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Jiang H, Yang J, Li T, Wang X, Fan Z, Ye Q, Du Y. JAK/STAT3 signaling in cardiac fibrosis: a promising therapeutic target. Front Pharmacol 2024; 15:1336102. [PMID: 38495094 PMCID: PMC10940489 DOI: 10.3389/fphar.2024.1336102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/18/2024] [Indexed: 03/19/2024] Open
Abstract
Cardiac fibrosis is a serious health problem because it is a common pathological change in almost all forms of cardiovascular diseases. Cardiac fibrosis is characterized by the transdifferentiation of cardiac fibroblasts (CFs) into cardiac myofibroblasts and the excessive deposition of extracellular matrix (ECM) components produced by activated myofibroblasts, which leads to fibrotic scar formation and subsequent cardiac dysfunction. However, there are currently few effective therapeutic strategies protecting against fibrogenesis. This lack is largely because the molecular mechanisms of cardiac fibrosis remain unclear despite extensive research. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade is an extensively present intracellular signal transduction pathway and can regulate a wide range of biological processes, including cell proliferation, migration, differentiation, apoptosis, and immune response. Various upstream mediators such as cytokines, growth factors and hormones can initiate signal transmission via this pathway and play corresponding regulatory roles. STAT3 is a crucial player of the JAK/STAT pathway and its activation is related to inflammation, malignant tumors and autoimmune illnesses. Recently, the JAK/STAT3 signaling has been in the spotlight for its role in the occurrence and development of cardiac fibrosis and its activation can promote the proliferation and activation of CFs and the production of ECM proteins, thus leading to cardiac fibrosis. In this manuscript, we discuss the structure, transactivation and regulation of the JAK/STAT3 signaling pathway and review recent progress on the role of this pathway in cardiac fibrosis. Moreover, we summarize the current challenges and opportunities of targeting the JAK/STAT3 signaling for the treatment of fibrosis. In summary, the information presented in this article is critical for comprehending the role of the JAK/STAT3 pathway in cardiac fibrosis, and will also contribute to future research aimed at the development of effective anti-fibrotic therapeutic strategies targeting the JAK/STAT3 signaling.
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Affiliation(s)
- Heng Jiang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Junjie Yang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Tao Li
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Xinyu Wang
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Zhongcai Fan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Qiang Ye
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yanfei Du
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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2
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Afrin F, Mateen S, Oman J, Lai JCK, Barrott JJ, Pashikanti S. Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells. Cancers (Basel) 2023; 15:4645. [PMID: 37760612 PMCID: PMC10527029 DOI: 10.3390/cancers15184645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Molecular targeting strategies have been used for years in order to control cancer progression and are often based on targeting various enzymes involved in metabolic pathways. Keeping this in mind, it is essential to determine the role of each enzyme in a particular metabolic pathway. In this review, we provide in-depth information on various enzymes such as ceramidase, sphingosine kinase, sphingomyelin synthase, dihydroceramide desaturase, and ceramide synthase which are associated with various types of cancers. We also discuss the physicochemical properties of well-studied inhibitors with natural product origins and their related structures in terms of these enzymes. Targeting ceramide metabolism exhibited promising mono- and combination therapies at preclinical stages in preventing cancer progression and cemented the significance of sphingolipid metabolism in cancer treatments. Targeting ceramide-metabolizing enzymes will help medicinal chemists design potent and selective small molecules for treating cancer progression at various levels.
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Affiliation(s)
- Farjana Afrin
- Biomedical and Pharmaceutical Sciences, Kasiska Division of Health Sciences, College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA; (F.A.); (S.M.); (J.O.); (J.C.K.L.)
| | - Sameena Mateen
- Biomedical and Pharmaceutical Sciences, Kasiska Division of Health Sciences, College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA; (F.A.); (S.M.); (J.O.); (J.C.K.L.)
| | - Jordan Oman
- Biomedical and Pharmaceutical Sciences, Kasiska Division of Health Sciences, College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA; (F.A.); (S.M.); (J.O.); (J.C.K.L.)
| | - James C. K. Lai
- Biomedical and Pharmaceutical Sciences, Kasiska Division of Health Sciences, College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA; (F.A.); (S.M.); (J.O.); (J.C.K.L.)
| | - Jared J. Barrott
- Cell Biology and Physiology, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA;
| | - Srinath Pashikanti
- Biomedical and Pharmaceutical Sciences, Kasiska Division of Health Sciences, College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA; (F.A.); (S.M.); (J.O.); (J.C.K.L.)
