, IL1A+TNF resulted in a relatively rapid RGC death, driving significant RGC loss two weeks after injection. JUN activation and SARM1 have been implicated in RGC death in glaucoma and after cytokine insult. Using mice deficient in JUN or SARM1, we show RGC loss after IL1A+TNF insult is JUN-independent and SARM1-dependent. Furthermore, RNA-seq analysis showed that RGC death by SARM1 deficiency does not stop the neuroinflammatory response to IL1A+TNF. These findings indicate that IL1A can potentiate TNF-induced RGC death after combined insult is likely driven by a SARM1-dependent RGC intrinsic signaling pathway.
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10
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Grayck MR, McCarthy WC, Solar M, Balasubramaniyan N, Zheng L, Orlicky DJ, Wright CJ. Implications of neonatal absence of innate immune mediated NFκB/AP1 signaling in the murine liver. Pediatr Res 2024; 95:1791-1802. [PMID: 38396130 DOI: 10.1038/s41390-024-03071-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/03/2024] [Accepted: 01/20/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND The developmental immaturity of the innate immune system helps explains the increased risk of infection in the neonatal period. Importantly, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for the prevention of hepatocyte apoptosis in adult animals, yet whether developmental immaturity of these pathways increases the risk of hepatic injury in the neonatal period is unknown. METHODS Using a murine model of endotoxemia (LPS 5 mg/kg IP x 1) in neonatal (P3) and adult mice, we evaluated histologic evidence of hepatic injury and apoptosis, presence of p65/NFκB and c-Jun/AP1 activation and associated transcriptional regulation of apoptotic genes. RESULTS We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis. This is associated with absent hepatic p65/NFκB signaling and impaired expression of anti-apoptotic target genes. Hepatic c-Jun/AP1 activity was attenuated in endotoxemic P3 mice, with resulting upregulation of pro-apoptotic factors. CONCLUSIONS These results demonstrate that developmental absence of innate immune p65/NFκB and c-Jun/AP1 signaling, and target gene expression is associated with apoptotic injury in neonatal mice. More work is needed to determine if this contributes to long-term hepatic dysfunction, and whether immunomodulatory approaches can prevent this injury. IMPACT Various aspects of developmental immaturity of the innate immune system may help explain the increased risk of infection in the neonatal period. In adult models of inflammation and infection, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for a protective, pro-inflammatory transcriptome and regulation of apoptosis. We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis associated with absent hepatic p65/NFκB signaling and c-Jun/AP1 activity. We believe that these results may explain in part hepatic dysfunction with neonatal sepsis, and that there may be unrecognized developmental and long-term hepatic implications of early life exposure to systemic inflammatory stress.
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Affiliation(s)
- Maya R Grayck
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - William C McCarthy
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mack Solar
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Natarajan Balasubramaniyan
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Lijun Zheng
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - David J Orlicky
- Dept of Pathology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Clyde J Wright
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
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11
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Redmer T, Raigel M, Sternberg C, Ziegler R, Probst C, Lindner D, Aufinger A, Limberger T, Trachtova K, Kodajova P, Högler S, Schlederer M, Stoiber S, Oberhuber M, Bolis M, Neubauer HA, Miranda S, Tomberger M, Harbusch NS, Garces de Los Fayos Alonso I, Sternberg F, Moriggl R, Theurillat JP, Tichy B, Bystry V, Persson JL, Mathas S, Aberger F, Strobl B, Pospisilova S, Merkel O, Egger G, Lagger S, Kenner L. JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression. Mol Cancer 2024; 23:114. [PMID: 38811984 PMCID: PMC11134959 DOI: 10.1186/s12943-024-02022-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 05/10/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. METHODS We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. RESULTS Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. CONCLUSIONS Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.
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Affiliation(s)
- Torben Redmer
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria.
| | - Martin Raigel
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
| | - Christina Sternberg
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Biochemical Institute, University of Kiel, Kiel, 24098, Germany
| | - Roman Ziegler
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Cell Biology, Charles University, Prague, Czech Republic and Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Vestec u Prahy, Czech Republic
| | - Clara Probst
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
| | - Desiree Lindner
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
| | - Astrid Aufinger
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Tanja Limberger
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Center for Biomarker Research in Medicine (CBmed) Vienna, Core-Lab2, Medical University of Vienna, Vienna, 1090, Austria
| | - Karolina Trachtova
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
- CEITEC-Central European Institute of Technology, Masaryk University, Brno, 625 00, Czech Republic
| | - Petra Kodajova
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Sandra Högler
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Michaela Schlederer
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Stefan Stoiber
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
- Christian Doppler Laboratory for Applied Metabolomics, Medical University of Vienna, Vienna, 1090, Austria
| | - Monika Oberhuber
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, 8010, Austria
| | - Marco Bolis
- Institute of Oncology Research, Bellinzona and Faculty of Biomedical Sciences, USI, Lugano, 6500, TI, Switzerland
- Computational Oncology Unit, Department of Oncology, Istituto di Richerche Farmacologiche 'Mario Negri' IRCCS, Milano, 20156, Italy
- Bioinformatics Core Unit, Swiss Institute of Bioinformatics, Bellinzona, 6500, TI, Switzerland
| | - Heidi A Neubauer
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Institute of Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Sara Miranda
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Martina Tomberger
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, 8010, Austria
| | - Nora S Harbusch
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, 8010, Austria
| | - Ines Garces de Los Fayos Alonso
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Felix Sternberg
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, Vienna, 1090, Austria
| | - Richard Moriggl
- Department of Biosciences and Medical Biology, Cancer Cluster Salzburg, Paris-Lodron University of Salzburg, Salzburg, 5020, Austria
| | - Jean-Philippe Theurillat
- Institute of Oncology Research, Bellinzona and Faculty of Biomedical Sciences, USI, Lugano, 6500, TI, Switzerland
| | - Boris Tichy
- CEITEC-Central European Institute of Technology, Masaryk University, Brno, 625 00, Czech Republic
| | - Vojtech Bystry
- CEITEC-Central European Institute of Technology, Masaryk University, Brno, 625 00, Czech Republic
| | - Jenny L Persson
- Department of Molecular Biology, Umeå University, Umeå, 901 87, Sweden
- Department of Biomedical Sciences, Malmö Universitet, Malmö, 206 06, Sweden
| | - Stephan Mathas
- Charité-Universitätsmedizin Berlin, Hematology, Oncology and Tumor Immunology, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, 10117, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Group Biology of Malignant Lymphomas, Berlin, 13125, Germany
- Experimental and Clinical Research Center (ECRC), a cooperation between the MDC and the Charité, Berlin, Germany
| | - Fritz Aberger
- Department of Biosciences and Medical Biology, Cancer Cluster Salzburg, Paris-Lodron University of Salzburg, Salzburg, 5020, Austria
| | - Birgit Strobl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Sarka Pospisilova
- CEITEC-Central European Institute of Technology, Masaryk University, Brno, 625 00, Czech Republic
| | - Olaf Merkel
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Gerda Egger
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Sabine Lagger
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria.
| | - Lukas Kenner
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria.
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria.
- Christian Doppler Laboratory for Applied Metabolomics, Medical University of Vienna, Vienna, 1090, Austria.
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, 8010, Austria.
- Comprehensive Cancer Center, Medical University Vienna, Vienna, 1090, Austria.
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12
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Xian L, Xiong Y, Qin L, Wei L, Zhou S, Wang Q, Fu Q, Chen M, Qin Y. Jun/Fos promotes migration and invasion of hepatocellular carcinoma cells by enhancing BORIS promoter activity. Int J Biochem Cell Biol 2024; 169:106540. [PMID: 38281696 DOI: 10.1016/j.biocel.2024.106540] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 01/16/2024] [Accepted: 01/24/2024] [Indexed: 01/30/2024]
Abstract
The Brother of the Regulator of Imprinted Sites (BORIS), as a specific indicator of hepatocellular carcinoma, exhibits a significant increase in expression. However, its upstream regulatory network remains enigmatic. Previous research has indicated a strong correlation between the Hippo pathway and the progression of hepatocellular carcinoma. It is well established that the Activator Protein-1 (AP-1) frequently engages in interactions with the Hippo pathway. Thus, we attempt to prove whether Jun and Fos, a major member of the AP-1 family, are involved in the regulation of BORIS expression. Bioinformatics analysis revealed the existence of binding sites for Jun and Fos within the BORIS promoter. Through a series of overexpression and knockdown experiments, we corroborated that Jun and Fos have the capacity to augment BORIS expression, thereby fostering the migration and invasion of hepatocellular carcinoma cells. Moreover, Methylation-Specific PCR and Bisulfite Sequencing PCR assays revealed that Jun and Fos do not have a significant impact on the demethylation of the BORIS promoter. However, luciferase reporter and chromatin immunoprecipitation experiments substantiated that Jun and Fos could directly bind to the BORIS promoter, thereby enhancing its transcription. In conclusion, these results suggest that Jun and Fos can promote the development of hepatocellular carcinoma by directly regulating the expression of BORIS. These findings may provide experimental evidence positioning BORIS as a novel target for the clinical intervention of hepatocellular carcinoma.
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Affiliation(s)
- Longjun Xian
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu 610041, Sichuan Province, China
| | - Yimei Xiong
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu 610041, Sichuan Province, China
| | - Lu Qin
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu 610041, Sichuan Province, China
| | - Ling Wei
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu 610041, Sichuan Province, China
| | - Siqi Zhou
- Department of Surgery Division of Liver Transplantation, West China Hospital, Sichuan University, 37 Guo Xue Rd., Chengdu 610041, Sichuan Province, China
| | - Qinda Wang
- Department of Surgery Division of Liver Transplantation, West China Hospital, Sichuan University, 37 Guo Xue Rd., Chengdu 610041, Sichuan Province, China
| | - Qiang Fu
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu 610041, Sichuan Province, China
| | - Mingmei Chen
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu 610041, Sichuan Province, China.
| | - Yang Qin
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu 610041, Sichuan Province, China.
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13
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Wilson ER, Nunes GDF, Shen S, Moore S, Gawron J, Maxwell J, Syed U, Hurley E, Lanka M, Qu J, Desaubry L, Wrabetz L, Poitelon Y, Feltri ML. Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.20.585915. [PMID: 38562812 PMCID: PMC10983910 DOI: 10.1101/2024.03.20.585915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Schwann cells are critical for the proper development and function of the peripheral nervous system, where they form a mutually beneficial relationship with axons. Past studies have highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. Here, we expand on this work, showing that drug-mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell-specific ablation of prohibitin 2 (Phb2) in vivo results in early and severe defects in peripheral nerve development. Using a proteomic approach in vitro, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on the presence of axonal signals. Furthermore, we show in vivo that loss of Phb2 in mouse Schwann cells causes ineffective proliferation and dysregulation of transcription factors EGR2 (KROX20), POU3F1 (OCT6) and POU3F2 (BRN2) that are necessary for proper Schwann cell maturation. Schwann cell-specific deletion of Jun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the development defect seen in mice lacking Schwann cell Phb2. This work develops our understanding of Schwann cell biology, revealing that Phb2 may directly or indirectly modulate the timely expression of transcription factors necessary for proper peripheral nervous system development, and proposing candidates that may play a role in PHB2-mediated integration of axon signals in the Schwann cell.