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3
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Kanno H, Matsumoto S, Yoshizumi T, Nakahara K, Kubo A, Murata H, Shuin T, U HS. Role of SOCS and VHL Proteins in Neuronal Differentiation and Development. Int J Mol Sci 2023; 24:ijms24043880. [PMID: 36835292 PMCID: PMC9960776 DOI: 10.3390/ijms24043880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin-proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin-proteasome system but also act directly on JAKs to suppress the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor-vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.
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Affiliation(s)
- Hiroshi Kanno
- Department of Neurosurgery, School of Medicine, Yokohama City University, Yokohama 232-0024, Japan
- Department of Neurosurgery, Asahi Hospital, Tokyo 121-0078, Japan
- Correspondence: ; Tel.: +81-3-5242-5800
| | - Shutaro Matsumoto
- Department of Neurosurgery, School of Medicine, Yokohama City University, Yokohama 232-0024, Japan
- Department of Neurosurgery, Asahi Hospital, Tokyo 121-0078, Japan
| | - Tetsuya Yoshizumi
- Department of Neurosurgery, St. Mariannna Medical University, Kawasaki 216-8511, Japan
| | - Kimihiro Nakahara
- Department of Neurosurgery, International University of Health and Welfare, Atami 413-0012, Japan
| | | | - Hidetoshi Murata
- Department of Neurosurgery, St. Mariannna Medical University, Kawasaki 216-8511, Japan
| | - Taro Shuin
- Kochi Medical School Hospital, Nangoku 783-0043, Japan
| | - Hoi-Sang U
- Department of Electrical Engineering, University of California San Diego, San Diego, CA 92093, USA
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4
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Chai H, Tjong H, Li P, Liao W, Wang P, Wong CH, Ngan CY, Leonard WJ, Wei CL, Ruan Y. ChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs. Nat Commun 2023; 14:213. [PMID: 36639381 PMCID: PMC9839710 DOI: 10.1038/s41467-023-35879-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 01/05/2023] [Indexed: 01/15/2023] Open
Abstract
Connecting genes to their cis-regulatory elements has been enabled by genome-wide mapping of chromatin interactions using proximity ligation in ChIA-PET, Hi-C, and their derivatives. However, these methods require millions of input cells for high-quality data and thus are unsuitable for many studies when only limited cells are available. Conversely, epigenomic profiling via transposase digestion in ATAC-seq requires only hundreds to thousands of cells to robustly map open chromatin associated with transcription activity, but it cannot directly connect active genes to their distal enhancers. Here, we combine proximity ligation in ChIA-PET and transposase accessibility in ATAC-seq into ChIATAC to efficiently map interactions between open chromatin loci in low numbers of input cells. We validate ChIATAC in Drosophila cells and optimize it for mapping 3D epigenomes in human cells robustly. Applying ChIATAC to primary human T cells, we reveal mechanisms that topologically regulate transcriptional programs during T cell activation.
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Affiliation(s)
- Haoxi Chai
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Harianto Tjong
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Peng Li
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Wei Liao
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ping Wang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Chee Hong Wong
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Chew Yee Ngan
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Warren J Leonard
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Chia-Lin Wei
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
| | - Yijun Ruan
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, P. R. China.
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5
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Qin YQ, Liu SY, Lv ML, Sun WL. Ambra1 in cancer: implications for clinical oncology. Apoptosis 2022; 27:720-729. [PMID: 35994214 DOI: 10.1007/s10495-022-01762-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2022] [Indexed: 11/28/2022]
Abstract
Activating molecule in Beclin-1-regulated autophagy protein 1 (Ambra1) is well known to mediate the autophagy process and promote the formation of autophagosomes. In addition, Ambra1 is involved in the execution of apoptosis. A growing number of studies have revealed that this protein modifies the sensitivity of cancer cells to anticancer drugs by controlling the balance between autophagy and apoptosis. In addition, Ambra1 is a key factor in regulating the cell cycle, proliferation, invasion and migration. Therefore, it plays a key role in tumorigenesis and progression. Moreover, Ambra1 is highly expressed in a variety of cancers and is closely related to the prognosis of patients. Thus, it appears that Ambra1 has multiple roles in tumorigenesis and progression, which may have implications for clinical oncology. The present review focuses on recent advances in the study of Ambra1, especially the role of the protein in tumorigenesis, progression and effects on anticancer drug sensitivity.