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Affiliation(s)
- Emma R Wilson
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
- Department of Clinical Neurosciences, Cambridge University, Cambridge, UK
| | - Gustavo Della-Flora Nunes
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
- Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Shichen Shen
- Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Seth Moore
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Joseph Gawron
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Jessica Maxwell
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Umair Syed
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Edward Hurley
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Meghana Lanka
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA
| | - Jun Qu
- Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Laurent Desaubry
- Center of Research in Biomedicine of Strasbourg, Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, 67000 Strasbourg, France
| | - Lawrence Wrabetz
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
- Department of Neurology, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Yannick Poitelon
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA
| | - M Laura Feltri
- Department of Biochemistry, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
- Department of Neurology, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
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14
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Shrestha N, Sleep SL, Holland OJ, Vidimce J, Bulmer AC, Cuffe JSM, Perkins AV, McAinch AJ, Hryciw DH. Maternal Diet High in Linoleic Acid Alters Offspring Lipids and Hepatic Regulators of Lipid Metabolism in an Adolescent Rat Model. Int J Mol Sci 2024; 25:1129. [PMID: 38256199 PMCID: PMC10816089 DOI: 10.3390/ijms25021129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/03/2024] [Accepted: 01/15/2024] [Indexed: 01/24/2024] Open
Abstract
Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. A maternal high LA (HLA) diet alters cardiovascular development in adolescent rats and hepatic function in adult rats in a sex-specific manner. We investigated the effects of an HLA diet on adolescent offspring hepatic lipids and hepatic lipid metabolism gene expression, and the ability of the postnatal diet to alter these effects. Female Wistar Kyoto rats were fed low LA (LLA; 1.44% energy from LA) or high LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring, weaned at postnatal day (PN) 25, were fed LLA or HLA and euthanised at PN40 (n = 6-8). Maternal HLA increased circulating uric acid, decreased hepatic cholesterol and increased hepatic Pparg in males, whereas only hepatic Srebf1 and Hmgcr increased in females. Postnatal (post-weaning) HLA decreased liver weight (% body weight) and increased hepatic Hmgcr in males, and decreased hepatic triglycerides in females. Maternal and postnatal HLA had an interaction effect on Lpl, Cpt1a and Pparg in females. These findings suggest that an HLA diet both during and after pregnancy should be avoided to improve offspring disease risk.
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Affiliation(s)
- Nirajan Shrestha
- School of Pharmacy and Medical Science, Griffith University, Southport, QLD 4222, Australia; (N.S.); (S.L.S.); (O.J.H.); (J.V.); (A.C.B.); (A.V.P.)
| | - Simone L. Sleep
- School of Pharmacy and Medical Science, Griffith University, Southport, QLD 4222, Australia; (N.S.); (S.L.S.); (O.J.H.); (J.V.); (A.C.B.); (A.V.P.)
| | - Olivia J. Holland
- School of Pharmacy and Medical Science, Griffith University, Southport, QLD 4222, Australia; (N.S.); (S.L.S.); (O.J.H.); (J.V.); (A.C.B.); (A.V.P.)
- Women’s, Newborn and Childrens Services, Gold Coast Health, Southport, QLD 4222, Australia
| | - Josif Vidimce
- School of Pharmacy and Medical Science, Griffith University, Southport, QLD 4222, Australia; (N.S.); (S.L.S.); (O.J.H.); (J.V.); (A.C.B.); (A.V.P.)
| | - Andrew C. Bulmer
- School of Pharmacy and Medical Science, Griffith University, Southport, QLD 4222, Australia; (N.S.); (S.L.S.); (O.J.H.); (J.V.); (A.C.B.); (A.V.P.)
| | - James S. M. Cuffe
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia;
| | - Anthony V. Perkins
- School of Pharmacy and Medical Science, Griffith University, Southport, QLD 4222, Australia; (N.S.); (S.L.S.); (O.J.H.); (J.V.); (A.C.B.); (A.V.P.)
- School of Health, University of Sunshine Coast, Sunshine Coast, Sippy Downs, QLD 4556, Australia
| | - Andrew J. McAinch
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3001, Australia;
- Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, St. Albans, VIC 3021, Australia
| | - Deanne H. Hryciw
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3001, Australia;
- School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia
- Griffith Institute of Drug Discovery, Griffith University, Nathan, QLD 4111, Australia
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15
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Zamora Z, Wang S, Chen YW, Diamante G, Yang X. Systematic transcriptome-wide meta-analysis across endocrine disrupting chemicals reveals shared and unique liver pathways, gene networks, and disease associations. ENVIRONMENT INTERNATIONAL 2024; 183:108339. [PMID: 38043319 PMCID: PMC11216742 DOI: 10.1016/j.envint.2023.108339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 11/03/2023] [Accepted: 11/19/2023] [Indexed: 12/05/2023]
Abstract
Cardiometabolic disorders (CMD) are a growing public health problem across the world. Among the known cardiometabolic risk factors are compounds that induce endocrine and metabolic dysfunctions, such as endocrine disrupting chemicals (EDCs). To date, how EDCs influence molecular programs and cardiometabolic risks has yet to be fully elucidated, especially considering the complexity contributed by species-, chemical-, and dose-specific effects. Moreover, different experimental and analytical methodologies employed by different studies pose challenges when comparing findings across studies. To explore the molecular mechanisms of EDCs in a systematic manner, we established a data-driven computational approach to meta-analyze 30 human, mouse, and rat liver transcriptomic datasets for 4 EDCs, namely bisphenol A (BPA), bis(2-ethylhexyl) phthalate (DEHP), tributyltin (TBT), and perfluorooctanoic acid (PFOA). Our computational pipeline uniformly re-analyzed pre-processed quality-controlled microarray data and raw RNAseq data, derived differentially expressed genes (DEGs) and biological pathways, modeled gene regulatory networks and regulators, and determined CMD associations based on gene overlap analysis. Our approach revealed that DEHP and PFOA shared stable transcriptomic signatures that are enriched for genes associated with CMDs, suggesting similar mechanisms of action such as perturbations of peroxisome proliferator-activated receptor gamma (PPARγ) signaling and liver gene network regulators VNN1 and ACOT2. In contrast, TBT exhibited highly divergent gene signatures, pathways, network regulators, and disease associations from the other EDCs. In addition, we found that the rat, mouse, and human BPA studies showed highly variable transcriptomic patterns, providing molecular support for the variability in BPA responses. Our work offers insights into the commonality and differences in the molecular mechanisms of various EDCs and establishes a streamlined data-driven workflow to compare molecular mechanisms of environmental substances to elucidate the underlying connections between chemical exposure and disease risks.
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Affiliation(s)
- Zacary Zamora
- Molecular Toxicology Interdepartmental Program, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Susanna Wang
- Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Yen-Wei Chen
- Molecular Toxicology Interdepartmental Program, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Graciel Diamante
- Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
| | - Xia Yang
- Molecular Toxicology Interdepartmental Program, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
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16
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Fisher AL, Wang CY, Xu Y, Phillips S, Paulo JA, Małachowska B, Xiao X, Fendler W, Mancias JD, Babitt JL. Quantitative proteomics and RNA-sequencing of mouse liver endothelial cells identify novel regulators of BMP6 by iron. iScience 2023; 26:108555. [PMID: 38125029 PMCID: PMC10730383 DOI: 10.1016/j.isci.2023.108555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 09/29/2023] [Accepted: 11/20/2023] [Indexed: 12/23/2023] Open
Abstract
Hepcidin is the master hormone governing systemic iron homeostasis. Iron regulates hepcidin by activating bone morphogenetic protein (BMP)6 expression in liver endothelial cells (LECs), but the mechanisms are incompletely understood. To address this, we performed proteomics and RNA-sequencing on LECs from iron-adequate and iron-loaded mice. Gene set enrichment analysis identified transcription factors activated by high iron, including Nrf-2, which was previously reported to contribute to BMP6 regulation, and c-Jun. Jun (encoding c-Jun) knockdown blocked Bmp6 but not Nrf-2 pathway induction by iron in LEC cultures. Chromatin immunoprecipitation of mouse livers showed iron-dependent c-Jun binding to predicted sites in Bmp6 regulatory regions. Finally, c-Jun inhibitor blunted induction of Bmp6 and hepcidin, but not Nrf-2 activity, in iron-loaded mice. However, Bmp6 and iron parameters were unchanged in endothelial Jun knockout mice. Our data suggest that c-Jun participates in iron-mediated BMP6 regulation independent of Nrf-2, though the mechanisms may be redundant and/or multifactorial.
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Affiliation(s)
- Allison L. Fisher
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Chia-Yu Wang
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Yang Xu
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Sydney Phillips
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Joao A. Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Beata Małachowska
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
- Department of Radiation Oncology, Albert Einstein College of Medicine, NYC, NY, USA
| | - Xia Xiao
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Joseph D. Mancias
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jodie L. Babitt
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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17
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Sundaram VK, Schütza V, Schröter NH, Backhaus A, Bilsing A, Joneck L, Seelbach A, Mutschler C, Gomez-Sanchez JA, Schäffner E, Sánchez EE, Akkermann D, Paul C, Schwagarus N, Müller S, Odle A, Childs G, Ewers D, Kungl T, Sitte M, Salinas G, Sereda MW, Nave KA, Schwab MH, Ost M, Arthur-Farraj P, Stassart RM, Fledrich R. Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration. Cell Metab 2023; 35:2136-2152.e9. [PMID: 37989315 PMCID: PMC10722468 DOI: 10.1016/j.cmet.2023.10.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 08/21/2023] [Accepted: 10/30/2023] [Indexed: 11/23/2023]
Abstract
The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.
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Affiliation(s)
- Venkat Krishnan Sundaram
- Institute of Anatomy, Leipzig University, Leipzig, Germany; Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany
| | - Vlad Schütza
- Institute of Anatomy, Leipzig University, Leipzig, Germany; Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany
| | | | - Aline Backhaus
- Institute of Anatomy, Leipzig University, Leipzig, Germany
| | - Annika Bilsing
- Institute of Anatomy, Leipzig University, Leipzig, Germany
| | - Lisa Joneck
- Institute of Anatomy, Leipzig University, Leipzig, Germany
| | - Anna Seelbach
- Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany
| | - Clara Mutschler
- John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK
| | - Jose A Gomez-Sanchez
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain; Instituto de Neurociencias CSIC-UMH, San Juan de Alicante, Spain
| | - Erik Schäffner
- Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany
| | | | - Dagmar Akkermann
- Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany
| | - Christina Paul
- Institute of Anatomy, Leipzig University, Leipzig, Germany
| | - Nancy Schwagarus
- Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany
| | - Silvana Müller
- Institute of Anatomy, Leipzig University, Leipzig, Germany
| | - Angela Odle
- Instituto de Neurociencias CSIC-UMH, San Juan de Alicante, Spain
| | - Gwen Childs
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Markham, AR, USA
| | - David Ewers
- Max Planck Institute of Experimental Medicine, Göttingen, Germany; Klinik für Neurologie, Universitätsmedizin Göttingen (UMG), Göttingen, Germany
| | - Theresa Kungl
- Institute of Anatomy, Leipzig University, Leipzig, Germany
| | - Maren Sitte
- NGS-Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Gabriela Salinas
- NGS-Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Michael W Sereda
- Max Planck Institute of Experimental Medicine, Göttingen, Germany; Klinik für Neurologie, Universitätsmedizin Göttingen (UMG), Göttingen, Germany
| | - Klaus-Armin Nave
- Max Planck Institute of Experimental Medicine, Göttingen, Germany
| | - Markus H Schwab
- Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany
| | - Mario Ost
- Institute of Anatomy, Leipzig University, Leipzig, Germany; Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany
| | - Peter Arthur-Farraj
- John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK
| | - Ruth M Stassart
- Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany.
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18
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Härle L, von Bülow V, Knedla L, Stettler F, Müller H, Zahner D, Haeberlein S, Windhorst A, Tschuschner A, Burg-Roderfeld M, Köhler K, Grevelding CG, Roeb E, Roderfeld M. Hepatocyte integrity depends on c-Jun-controlled proliferation in Schistosoma mansoni infected mice. Sci Rep 2023; 13:20390. [PMID: 37990129 PMCID: PMC10663609 DOI: 10.1038/s41598-023-47646-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 11/16/2023] [Indexed: 11/23/2023] Open
Abstract
Schistosomiasis is a parasitic disease affecting more than 250 million people worldwide. The transcription factor c-Jun, which is induced in S. mansoni infection-associated liver disease, can promote hepatocyte survival but can also trigger hepatocellular carcinogenesis. We aimed to analyze the hepatic role of c-Jun following S. mansoni infection. We adopted a hepatocyte-specific c-Jun knockout mouse model (Alb-Cre/c-Jun loxP) and analyzed liver tissue and serum samples by quantitative real-time PCR array, western blotting, immunohistochemistry, hydroxyproline quantification, and functional analyses. Hepatocyte-specific c-Jun knockout (c-JunΔli) was confirmed by immunohistochemistry and western blotting. Infection with S. mansoni induced elevated aminotransferase-serum levels in c-JunΔli mice. Of note, hepatic Cyclin D1 expression was induced in infected c-Junf/f control mice but to a lower extent in c-JunΔli mice. S. mansoni soluble egg antigen-induced proliferation in a human hepatoma cell line was diminished by inhibition of c-Jun signaling. Markers for apoptosis, oxidative stress, ER stress, inflammation, autophagy, DNA-damage, and fibrosis were not altered in S. mansoni infected c-JunΔli mice compared to infected c-Junf/f controls. Enhanced liver damage in c-JunΔli mice suggested a protective role of c-Jun. A reduced Cyclin D1 expression and reduced hepatic regeneration could be the reason. In addition, it seems likely that the trends in pathological changes in c-JunΔli mice cumulatively led to a loss of the protective potential being responsible for the increased hepatocyte damage and loss of regenerative ability.
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Affiliation(s)
- Lukas Härle
- Department of Gastroenterology, Justus Liebig University Giessen, Gaffkystr. 11c, 35392, Giessen, Germany
| | - Verena von Bülow
- Department of Gastroenterology, Justus Liebig University Giessen, Gaffkystr. 11c, 35392, Giessen, Germany
| | - Lukas Knedla
- Department of Gastroenterology, Justus Liebig University Giessen, Gaffkystr. 11c, 35392, Giessen, Germany
| | - Frederik Stettler
- Department of Gastroenterology, Justus Liebig University Giessen, Gaffkystr. 11c, 35392, Giessen, Germany
| | - Heike Müller
- Department of Gastroenterology, Justus Liebig University Giessen, Gaffkystr. 11c, 35392, Giessen, Germany
| | - Daniel Zahner
- Central Laboratory Animal Facility, Justus Liebig University Giessen, 35392, Giessen, Germany
| | - Simone Haeberlein
- Institute of Parasitology, BFS, Justus Liebig University Giessen, 35392, Giessen, Germany
| | - Anita Windhorst
- Institute of Medical Informatics, Justus Liebig University Giessen, 35392, Giessen, Germany
| | - Annette Tschuschner
- Department of Gastroenterology, Justus Liebig University Giessen, Gaffkystr. 11c, 35392, Giessen, Germany
| | | | - Kernt Köhler
- Institute of Veterinary Pathology, Justus Liebig University Giessen, Giessen, Germany
| | - Christoph G Grevelding
- Institute of Parasitology, BFS, Justus Liebig University Giessen, 35392, Giessen, Germany
| | - Elke Roeb
- Department of Gastroenterology, Justus Liebig University Giessen, Gaffkystr. 11c, 35392, Giessen, Germany
| | - Martin Roderfeld
- Department of Gastroenterology, Justus Liebig University Giessen, Gaffkystr. 11c, 35392, Giessen, Germany.
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19
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Veltman CHJ, Pennings JLA, van de Water B, Luijten M. An Adverse Outcome Pathway Network for Chemically Induced Oxidative Stress Leading to (Non)genotoxic Carcinogenesis. Chem Res Toxicol 2023. [PMID: 37156502 DOI: 10.1021/acs.chemrestox.2c00396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Nongenotoxic (NGTX) carcinogens induce cancer via other mechanisms than direct DNA damage. A recognized mode of action for NGTX carcinogens is induction of oxidative stress, a state in which the amount of oxidants in a cell exceeds its antioxidant capacity, leading to regenerative proliferation. Currently, carcinogenicity assessment of environmental chemicals primarily relies on genetic toxicity end points. Since NGTX carcinogens lack genotoxic potential, these chemicals may remain undetected in such evaluations. To enhance the predictivity of test strategies for carcinogenicity assessment, a shift toward mechanism-based approaches is required. Here, we present an adverse outcome pathway (AOP) network for chemically induced oxidative stress leading to (NGTX) carcinogenesis. To develop this AOP network, we first investigated the role of oxidative stress in the various cancer hallmarks. Next, possible mechanisms for chemical induction of oxidative stress and the biological effects of oxidative damage to macromolecules were considered. This resulted in an AOP network, of which associated uncertainties were explored. Ultimately, development of AOP networks relevant for carcinogenesis in humans will aid the transition to a mechanism-based, human relevant carcinogenicity assessment that involves a substantially lower number of laboratory animals.
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Affiliation(s)
- Christina H J Veltman
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands
| | - Jeroen L A Pennings
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
| | - Bob van de Water
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands
| | - Mirjam Luijten
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
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20
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Guo J, Han S, Chen Q, Wang T, Yu B, Zhou J, Qiu T. Analysis of potential immune-related genes involved in the pathogenesis of ischemia-reperfusion injury following liver transplantation. Front Immunol 2023; 14:1126497. [PMID: 37006305 PMCID: PMC10060527 DOI: 10.3389/fimmu.2023.1126497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 02/20/2023] [Indexed: 03/18/2023] Open
Abstract
BackgroundHepatic ischemia-reperfusion (I/R) injury is an unavoidable pathological process that occurs after liver transplantation. However, the immune-related molecular mechanism still remains unclear. This study aims to further explore the biological mechanisms of immune-related genes in hepatic I/R injury.MethodsGene microarray data was downloaded from the Gene Expression Omnibus (GEO) expression profile database and the differentially expressed genes (DEGs) were taken for intersection. After identifying common DEGs, functional annotation, protein-protein interaction (PPI) network, and modular construction were performed. The immune-related hub genes were obtained, which their upstream transcription factors and non-RNAs were predicted. Validation of the hub genes expression and immune infiltration were performed in a mouse model of hepatic I/R injury.ResultsA total of 71 common DEGs were obtained from three datasets (GSE12720, GSE14951, GSE15480). The GO and KEGG enrichment analysis results indicated that immune and inflammatory response played an important role in hepatic I/R injury. Finally, 9 immune-related hub genes were identified by intersecting cytoHubba with immune-related genes, including SOCS3, JUND, CCL4, NFKBIA, CXCL8, ICAM1, IRF1, TNFAIP3, and JUN.ConclusionOur study revealed the importance of the immune and inflammatory response in I/R injury following liver transplantation and provided new insights into the therapeutic of hepatic I/R injury.
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Affiliation(s)
- Jiayu Guo
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Shangting Han
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Qi Chen
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Tianyu Wang
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Bo Yu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jiangqiao Zhou
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- *Correspondence: Jiangqiao Zhou, ; Tao Qiu,
| | - Tao Qiu
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- *Correspondence: Jiangqiao Zhou, ; Tao Qiu,
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21
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4-Methylumbelliferone Targets Revealed by Public Data Analysis and Liver Transcriptome Sequencing. Int J Mol Sci 2023; 24:ijms24032129. [PMID: 36768453 PMCID: PMC9917189 DOI: 10.3390/ijms24032129] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 01/09/2023] [Accepted: 01/18/2023] [Indexed: 01/25/2023] Open
Abstract
4-methylumbelliferone (4MU) is a well-known hyaluronic acid synthesis inhibitor and an approved drug for the treatment of cholestasis. In animal models, 4MU decreases inflammation, reduces fibrosis, and lowers body weight, serum cholesterol, and insulin resistance. It also inhibits tumor progression and metastasis. The broad spectrum of effects suggests multiple and yet unknown targets of 4MU. Aiming at 4MU target deconvolution, we have analyzed publicly available data bases, including: 1. Small molecule library Bio Assay screening (PubChemBioAssay); 2. GO pathway databases screening; 3. Protein Atlas Database. We also performed comparative liver transcriptome analysis of mice on normal diet and mice fed with 4MU for two weeks. Potential targets of 4MU public data base analysis fall into two big groups, enzymes and transcription factors (TFs), including 13 members of the nuclear receptor superfamily regulating lipid and carbohydrate metabolism. Transcriptome analysis revealed changes in the expression of genes involved in bile acid metabolism, gluconeogenesis, and immune response. It was found that 4MU feeding decreased the accumulation of the glycogen granules in the liver. Thus, 4MU has multiple targets and can regulate cell metabolism by modulating signaling via nuclear receptors.
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22
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Xu Z, Jiang N, Xiao Y, Yuan K, Wang Z. The role of gut microbiota in liver regeneration. Front Immunol 2022; 13:1003376. [PMID: 36389782 PMCID: PMC9647006 DOI: 10.3389/fimmu.2022.1003376] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/12/2022] [Indexed: 12/02/2022] Open
Abstract
The liver has unique regeneration potential, which ensures the continuous dependence of the human body on hepatic functions. As the composition and function of gut microbiota has been gradually elucidated, the vital role of gut microbiota in liver regeneration through gut-liver axis has recently been accepted. In the process of liver regeneration, gut microbiota composition is changed. Moreover, gut microbiota can contribute to the regulation of the liver immune microenvironment, thereby modulating the release of inflammatory factors including IL-6, TNF-α, HGF, IFN-γ and TGF-β, which involve in different phases of liver regeneration. And previous research have demonstrated that through enterohepatic circulation, bile acids (BAs), lipopolysaccharide, short-chain fatty acids and other metabolites of gut microbiota associate with liver and may promote liver regeneration through various pathways. In this perspective, by summarizing gut microbiota-derived signaling pathways that promote liver regeneration, we unveil the role of gut microbiota in liver regeneration and provide feasible strategies to promote liver regeneration by altering gut microbiota composition.
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Affiliation(s)
- Zhe Xu
- Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Nan Jiang
- Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yuanyuan Xiao
- Department of Obstetrics and Gynecology, West China Second Hospital of Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
- *Correspondence: Zhen Wang, ; Kefei Yuan, ; Yuanyuan Xiao,
| | - Kefei Yuan
- Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- *Correspondence: Zhen Wang, ; Kefei Yuan, ; Yuanyuan Xiao,
| | - Zhen Wang
- Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- *Correspondence: Zhen Wang, ; Kefei Yuan, ; Yuanyuan Xiao,
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Molecular docking and in vitro experiments verified that kaempferol induced apoptosis and inhibited human HepG2 cell proliferation by targeting BAX, CDK1, and JUN. Mol Cell Biochem 2022; 478:767-780. [PMID: 36083512 DOI: 10.1007/s11010-022-04546-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 08/12/2022] [Indexed: 10/14/2022]
Abstract
Hepatocellular carcinoma, as a common liver cirrhosis complication, has become the sixth most common cancer worldwide, and its increasing incidence has resulted in considerable medical and economic burdens. As a natural polyphenolic compound, kaempferol has exhibits a wide range of antitumor activities against multiple cancer targets. In this study, the Autodock software was used for molecular docking to simulate the interaction process between kaempferol and HCC targets and the PyMOL software was used for visualization. Proliferation of kaempferol HepG2 cells under the effect of kaempferol was detected using Cell Counting Kit-8 (CCK-8) assay, and the apoptosis rate of HepG2 cells was detected using flow cytometry. The expressions of proteins BAX, CDK1, and JUN protein expressions were detected by Western blot. Molecular docking found that the kaempferol ligand has 3 rotatable bonds, 6 nonpolar hydrogen atoms, and 12 aromatic carbon atoms, and can form complexes with the kaempferol targets P53, BAX, AR, CDK1, and JUN through electrostatic energy. GO (Gene Ontology) enrichment analysis suggests that kaempferol regulates the biological function of hepatocellular carcinoma cells and is related to apoptosis. Cell Counting Kit-8 assay suggested that Kaempferol can significantly inhibited HepG2 cell proliferation, and the inhibition rate increased with the increase in drug concentration and incubation time. Moreover, kaempferol can promoted HepG2 cell apoptosis in a dose-dependent manner. This compound upregulated BAX and JUN expression and downregulated CDK1 expression. Thus, Kaempferol can promote HepG2 cell apoptosis, and the regulatory mechanism may be related to the regulation of the expression levels of the apoptosis-related proteins BAX, CDK1, and JUN.
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Serna R, Ramrakhiani A, Hernandez JC, Chen CL, Nakagawa C, Machida T, Ray RB, Zhan X, Tahara SM, Machida K. c-JUN inhibits mTORC2 and glucose uptake to promote self-renewal and obesity. iScience 2022; 25:104325. [PMID: 35601917 PMCID: PMC9121277 DOI: 10.1016/j.isci.2022.104325] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/30/2021] [Accepted: 04/26/2022] [Indexed: 02/08/2023] Open
Abstract
Metabolic syndrome is associated with obesity, insulin resistance, and the risk of cancer. We tested whether oncogenic transcription factor c-JUN metabolically reprogrammed cells to induce obesity and cancer by reduction of glucose uptake, with promotion of the stemness phenotype leading to malignant transformation. Liquid alcohol, high-cholesterol, fat diet (HCFD), and isocaloric dextrin were fed to wild-type or experimental mice for 12 months to promote hepatocellular carcinoma (HCC). We demonstrated 40% of mice developed liver tumors after chronic HCFD feeding. Disruption of liver-specific c-Jun reduced tumor incidence 4-fold and improved insulin sensitivity. Overexpression of c-JUN downregulated RICTOR transcription, leading to inhibition of the mTORC2/AKT and glycolysis pathways. c-JUN inhibited GLUT1, 2, and 3 transactivation to suppress glucose uptake. Silencing of RICTOR or c-JUN overexpression promoted self-renewal ability. Taken together, c-JUN inhibited mTORC2 via RICTOR downregulation and inhibited glucose uptake via downregulation of glucose intake, leading to self-renewal and obesity.
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Affiliation(s)
- Raphael Serna
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
| | - Ambika Ramrakhiani
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
| | - Juan Carlos Hernandez
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
| | - Chia-Lin Chen
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
| | - Chad Nakagawa
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
| | - Tatsuya Machida
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
| | | | - Xiaohang Zhan
- Chinese Academy of Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Stanley M. Tahara
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
| | - Keigo Machida
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
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25
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Syc-Mazurek SB, Yang HS, Marola OJ, Howell GR, Libby RT. Transcriptional control of retinal ganglion cell death after axonal injury. Cell Death Dis 2022; 13:244. [PMID: 35296661 PMCID: PMC8927149 DOI: 10.1038/s41419-022-04666-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 01/19/2022] [Accepted: 02/09/2022] [Indexed: 11/25/2022]
Abstract
Injury to the axons of retinal ganglion cells (RGCs) is a key pathological event in glaucomatous neurodegeneration. The transcription factors JUN (the target of the c-Jun N-terminal kinases, JNKs) and DDIT3/CHOP (a mediator of the endoplasmic reticulum stress response) have been shown to control the majority of proapoptotic signaling after mechanical axonal injury in RGCs and in other models of neurodegeneration. The downstream transcriptional networks controlled by JUN and DDIT3, which are critical for RGC death, however, are not well defined. To determine these networks, RNA was isolated from the retinas of wild-type mice and mice deficient in Jun, Ddit3, and both Jun and Ddit3 three days after mechanical optic nerve crush injury (CONC). RNA-sequencing data analysis was performed and immunohistochemistry was used to validate potential transcriptional signaling changes after axonal injury. This study identified downstream transcriptional changes after injury including both neuronal survival and proinflammatory signaling that were attenuated to differing degrees by loss of Ddit3, Jun, and Ddit3/Jun. These data suggest proinflammatory signaling in the retina might be secondary to activation of pro-death pathways in RGCs after acute axonal injury. These results determine the downstream transcriptional networks important for apoptotic signaling which may be important for ordering and staging the pro-degenerative signals after mechanical axonal injury.
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Affiliation(s)
- Stephanie B Syc-Mazurek
- Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, USA
- Medical Scientist Training Program, University of Rochester Medical Center, Rochester, NY, USA
| | | | - Olivia J Marola
- Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, USA
- Cell Biology of Disease Graduate Program, University of Rochester Medical Center, Rochester, NY, USA
- The Center for Visual Sciences, University of Rochester, Rochester, NY, USA
| | | | - Richard T Libby
- Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, USA.
- The Center for Visual Sciences, University of Rochester, Rochester, NY, USA.
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
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26
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Pal R, Kowalik MA, Serra M, Migliore C, Giordano S, Columbano A, Perra A. Diverse MicroRNAs-mRNA networks regulate the priming phase of mouse liver regeneration and of direct hyperplasia. Cell Prolif 2022; 55:e13199. [PMID: 35174557 PMCID: PMC9055901 DOI: 10.1111/cpr.13199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/21/2021] [Accepted: 01/21/2022] [Indexed: 11/28/2022] Open
Abstract
Objectives Adult hepatocytes are quiescent cells that can be induced to proliferate in response to a reduction in liver mass (liver regeneration) or by agents endowed with mitogenic potency (primary hyperplasia). The latter condition is characterized by a more rapid entry of hepatocytes into the cell cycle, but the mechanisms responsible for the accelerated entry into the S phase are unknown. Materials and methods Next generation sequencing and Illumina microarray were used to profile microRNA and mRNA expression in CD‐1 mice livers 1, 3 and 6 h after 2/3 partial hepatectomy (PH) or a single dose of TCPOBOP, a ligand of the constitutive androstane receptor (CAR). Ingenuity pathway and DAVID analyses were performed to identify deregulated pathways. MultiMiR analysis was used to construct microRNA‐mRNA networks. Results Following PH or TCPOBOP we identified 810 and 527 genes, and 102 and 10 miRNAs, respectively, differentially expressed. Only 20 genes and 8 microRNAs were shared by the two conditions. Many miRNAs targeting negative regulators of cell cycle were downregulated early after PH, concomitantly with increased expression of their target genes. On the contrary, negative regulators were not modified after TCPOBOP, but Ccnd1 targeting miRNAs, such as miR‐106b‐5p, were downregulated. Conclusions While miRNAs targeting negative regulators of the cell cycle are downregulated after PH, TCPOBOP caused downregulation of miRNAs targeting genes required for cell cycle entry. The enhanced Ccnd1 expression may explain the more rapid entry into the S phase of mouse hepatocytes following TCPOBOP.
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Affiliation(s)
- Rajesh Pal
- Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Italy
| | - Marta Anna Kowalik
- Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Italy
| | - Marina Serra
- Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Italy
| | - Cristina Migliore
- Department of Oncology, University of Torino, Torino, Italy.,Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy
| | - Silvia Giordano
- Department of Oncology, University of Torino, Torino, Italy.,Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy
| | - Amedeo Columbano
- Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Italy
| | - Andrea Perra
- Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Italy
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27
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Liang R, Lin YH, Zhu H. Genetic and Cellular Contributions to Liver Regeneration. Cold Spring Harb Perspect Biol 2021; 14:a040832. [PMID: 34750173 PMCID: PMC9438780 DOI: 10.1101/cshperspect.a040832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The regenerative capabilities of the liver represent a paradigm for understanding tissue repair in solid organs. Regeneration after partial hepatectomy in rodent models is well understood, while regeneration in the context of clinically relevant chronic injuries is less studied. Given the growing incidence of fatty liver disease, cirrhosis, and liver cancer, interest in liver regeneration is increasing. Here, we will review the principles, genetics, and cell biology underlying liver regeneration, as well as new approaches being used to study heterogeneity in liver tissue maintenance and repair.
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Affiliation(s)
- Roger Liang
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Yu-Hsuan Lin
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Hao Zhu
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
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28
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Mason MRJ, Erp S, Wolzak K, Behrens A, Raivich G, Verhaagen J. The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity. Hum Mol Genet 2021; 31:1242-1262. [PMID: 34718572 PMCID: PMC9029231 DOI: 10.1093/hmg/ddab315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/13/2021] [Accepted: 10/25/2021] [Indexed: 11/25/2022] Open
Abstract
The regeneration-associated gene (RAG) expression program is activated in injured peripheral neurons after axotomy and enables long-distance axon re-growth. Over 1000 genes are regulated, and many transcription factors are upregulated or activated as part of this response. However, a detailed picture of how RAG expression is regulated is lacking. In particular, the transcriptional targets and specific functions of the various transcription factors are unclear. Jun was the first-regeneration-associated transcription factor identified and the first shown to be functionally important. Here we fully define the role of Jun in the RAG expression program in regenerating facial motor neurons. At 1, 4 and 14 days after axotomy, Jun upregulates 11, 23 and 44% of the RAG program, respectively. Jun functions relevant to regeneration include cytoskeleton production, metabolic functions and cell activation, and the downregulation of neurotransmission machinery. In silico analysis of promoter regions of Jun targets identifies stronger over-representation of AP1-like sites than CRE-like sites, although CRE sites were also over-represented in regions flanking AP1 sites. Strikingly, in motor neurons lacking Jun, an alternative SRF-dependent gene expression program is initiated after axotomy. The promoters of these newly expressed genes exhibit over-representation of CRE sites in regions near to SRF target sites. This alternative gene expression program includes plasticity-associated transcription factors and leads to an aberrant early increase in synapse density on motor neurons. Jun thus has the important function in the early phase after axotomy of pushing the injured neuron away from a plasticity response and towards a regenerative phenotype.
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Affiliation(s)
- Matthew R J Mason
- Laboratory for Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Meibergdreef 47, 1105, BA, Amsterdam, The Netherlands
| | - Susan Erp
- Laboratory for Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Meibergdreef 47, 1105, BA, Amsterdam, The Netherlands
| | - Kim Wolzak
- Laboratory for Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Meibergdreef 47, 1105, BA, Amsterdam, The Netherlands
| | - Axel Behrens
- Adult Stem Cell Laboratory, The Francis Crick Institute, London, NW1 1AT, United Kingdom
| | - Gennadij Raivich
- UCL Institute for Women's Health, Maternal and Fetal Medicine, Perinatal Brain Repair Group, London, WC1E 6HX, United Kingdom
| | - Joost Verhaagen
- Laboratory for Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Meibergdreef 47, 1105, BA, Amsterdam, The Netherlands.,Center for Neurogenomics and Cognition Research, Neuroscience Campus Amsterdam, Vrije Universiteit Amsterdam, 1081HV, Amsterdam, The Netherlands
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29
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Elmore SA. Prenatal Evaluations: A Prologue to Postnatal Pathology Interpretations. Toxicol Pathol 2021; 49:1425-1436. [PMID: 34652981 DOI: 10.1177/01926233211046540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Animal models are commonly used to investigate the developmental basis of human birth defects. Such models may be used for safety assessment studies designed to reveal xenobiotic-related alterations in juvenile animals, or to investigate gene function or generate models of human disease, as with transgenics. Therefore, the evaluation of rodent embryos and placentas can be used to provide insight into various postnatal abnormalities such as structural or cellular abnormalities and early death. Depending on the defect, pups may be born dead, survive for only a short period of time, survive but with poor growth, or survive and be clinically normal. Mice are generally used to generate genetic alterations that can help in identifying genes involved in embryogenesis. Rats are more commonly used for toxicology studies. This article aims to share information on the importance of, and strategies for, mouse embryo, placenta, and metrial gland evaluations. Information on early postnatal development is also provided as well as select examples of developmental information on organ systems needed for postnatal evaluations. A list of additional studies that can aid in the evaluation of prenatal and postnatal phenotypes is also provided.
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Affiliation(s)
- Susan A Elmore
- National Toxicology Program, 6857NIEHS, Comparative and Molecular Pathogenesis Branch, Research Triangle Park, NC, USA
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30
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Della-Flora Nunes G, Wilson ER, Hurley E, He B, O'Malley BW, Poitelon Y, Wrabetz L, Feltri ML. Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination. eLife 2021; 10:e66278. [PMID: 34519641 PMCID: PMC8478418 DOI: 10.7554/elife.66278] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 09/13/2021] [Indexed: 12/26/2022] Open
Abstract
Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.
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Affiliation(s)
- Gustavo Della-Flora Nunes
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
- Department of Biochemistry, University at BuffaloBuffaloUnited States
| | - Emma R Wilson
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
- Department of Biochemistry, University at BuffaloBuffaloUnited States
| | - Edward Hurley
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
| | - Bin He
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist HospitalHoustonUnited States
| | - Bert W O'Malley
- Department of Medicine and Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
| | - Yannick Poitelon
- Department of Neuroscience and Experimental Therapeutics, Albany Medical CollegeAlbanyUnited States
| | - Lawrence Wrabetz
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
- Department of Biochemistry, University at BuffaloBuffaloUnited States
- Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at BuffaloBuffaloUnited States
| | - M Laura Feltri
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
- Department of Biochemistry, University at BuffaloBuffaloUnited States
- Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at BuffaloBuffaloUnited States
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31
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Backes TM, Langfermann DS, Lesch A, Rössler OG, Laschke MW, Vinson C, Thiel G. Regulation and function of AP-1 in insulinoma cells and pancreatic β-cells. Biochem Pharmacol 2021; 193:114748. [PMID: 34461116 DOI: 10.1016/j.bcp.2021.114748] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/25/2021] [Accepted: 08/25/2021] [Indexed: 12/16/2022]
Abstract
Cav1.2 L-type voltage-gated Ca2+ channels play a central role in pancreatic β-cells by integrating extracellular signals with intracellular signaling events leading to insulin secretion and altered gene transcription. Here, we investigated the intracellular signaling pathway following stimulation of Cav1.2 Ca2+ channels and addressed the function of the transcription factor activator protein-1 (AP-1) in pancreatic β-cells of transgenic mice. Stimulation of Cav1.2 Ca2+ channels activates AP-1 in insulinoma cells. Pharmacological and genetic experiments identified c-Jun N-terminal protein kinase as a signal transducer connecting Cav1.2 Ca2+ channel activation with gene transcription. Moreover, the basic region-leucine zipper proteins ATF2 and c-Jun or c-Jun-related proteins were involved in stimulus-transcription coupling. We addressed the functions of AP-1 in pancreatic β-cells analyzing a newly generated transgenic mouse model. These transgenic mice expressed A-Fos, a mutant of c-Fos that attenuates DNA binding of c-Fos dimerization partners. In insulinoma cells, A-Fos completely blocked AP-1 activation following stimulation of Cav1.2 Ca2+ channels. The analysis of transgenic A-Fos-expressing mice revealed that the animals displayed impaired glucose tolerance. Thus, we show here for the first time that AP-1 controls an important function of pancreatic β-cells in vivo, the regulation of glucose homeostasis.
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Affiliation(s)
- Tobias M Backes
- Saarland University Medical Faculty, Department of Medical Biochemistry and Molecular Biology, D-66421 Homburg, Germany
| | - Daniel S Langfermann
- Saarland University Medical Faculty, Department of Medical Biochemistry and Molecular Biology, D-66421 Homburg, Germany
| | - Andrea Lesch
- Saarland University Medical Faculty, Department of Medical Biochemistry and Molecular Biology, D-66421 Homburg, Germany
| | - Oliver G Rössler
- Saarland University Medical Faculty, Department of Medical Biochemistry and Molecular Biology, D-66421 Homburg, Germany
| | - Matthias W Laschke
- Saarland University Medical Faculty, Institute for Clinical and Experimental Surgery, D-66421 Homburg, Germany
| | | | - Gerald Thiel
- Saarland University Medical Faculty, Department of Medical Biochemistry and Molecular Biology, D-66421 Homburg, Germany.
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32
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Novoszel P, Drobits B, Holcmann M, Fernandes CDS, Tschismarov R, Derdak S, Decker T, Wagner EF, Sibilia M. The AP-1 transcription factors c-Jun and JunB are essential for CD8α conventional dendritic cell identity. Cell Death Differ 2021; 28:2404-2420. [PMID: 33758366 PMCID: PMC8329169 DOI: 10.1038/s41418-021-00765-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/17/2021] [Accepted: 02/24/2021] [Indexed: 01/31/2023] Open
Abstract
Dendritic cell (DC) development is orchestrated by lineage-determining transcription factors (TFs). Although, members of the activator-protein-1 (AP-1) family, including Batf3, have been implicated in conventional (c)DC specification, the role of Jun proteins is poorly understood. Here, we identified c-Jun and JunB as essential for cDC1 fate specification and function. In mice, Jun proteins regulate extrinsic and intrinsic pathways, which control CD8α cDC1 diversification, whereas CD103 cDC1 development is unaffected. The loss of c-Jun and JunB in DC progenitors diminishes the CD8α cDC1 pool and thus confers resistance to Listeria monocytogenes infection. Their absence in CD8α cDC1 results in impaired TLR triggering and antigen cross-presentation. Both TFs are required for the maintenance of the CD8α cDC1 subset and suppression of cDC2 identity on a transcriptional and phenotypic level. Taken together, these results demonstrate the essential role of c-Jun and JunB in CD8α cDC1 diversification, function, and maintenance of their identity.
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Affiliation(s)
- Philipp Novoszel
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Barbara Drobits
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Martin Holcmann
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Cristiano De Sa Fernandes
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Roland Tschismarov
- Department of Microbiology, Immunobiology and Genetics, Max Perutz Labs, University of Vienna, Vienna, Austria
| | - Sophia Derdak
- Core Facilities, Medical University of Vienna, Vienna, Austria
| | - Thomas Decker
- Department of Microbiology, Immunobiology and Genetics, Max Perutz Labs, University of Vienna, Vienna, Austria
| | - Erwin F Wagner
- Department of Dermatology and Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Maria Sibilia
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
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Lei M, Zhao K, Hua W, Wang K, Li S, Wu X, Yang C. An in vivo study of the effect of c-Jun on intervertebral disc degeneration in rats. Bioengineered 2021; 12:4320-4330. [PMID: 34308759 PMCID: PMC8806816 DOI: 10.1080/21655979.2021.1946459] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Intervertebral disc degeneration (IDD) has been well-recognized as one of the causes of vast lower back pain. The objective of the current study intends to elucidate the influence and regulatory molecular mechanisms of c-Jun on IDD. This study established an IDD model of Sprague-Dawley (SD) rats by needle puncture. An LV5-c-Jun lentiviral vector was constructed and injected into rats’ intervertebral disc (IVD) tissue to increase the c-Jun expression following the establishment of modeling. The pathological changes of IVD tissue structure and collagen fibers were visualized following the processes of hematoxylin-eosin (HE) staining method and transmission electron microscopy. Real-time PCR, western blot, immunohistochemistry, and ELISA assays were performed to detect the expression levels of TGF-β, TIMP-3, COL2A1, and inflammatory cytokines. The collagen fibers were arranged in parallel and the surface was smooth after c-Jun overexpression, whereas the collagen fibers in the control group were disorderly arranged with a rough surface. The findings indicated that c-Jun was responsible for upregulating expression levels of TGF-β, TIMP-3, and COL2A1 in the mRNA and proteins, but simultaneously downregulating expression levels of inflammatory factors IL-1β, IL-17, IL-6, and TNF-α. c-Jun overexpression produced a positive effect on IDD, inhibited inflammatory response in vivo, and might delay the degeneration of IVD. Thus, c-Jun may act as a novel potential agent in treating IDD.
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Affiliation(s)
- Ming Lei
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kangcheng Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenbin Hua
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinghuo Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cao Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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34
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Ruiz EJ, Lan L, Diefenbacher ME, Riising EM, Da Costa C, Chakraborty A, Hoeck JD, Spencer-Dene B, Kelly G, David JP, Nye E, Downward J, Behrens A. JunD, not c-Jun, is the AP-1 transcription factor required for Ras-induced lung cancer. JCI Insight 2021; 6:e124985. [PMID: 34236045 PMCID: PMC8410048 DOI: 10.1172/jci.insight.124985] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 05/28/2021] [Indexed: 12/15/2022] Open
Abstract
The AP-1 transcription factor c-Jun is required for Ras-driven tumorigenesis in many tissues and is considered as a classical proto-oncogene. To determine the requirement for c-Jun in a mouse model of K-RasG12D-induced lung adenocarcinoma, we inducibly deleted c-Jun in the adult lung. Surprisingly, we found that inactivation of c-Jun, or mutation of its JNK phosphorylation sites, actually increased lung tumor burden. Mechanistically, we found that protein levels of the Jun family member JunD were increased in the absence of c-Jun. In c-Jun-deficient cells, JunD phosphorylation was increased, and expression of a dominant-active JNKK2-JNK1 transgene further increased lung tumor formation. Strikingly, deletion of JunD completely abolished Ras-driven lung tumorigenesis. This work identifies JunD, not c-Jun, as the crucial substrate of JNK signaling and oncogene required for Ras-induced lung cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Gavin Kelly
- Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom
| | - Jean-Pierre David
- Institute of Osteology and Biomechanics, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany
| | - Emma Nye
- Experimental Histopathology, and
| | - Julian Downward
- Oncogene Biology Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Axel Behrens
- Adult Stem Cell Laboratory.,Cancer Stem Cell Laboratory, Institute of Cancer Research, London, United Kingdom.,Imperial College, Division of Cancer, Department of Surgery and Cancer, London, United Kingdom.,Convergence Science Centre, Imperial College, London, United Kingdom
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Novoszel P, Holcmann M, Stulnig G, De Sa Fernandes C, Zyulina V, Borek I, Linder M, Bogusch A, Drobits B, Bauer T, Tam‐Amersdorfer C, Brunner PM, Stary G, Bakiri L, Wagner EF, Strobl H, Sibilia M. Psoriatic skin inflammation is promoted by c-Jun/AP-1-dependent CCL2 and IL-23 expression in dendritic cells. EMBO Mol Med 2021; 13:e12409. [PMID: 33724710 PMCID: PMC8033525 DOI: 10.15252/emmm.202012409] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 01/28/2021] [Accepted: 02/01/2021] [Indexed: 12/13/2022] Open
Abstract
Toll-like receptor (TLR) stimulation induces innate immune responses involved in many inflammatory disorders including psoriasis. Although activation of the AP-1 transcription factor complex is common in TLR signaling, the specific involvement and induced targets remain poorly understood. Here, we investigated the role of c-Jun/AP-1 protein in skin inflammation following TLR7 activation using human psoriatic skin, dendritic cells (DC), and genetically engineered mouse models. We show that c-Jun regulates CCL2 production in DCs leading to impaired recruitment of plasmacytoid DCs to inflamed skin after treatment with the TLR7/8 agonist Imiquimod. Furthermore, deletion of c-Jun in DCs or chemical blockade of JNK/c-Jun signaling ameliorates psoriasis-like skin inflammation by reducing IL-23 production in DCs. Importantly, the control of IL-23 and CCL2 by c-Jun is most pronounced in murine type-2 DCs. CCL2 and IL-23 expression co-localize with c-Jun in type-2/inflammatory DCs in human psoriatic skin and JNK-AP-1 inhibition reduces the expression of these targets in TLR7/8-stimulated human DCs. Therefore, c-Jun/AP-1 is a central driver of TLR7-induced immune responses by DCs and JNK/c-Jun a potential therapeutic target in psoriasis.
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Affiliation(s)
- Philipp Novoszel
- Department of Medicine IComprehensive Cancer CenterInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Martin Holcmann
- Department of Medicine IComprehensive Cancer CenterInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Gabriel Stulnig
- Department of Medicine IComprehensive Cancer CenterInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Cristiano De Sa Fernandes
- Department of Medicine IComprehensive Cancer CenterInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Victoria Zyulina
- Division of Immunology and PathophysiologyOtto Loewi Research CenterMedical University of GrazGrazAustria
| | - Izabela Borek
- Division of Immunology and PathophysiologyOtto Loewi Research CenterMedical University of GrazGrazAustria
| | - Markus Linder
- Department of Medicine IComprehensive Cancer CenterInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Alexandra Bogusch
- Department of Medicine IComprehensive Cancer CenterInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Barbara Drobits
- Department of Medicine IComprehensive Cancer CenterInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Thomas Bauer
- Department of Medicine IComprehensive Cancer CenterInstitute of Cancer ResearchMedical University of ViennaViennaAustria
| | - Carmen Tam‐Amersdorfer
- Division of Immunology and PathophysiologyOtto Loewi Research CenterMedical University of GrazGrazAustria
| | - Patrick M Brunner
- Division of Immunology, Allergy and Infectious DiseasesDepartment of DermatologyMedical University of ViennaViennaAustria
| | - Georg Stary
- Division of Immunology, Allergy and Infectious DiseasesDepartment of DermatologyMedical University of ViennaViennaAustria
| | - Latifa Bakiri
- Division of Immunology, Allergy and Infectious DiseasesDepartment of DermatologyMedical University of ViennaViennaAustria
- Department of Laboratory MedicineMedical University of ViennaViennaAustria
| | - Erwin F Wagner
- Division of Immunology, Allergy and Infectious DiseasesDepartment of DermatologyMedical University of ViennaViennaAustria
- Department of Laboratory MedicineMedical University of ViennaViennaAustria
| | - Herbert Strobl
- Division of Immunology and PathophysiologyOtto Loewi Research CenterMedical University of GrazGrazAustria
| | - Maria Sibilia
- Department of Medicine IComprehensive Cancer CenterInstitute of Cancer ResearchMedical University of ViennaViennaAustria
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36
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Seo J, Koçak DD, Bartelt LC, Williams CA, Barrera A, Gersbach CA, Reddy TE. AP-1 subunits converge promiscuously at enhancers to potentiate transcription. Genome Res 2021; 31:538-550. [PMID: 33674350 PMCID: PMC8015846 DOI: 10.1101/gr.267898.120] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 02/17/2021] [Indexed: 12/12/2022]
Abstract
The AP-1 transcription factor (TF) dimer contributes to many biological processes and environmental responses. AP-1 can be composed of many interchangeable subunits. Unambiguously determining the binding locations of these subunits in the human genome is challenging because of variable antibody specificity and affinity. Here, we definitively establish the genome-wide binding patterns of five AP-1 subunits by using CRISPR to introduce a common antibody tag on each subunit. We find limited evidence for strong dimerization preferences between subunits at steady state and find that, under a stimulus, dimerization patterns reflect changes in the transcriptome. Further, our analysis suggests that canonical AP-1 motifs indiscriminately recruit all AP-1 subunits to genomic sites, which we term AP-1 hotspots. We find that AP-1 hotspots are predictive of cell type–specific gene expression and of genomic responses to glucocorticoid signaling (more so than super-enhancers) and are significantly enriched in disease-associated genetic variants. Together, these results support a model where promiscuous binding of many AP-1 subunits to the same genomic location play a key role in regulating cell type–specific gene expression and environmental responses.
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Affiliation(s)
- Jungkyun Seo
- Department of Biostatistics and Bioinformatics, Division of Integrative Genomics, Duke University Medical Center, Durham, North Carolina 27708, USA.,Computational Biology and Bioinformatics Graduate Program, Duke University, Durham, North Carolina 27708, USA.,Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA.,Center for Advanced Genomic Technologies, Duke University, Durham, North Carolina 27708, USA
| | - D Dewran Koçak
- Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA.,Center for Advanced Genomic Technologies, Duke University, Durham, North Carolina 27708, USA.,Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA
| | - Luke C Bartelt
- Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA.,University Program in Genetics and Genomics, Duke University, Durham, North Carolina 27708, USA
| | - Courtney A Williams
- Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA.,Center for Advanced Genomic Technologies, Duke University, Durham, North Carolina 27708, USA
| | - Alejandro Barrera
- Department of Biostatistics and Bioinformatics, Division of Integrative Genomics, Duke University Medical Center, Durham, North Carolina 27708, USA.,Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA.,Center for Advanced Genomic Technologies, Duke University, Durham, North Carolina 27708, USA
| | - Charles A Gersbach
- Computational Biology and Bioinformatics Graduate Program, Duke University, Durham, North Carolina 27708, USA.,Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA.,Center for Advanced Genomic Technologies, Duke University, Durham, North Carolina 27708, USA.,Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.,University Program in Genetics and Genomics, Duke University, Durham, North Carolina 27708, USA.,Department of Surgery, Duke University Medical Center, Durham, North Carolina 27708, USA
| | - Timothy E Reddy
- Department of Biostatistics and Bioinformatics, Division of Integrative Genomics, Duke University Medical Center, Durham, North Carolina 27708, USA.,Computational Biology and Bioinformatics Graduate Program, Duke University, Durham, North Carolina 27708, USA.,Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA.,Center for Advanced Genomic Technologies, Duke University, Durham, North Carolina 27708, USA.,Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.,University Program in Genetics and Genomics, Duke University, Durham, North Carolina 27708, USA.,Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina 27708, USA
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37
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Ishikawa M, Brooks AJ, Fernández-Rojo MA, Medina J, Chhabra Y, Minami S, Tunny KA, Parton RG, Vivian JP, Rossjohn J, Chikani V, Ramm GA, Ho KKY, Waters MJ. Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy, Allowing Liver Regeneration and Survival Through Induction of H2-Bl/HLA-G. Hepatology 2021; 73:759-775. [PMID: 32342533 PMCID: PMC7894545 DOI: 10.1002/hep.31297] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. APPROACH AND RESULTS PHx was performed on C57BL/6 mice lacking GHR (Ghr-/- ), disabled for all GH-dependent Janus kinase 2 signaling (Box1-/- ), or lacking only GH-dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391-/- ), and wild-type littermates. C57BL/6 Ghr-/- mice showed striking mortality within 48 hours after PHx, whereas Box1-/- or Ghr391-/- mice survived with normal liver regeneration. Ghr-/- mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2-Bl, a key immunotolerance protein, which is up-regulated by PHx through a GH-mediated, Janus kinase 2-independent, SRC family kinase-dependent pathway. GH treatment was confirmed to up-regulate expression of the human homolog of H2-Bl (human leukocyte antigen G [HLA-G]) in primary human hepatocytes and in the serum of GH-deficient patients. We find that injury-associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr-/- mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. Further, H2-Bl knockdown in wild-type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr-/- backcrossed on a strain with high endogenous H2-Bl expression showed a high rate of survival following PHx. CONCLUSIONS GH induction of H2-Bl expression is crucial for reducing innate immune-mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA-G may lead to improved clinical outcomes following liver surgery or transplantation.
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Affiliation(s)
- Mayumi Ishikawa
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,Center for Endocrinology, Diabetes and ArteriosclerosisNippon Medical School Musashikosugi HospitalKawasakiJapan
| | - Andrew J Brooks
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia
| | - Manuel A Fernández-Rojo
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia.,Hepatic Fibrosis GroupQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia.,School of MedicineThe University of QueenslandBrisbaneQLDAustralia.,Hepatic Regenerative Medicine LaboratoryMadrid Institute for Advanced Studies in FoodCEI UAM+CSICMadridSpain
| | - Johan Medina
- The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia
| | - Yash Chhabra
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia
| | - Shiro Minami
- Center for Endocrinology, Diabetes and ArteriosclerosisNippon Medical School Musashikosugi HospitalKawasakiJapan
| | - Kathryn A Tunny
- The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia
| | - Robert G Parton
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,Centre for Microscopy and MicroanalysisThe University of QueenslandBrisbaneQLDAustralia
| | - Julian P Vivian
- Department of Biochemistry and Molecular Biology School of Biomedical SciencesMonash UniversityClaytonVICAustralia.,Australian Research Council Centre of Excellence in Advanced Molecular ImagingMonash UniversityClaytonVICAustralia
| | - Jamie Rossjohn
- Department of Biochemistry and Molecular Biology School of Biomedical SciencesMonash UniversityClaytonVICAustralia.,Australian Research Council Centre of Excellence in Advanced Molecular ImagingMonash UniversityClaytonVICAustralia.,Institute of Infection and ImmunityCardiff University School of MedicineHeath ParkCardiffUnited Kingdom
| | - Viral Chikani
- Princess Alexandra Hospital and Faculty of MedicineThe University of QueenslandBrisbaneQLDAustralia
| | - Grant A Ramm
- Hepatic Fibrosis GroupQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia.,School of MedicineThe University of QueenslandBrisbaneQLDAustralia
| | - Ken K Y Ho
- Princess Alexandra Hospital and Faculty of MedicineThe University of QueenslandBrisbaneQLDAustralia
| | - Michael J Waters
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia
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Xie M, Chia RH, Li D, Teo FX, Krueger C, Sabapathy K. Functional interaction between macrophages and hepatocytes dictate the outcome of liver fibrosis. Life Sci Alliance 2021; 4:4/4/e202000803. [PMID: 33514653 PMCID: PMC7893818 DOI: 10.26508/lsa.202000803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 01/07/2021] [Accepted: 01/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocytes and liver-resident macrophages known as Kupffer cells (KCs) are key cell types involved in liver fibrosis. The transcription factor c-Jun plays a fundamental role in regulating hepatocyte and macrophage functions. We have examined c-Jun's role in the functional interaction of these cells during liver fibrosis induced by carbon tetrachloride. While hepatocyte-specific c-jun deletion led to increased fibrosis, the opposite outcome was observed when c-jun was deleted in both hepatocytes and KCs. Molecular analyses revealed compromised cytokine gene expression as the apical event related to the phenotype. Yet, purified hepatocytes from both mouse cohorts showed similar defects in cytokine gene expression. However, we noted increased macrophage infiltration in the absence of c-Jun in hepatocytes, which when chemically depleted, reversed the phenotype. Consistently, c-jun deletion in KCs alone also led to reduced fibrosis and cytokine gene expression. By contrast, c-jun deletion in hepatocytes and KCs did not affect the resolution phase after fibrotic injury. These data together demonstrate a pro-fibrogenic role for c-Jun in hepatocytes and KCs that functionally interact to regulate liver fibrosis.
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Affiliation(s)
- Min Xie
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Ren Hui Chia
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Dan Li
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Fanny Xueting Teo
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Christian Krueger
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Kanaga Sabapathy
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore .,Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Institute of Molecular and Cellular Biology, Singapore, Singapore
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39
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Marola OJ, Syc-Mazurek SB, Howell GR, Libby RT. Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation. Cell Death Dis 2020; 11:811. [PMID: 32980857 PMCID: PMC7519907 DOI: 10.1038/s41419-020-02990-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 01/02/2023]
Abstract
Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun-/-), Ddit3 null (Ddit3-/-), and Ddit3-/-Jun-/- mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation.
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Affiliation(s)
- Olivia J. Marola
- grid.412750.50000 0004 1936 9166Department of Ophthalmology, Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY USA ,grid.412750.50000 0004 1936 9166Cell Biology of Disease Graduate Program, University of Rochester Medical Center, Rochester, NY USA ,grid.16416.340000 0004 1936 9174The Center for Visual Sciences, University of Rochester, Rochester, NY USA
| | - Stephanie B. Syc-Mazurek
- grid.412750.50000 0004 1936 9166Department of Ophthalmology, Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY USA ,grid.412750.50000 0004 1936 9166Medical Scientist Training Program, University of Rochester Medical Center, Rochester, NY USA
| | - Gareth R. Howell
- grid.249880.f0000 0004 0374 0039The Jackson Laboratory, 600 Main Street, Bar Harbor, ME USA
| | - Richard T. Libby
- grid.412750.50000 0004 1936 9166Department of Ophthalmology, Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY USA ,grid.16416.340000 0004 1936 9174The Center for Visual Sciences, University of Rochester, Rochester, NY USA ,grid.412750.50000 0004 1936 9166Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY USA
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40
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Syndecan-1 Promotes Hepatocyte-Like Differentiation of Hepatoma Cells Targeting Ets-1 and AP-1. Biomolecules 2020; 10:biom10101356. [PMID: 32977498 PMCID: PMC7598270 DOI: 10.3390/biom10101356] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 01/10/2023] Open
Abstract
Syndecan-1 is a transmembrane heparan sulfate proteoglycan which is indispensable in the structural and functional integrity of epithelia. Normal hepatocytes display strong cell surface expression of syndecan-1; however, upon malignant transformation, they may lose it from their cell surfaces. In this study, we demonstrate that re-expression of full-length or ectodomain-deleted syndecan-1 in hepatocellular carcinoma cells downregulates phosphorylation of ERK1/2 and p38, with the truncated form exerting an even stronger effect than the full-length protein. Furthermore, overexpression of syndecan-1 in hepatoma cells is associated with a shift of heparan sulfate structure toward a highly sulfated type specific for normal liver. As a result, cell proliferation and proteolytic shedding of syndecan-1 from the cell surface are restrained, which facilitates redifferentiation of hepatoma cells to a more hepatocyte-like phenotype. Our results highlight the importance of syndecan-1 in the formation and maintenance of differentiated epithelial characteristics in hepatocytes partly via the HGF/ERK/Ets-1 signal transduction pathway. Downregulation of Ets-1 expression alone, however, was not sufficient to replicate the phenotype of syndecan-1 overexpressing cells, indicating the need for additional molecular mechanisms. Accordingly, a reporter gene assay revealed the inhibition of Ets-1 as well as AP-1 transcription factor-induced promoter activation, presumably an effect of the heparan sulfate switch.
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Lei M, Wang K, Li S, Zhao K, Hua W, Wu X, Yang C. The c-Jun signaling pathway has a protective effect on nucleus pulposus cells in patients with intervertebral disc degeneration. Exp Ther Med 2020; 20:123. [PMID: 33005249 PMCID: PMC7523272 DOI: 10.3892/etm.2020.9251] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 07/01/2020] [Indexed: 12/17/2022] Open
Abstract
Among a range of diverse clinical symptoms, intervertebral disc degeneration (IDD) contributes mostly to the onset of lower back pain. The present study aimed to investigate the effects of c-Jun on nucleus pulposus (NP) cells of IDD and its regulation on molecular mechanisms. Intervertebral disc (IVD) tissues were collected from patients suffering from IDD disease, and NP cells were subsequently isolated and cultured. By overexpressing c-Jun in NP cells, expression levels of mRNAs and proteins of IDD-related genes and inflammatory cytokines were subjected to reverse transcription-quantitative PCR, western blot and ELISA assays. Additional transforming growth factor-β (TGF-β) antibodies were administrated to suppress the function of TGF-β. Cell proliferation and apoptosis were determined via Cell Counting Kit-8 and TUNEL assays, respectively. The results demonstrated that the overexpression of c-Jun robustly upregulated both mRNA and protein expression of TGF-β, TIMP metallopeptidase inhibitor 3, aggrecan and collagen type II alpha 1 chain and simultaneously downregulated the expression of the inflammatory cytokines TNF-α, interleukin (IL)-1β, IL-6 and IL-17. Furthermore, following c-Jun overexpression, survival rates of NP cells were increased while apoptosis rates were decreased. However, the addition of a TGF-β antibody significantly promoted apoptosis and restricted cell survival, which differed from the results of the c-Jun overexpression group. The present study hypothesized therefore that c-Jun may positively regulate TGF-β expression within NP cells of IDD, which could promote the proliferation of IDD-NP cells and accelerate cell viability via reducing apoptosis and the inflammatory response.
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Affiliation(s)
- Ming Lei
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Kun Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Shuai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Kangcheng Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Wenbin Hua
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xinghuo Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Cao Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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Bhat M, Pasini E, Baciu C, Angeli M, Humar A, Macparland S, Feld J, McGilvray I. The basis of liver regeneration: A systems biology approach. Ann Hepatol 2020; 18:422-428. [PMID: 31047847 DOI: 10.1016/j.aohep.2018.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 06/18/2018] [Accepted: 07/01/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Liver regeneration is a normal response to liver injury. The aim of this study was to determine the molecular basis of liver regeneration, through an integrative analysis of high-throughput gene expression datasets. METHODS We identified and curated datasets pertaining to liver regeneration from the Gene Expression Omnibus, where regenerating liver tissue was compared to healthy liver samples. The key dysregulated genes and pathways were identified using Ingenuity Pathway Analysis software. There were three eligible datasets in total. RESULTS In the early phase after hepatectomy, inflammatory pathways such as Nrf2 oxidative stress-mediated response and cytokine signaling were significantly upregulated. At peak regeneration, we discovered that cell cycle genes were predominantly expressed to promote cell proliferation. Using the Betweenness centrality algorithm, we discovered that Jun is the key central gene in liver regeneration. Calcineurin inhibitors may inhibit liver regeneration, based on predictive modeling. CONCLUSION There is a paucity of human literature in defining the molecular mechanisms of liver regeneration along a time continuum. Nonetheless, using an integrative computational analysis approach to the available high-throughput data, we determine that the oxidative stress response and cytokine signaling are key early after hepatectomy, whereas cell cycle control is important at peak regeneration. The transcription factor Jun is central to liver regeneration and a potential therapeutic target. Future studies of regeneration in humans along a time continuum are needed to better define the underlying mechanisms, and ultimately enhance care of patients with acute and chronic liver failure while awaiting transplant.
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Affiliation(s)
- Mamatha Bhat
- Multi Organ Transplant Program, University Health Network, Toronto, Canada; Division of Gastroenterology and Hepatology, University Health Network and University of Toronto, Toronto, Canada.
| | - Elisa Pasini
- Multi Organ Transplant Program, University Health Network, Toronto, Canada
| | - Cristina Baciu
- Multi Organ Transplant Program, University Health Network, Toronto, Canada
| | - Marc Angeli
- Multi Organ Transplant Program, University Health Network, Toronto, Canada
| | - Atul Humar
- Multi Organ Transplant Program, University Health Network, Toronto, Canada
| | - Sonya Macparland
- Multi Organ Transplant Program, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, Toronto, Canada
| | - Jordan Feld
- Division of Gastroenterology and Hepatology, University Health Network and University of Toronto, Toronto, Canada; Toronto Centre for Liver Disease, University of Toronto, Ontario, Canada
| | - Ian McGilvray
- Multi Organ Transplant Program, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, Toronto, Canada
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Lau-Corona D, Bae WK, Hennighausen L, Waxman DJ. Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2. PLoS Genet 2020; 16:e1008796. [PMID: 32428001 PMCID: PMC7263639 DOI: 10.1371/journal.pgen.1008796] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 06/01/2020] [Accepted: 04/24/2020] [Indexed: 12/15/2022] Open
Abstract
Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, Ezh1 and Ezh2. Here, we used Ezh1-knockout mice with a hepatocyte-specific knockout of Ezh2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, Ezh1/Ezh2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, Ezh1/Ezh2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility. Sex-differences in the expression of genes in liver have a direct impact on liver diseases whose incidence and severity is sex-biased, and is controlled by hormones that regulate chemical alterations to histone proteins used to package chromosomal DNA. However, a direct demonstration of the functional importance of such sex differences in histone protein modifications has been elusive. Here, we address this question using a mouse model deficient in two enzymes, Ezh1/Ezh2, which generate the histone repressive mark H3K27me3. Remarkably, although H3K27me3 marks are formed by Ezh1/Ezh2 throughout the genome, loss of liver Ezh1/Ezh2 preferentially disrupts the control of sex-biased genes, with expression increasing in male mouse liver for many female-biased genes and decreasing for many male-biased genes. Sex-biased H3K27me3 repressive marks were abolished, and there was a gain of active histone marks at gene enhancers. We also found increased expression of many genes associated with liver fibrosis and hepatocellular carcinoma, which may help explain the increased sensitivity of Ezh1/Ezh2-deficient livers to hepatotoxic chemicals whose exposure may lead to sex differences in liver disease incidence and susceptibility. Thus, our findings highlight the potential role of sex differences in histone modifications catalyzed by Ezh1/Ezh2 in widespread sex differences in liver diseases.
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Affiliation(s)
- Dana Lau-Corona
- Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America
| | - Woo Kyun Bae
- Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Lothar Hennighausen
- Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - David J. Waxman
- Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America
- * E-mail:
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Roh E, Han Y, Reddy K, Zykova TA, Lee MH, Yao K, Bai R, Curiel-Lewandrowski C, Dong Z. Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032. Oncogene 2020; 39:4170-4182. [PMID: 32277233 PMCID: PMC8313813 DOI: 10.1038/s41388-020-1286-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 03/18/2020] [Accepted: 03/25/2020] [Indexed: 12/31/2022]
Abstract
Nonmelanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared with normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development.
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Affiliation(s)
- Eunmiri Roh
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Yaping Han
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Kanamata Reddy
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Tatyana A Zykova
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Mee Hyun Lee
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Ke Yao
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Ruihua Bai
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | | | - Zigang Dong
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China.
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Khan MGM, Ghosh A, Variya B, Santharam MA, Kandhi R, Ramanathan S, Ilangumaran S. Hepatocyte growth control by SOCS1 and SOCS3. Cytokine 2019; 121:154733. [PMID: 31154249 DOI: 10.1016/j.cyto.2019.154733] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 05/18/2019] [Accepted: 05/21/2019] [Indexed: 02/06/2023]
Abstract
The extraordinary capacity of the liver to regenerate following injury is dependent on coordinated and regulated actions of cytokines and growth factors. Whereas hepatocyte growth factor (HGF) and epidermal growth factor (EGF) are direct mitogens to hepatocytes, inflammatory cytokines such as TNFα and IL-6 also play essential roles in the liver regeneration process. These cytokines and growth factors activate different signaling pathways in a sequential manner to elicit hepatocyte proliferation. The kinetics and magnitude of these hepatocyte-activating stimuli are tightly regulated to ensure restoration of a functional liver mass without causing uncontrolled cell proliferation. Hepatocyte proliferation can become deregulated under conditions of chronic inflammation, leading to accumulation of genetic aberrations and eventual neoplastic transformation. Among the control mechanisms that regulate hepatocyte proliferation, negative feedback inhibition by the 'suppressor of cytokine signaling (SOCS)' family proteins SOCS1 and SOCS3 play crucial roles in attenuating cytokine and growth factor signaling. Loss of SOCS1 or SOCS3 in the mouse liver increases the rate of liver regeneration and renders hepatocytes susceptible to neoplastic transformation. The frequent epigenetic repression of the SOCS1 and SOCS3 genes in hepatocellular carcinoma has stimulated research in understanding the growth regulatory mechanisms of SOCS1 and SOCS3 in hepatocytes. Whereas SOCS3 is implicated in regulating JAK-STAT signaling induced by IL-6 and attenuating EGFR signaling, SOCS1 is crucial for the regulation of HGF signaling. These two proteins also module the functions of certain key proteins that control the cell cycle. In this review, we discuss the current understanding of the functions of SOCS1 and SOCS3 in controlling hepatocyte proliferation, and its implications to liver health and disease.
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Affiliation(s)
- Md Gulam Musawwir Khan
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Amit Ghosh
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Bhavesh Variya
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Madanraj Appiya Santharam
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Rajani Kandhi
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Sheela Ramanathan
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Subburaj Ilangumaran
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
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Buffalo liver transcriptome analysis suggests immune tolerance as its key adaptive mechanism during early postpartum negative energy balance. Funct Integr Genomics 2019; 19:759-773. [DOI: 10.1007/s10142-019-00676-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 03/03/2019] [Accepted: 04/01/2019] [Indexed: 01/25/2023]
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Dihydrotestosterone activates AP-1 in LNCaP prostate cancer cells. Int J Biochem Cell Biol 2019; 110:9-20. [DOI: 10.1016/j.biocel.2019.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 02/15/2019] [Accepted: 02/19/2019] [Indexed: 02/06/2023]
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48
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Schulien I, Hockenjos B, Schmitt-Graeff A, Perdekamp MG, Follo M, Thimme R, Hasselblatt P. The transcription factor c-Jun/AP-1 promotes liver fibrosis during non-alcoholic steatohepatitis by regulating Osteopontin expression. Cell Death Differ 2019; 26:1688-1699. [PMID: 30778201 PMCID: PMC6748141 DOI: 10.1038/s41418-018-0239-8] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 10/01/2018] [Accepted: 10/31/2018] [Indexed: 12/13/2022] Open
Abstract
Progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to non-alcoholic steatohepatitis (NASH) is a key step of NASH pathogenesis. The AP-1 transcription factor c-Jun is an important regulator of hepatic stress responses, but its contribution to NASH pathogenesis remains poorly defined. We therefore addressed c-Jun expression in liver biopsies of patients with steatosis and NASH. The role of c-Jun during NASH pathogenesis was analyzed mechanistically in c-Jun mutant mice fed with a methionine- and choline-deficient diet (MCDD). Disease progression from steatosis to NASH in patients correlated with increased c-Jun expression in hepatocytes, while its expression in non-parenchymal liver cells (NPLCs) particularly correlated with fibrosis. Analysis of untreated and MCDD-fed mice lacking c-Jun in hepatocytes (c-Jun∆li) revealed that c-Jun promotes hepatocyte survival, thereby protecting against the regenerative ductular reaction (DR) of Sox9/Osteopontin (Opn) co-expressing NPLCs, expression of the Opn receptor CD44 and fibrosis, which were all exacerbated in c-Jun∆li mice. Since Opn and c-Jun were co-expressed by NPLCs in mice and patients with NASH, we wondered whether the increased fibrosis observed in c-Jun∆li mice could be rescued by additional c-Jun deletion in NPLCs (c-Jun∆li*). c-Jun∆li* mice with NASH indeed exhibited reduced expression of Opn and CD44 in NPLCs, impaired DR and reduced fibrosis. A similar phenotype was observed in Opn knockout mice, suggesting that the observed functions of c-Jun were indeed Opn-dependent. In conclusion, c-Jun expression correlates with disease progression from steatosis to NASH in patients and exerts cell-type-specific functions in mice: In hepatocytes, it promotes cell survival thereby limiting the DR and fibrogenesis. In NPLCs, it rather promotes the DR and fibrogenesis by regulating expression of Opn and CD44.
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Affiliation(s)
- Isabel Schulien
- Department of Medicine II, Medical Center-University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany.,Faculty of Biology, Albert-Ludwigs University Freiburg, Freiburg, Germany
| | - Birgit Hockenjos
- Department of Medicine II, Medical Center-University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Annette Schmitt-Graeff
- Institute of Pathology, Medical Center-University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Markus Große Perdekamp
- Institute of Forensic Medicine, Medical Center-University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Marie Follo
- Department of Medicine I, Medical Center-University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center-University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Peter Hasselblatt
- Department of Medicine II, Medical Center-University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany.
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Hu K, Huang Q, Liu C, Li Y, Liu Y, Wang H, Li M, Ma S. c-Jun/Bim Upregulation in Dopaminergic Neurons Promotes Neurodegeneration in the MPTP Mouse Model of Parkinson's Disease. Neuroscience 2018; 399:117-124. [PMID: 30590105 DOI: 10.1016/j.neuroscience.2018.12.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 12/07/2018] [Accepted: 12/17/2018] [Indexed: 01/26/2023]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The proapoptotic BH3-only protein Bim has been reported to be involved in dopaminergic neurodegeneration of experimental PD. However, an in situ expression profile of Bim in PD has not been performed, and the cell types of which Bim accounts for PD pathogenesis is unclear. Here, we report with in situ observations that Bim is transcriptionally induced in the dopaminergic neurons of the SNpc in 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. To investigate the precise role of Bim in the dopaminergic neurons in parkinsonian neuronal death, we obtained dopaminergic neuron-specific Bim null (Bim△Dat) mice. Bim△Dat mice are shown to be resistant to MPTP-induced neurotoxicity, confirming that the induction of Bim in dopaminergic neurons is responsible for parkinsonian neurodegeneration. Furthermore, we demonstrated with dopaminergic neuron-specific c-Jun knockout (c-Jun△Dat) that the transcriptional upregulation of Bim of nigral dopaminergic neurons was c-Jun-dependent and further validated the detrimental role of c-Jun in dopaminergic neurodegeneration. Together, these data specify that c-Jun-mediated Bim upregulation in nigral dopaminergic neurons contributes to parkinsonian neurodegeneration.
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Affiliation(s)
- Kunhua Hu
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China
| | - Qiaoying Huang
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China
| | - Chong Liu
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China
| | - Yongyi Li
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China
| | - Yueyue Liu
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China
| | - Hao Wang
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China
| | - Mingtao Li
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
| | - Shanshan Ma
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
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50
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Xiao F, Guo Y, Deng J, Yuan F, Xiao Y, Hui L, Li Y, Hu Z, Zhou Y, Li K, Han X, Fang Q, Jia W, Chen Y, Ying H, Zhai Q, Chen S, Guo F. Hepatic c-Jun regulates glucose metabolism via FGF21 and modulates body temperature through the neural signals. Mol Metab 2018; 20:138-148. [PMID: 30579932 PMCID: PMC6358569 DOI: 10.1016/j.molmet.2018.12.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 11/28/2018] [Accepted: 12/06/2018] [Indexed: 12/13/2022] Open
Abstract
Objective c-Jun, a prominent member of the activator protein 1 (AP-1) family, is involved in various physiology processes such as cell death and survival. However, a role of hepatic c-Jun in the whole-body metabolism is poorly understood. Methods We generated liver-specific c-Jun knock-out (c-jun△li) mice to investigate the effect of hepatic c-Jun on the whole-body physiology, particularly in blood glucose and body temperature. Primary hepatocytes were also used to explore a direct regulation of c-Jun in gluconeogenesis. Results c-jun△li mice showed higher hepatic gluconeogenic capacity compared with control mice, and similar results were obtained in vitro. In addition, fibroblast growth factor 21 (FGF21) expression was directly inhibited by c-Jun knockdown and adenovirus-mediated hepatic FGF21 over-expression blocked the effect of c-Jun on gluconeogenesis in c-jun△li mice. Interestingly, c-jun△li mice also exhibited higher body temperature, with induced thermogenesis and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). Furthermore, the body temperature became comparable between c-jun△li and control mice at thermoneutral temperature (30 °C). Moreover, the activity of sympathetic nervous system (SNS) was increased in c-jun△li mice and the higher body temperature was inhibited by beta-adrenergic receptor blocker injection. Finally, the activated SNS and increased body temperature in c-jun△li mice was most likely caused by the signals from the brain and hepatic vagus nerve, as the expression of c-Fos (the molecular marker of neuronal activation) was changed in several brain areas controlling body temperature and body temperature was decreased by selective hepatic vagotomy. Conclusions These data demonstrate a novel function of hepatic c-Jun in the regulation of gluconeogenesis and body temperature via FGF21 and neural signals. Our results also provide novel insights into the organ crosstalk in the regulation of the whole-body physiology.
Liver-specific inactivation of c-Jun increased gluconeogenesis via decreasing FGF21 expression. Liver-specific inactivation of c-Jun increased body temperature by promoting thermogenesis in BAT. Hepatic c-Jun modulates body temperature via regulating sympathetic nervous system activity and vagus nerve.
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Affiliation(s)
- Fei Xiao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Yajie Guo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Jiali Deng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Feixiang Yuan
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Yuzhong Xiao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Lijian Hui
- State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Yu Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Zhimin Hu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Yuncai Zhou
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, China
| | - Kai Li
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, China
| | - Qichen Fang
- Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, China
| | - Weiping Jia
- Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, China
| | - Yan Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Hao Ying
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Qiwei Zhai
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Shanghai Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Feifan Guo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China.
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