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Affiliation(s)
- Yan-Qiu Qin
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, No. 166 Daxuedong Road, Nanning, 530007, Guangxi, People's Republic of China
| | - Si-Yu Liu
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, No. 166 Daxuedong Road, Nanning, 530007, Guangxi, People's Republic of China
| | - Mei-Ling Lv
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, No. 166 Daxuedong Road, Nanning, 530007, Guangxi, People's Republic of China
| | - Wei-Liang Sun
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, No. 166 Daxuedong Road, Nanning, 530007, Guangxi, People's Republic of China.
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6
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Sobah ML, Liongue C, Ward AC. SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer. Front Med (Lausanne) 2021; 8:727987. [PMID: 34604264 PMCID: PMC8481645 DOI: 10.3389/fmed.2021.727987] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 08/16/2021] [Indexed: 01/10/2023] Open
Abstract
Cytokine signaling represents one of the cornerstones of the immune system, mediating the complex responses required to facilitate appropriate immune cell development and function that supports robust immunity. It is crucial that these signals be tightly regulated, with dysregulation underpinning immune defects, including excessive inflammation, as well as contributing to various immune-related malignancies. A specialized family of proteins called suppressors of cytokine signaling (SOCS) participate in negative feedback regulation of cytokine signaling, ensuring it is appropriately restrained. The eight SOCS proteins identified regulate cytokine and other signaling pathways in unique ways. SOCS1–3 and CISH are most closely involved in the regulation of immune-related signaling, influencing processes such polarization of lymphocytes and the activation of myeloid cells by controlling signaling downstream of essential cytokines such as IL-4, IL-6, and IFN-γ. SOCS protein perturbation disrupts these processes resulting in the development of inflammatory and autoimmune conditions as well as malignancies. As a consequence, SOCS proteins are garnering increased interest as a unique avenue to treat these disorders.
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Affiliation(s)
| | - Clifford Liongue
- School of Medicine, Deakin University, Geelong, VIC, Australia.,Institue of Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia
| | - Alister C Ward
- School of Medicine, Deakin University, Geelong, VIC, Australia.,Institue of Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia
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7
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Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling. Acta Neuropathol 2021; 142:537-564. [PMID: 34302498 PMCID: PMC8357694 DOI: 10.1007/s00401-021-02347-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/09/2021] [Accepted: 07/10/2021] [Indexed: 12/11/2022]
Abstract
Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MBGroup3) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MBGroup3 stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MBGroup3 stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MBGroup3 outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MBGroup3.
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8
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Keewan E, Matlawska-Wasowska K. The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia. Cancers (Basel) 2021; 13:4000. [PMID: 34439155 PMCID: PMC8393695 DOI: 10.3390/cancers13164000] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/12/2022] Open
Abstract
Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.
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Affiliation(s)
- Esra’a Keewan
- Department of Pediatrics, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA;
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
| | - Ksenia Matlawska-Wasowska
- Department of Pediatrics, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA;
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
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9
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ÇaĞlayan E, Turan K. Expression profiles of interferon-related genes in cells infected with influenza A viruses or transiently transfected with plasmids encoding viral RNA polymerase. ACTA ACUST UNITED AC 2021; 45:88-103. [PMID: 33597825 PMCID: PMC7877717 DOI: 10.3906/biy-2005-73] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 11/01/2020] [Indexed: 11/30/2022]
Abstract
Influenza A viruses frequently change their genetic characteristics, which leads to the emergence of new viruses. Consequently, elucidation of the relationship between influenza A virus and host cells has a great importance to cope with viral infections. In this study, it was aimed to determine expression profiles of interferon response genes in human embryonic kidney 293 (HEK293) cells infected with human (A/WSN-H1N1) and avian influenza A viruses (duck/Pennsylvania/10218/84/H5N2) or transfected with plasmids encoding viral RdRP subunits and, to obtain clues about the genes that may be important for the viral pathogenesis. The HEK293 cells cultured in a 12-well plate were infected with influenza A viruses or transfected with plasmids encoding viral polymerase. Total RNA extraction and cDNA preparation were carried out with commercial kits. Qiagen 96-well-RT2 Profiler PCR Array plates designated for interferons response genes were used for quantitation of the transcripts. The relative quantities of transcripts were normalized with STAT3 gen, and the results were evaluated. Quantitative RT-PCR results showed that there are substantial differences of the interferon response gene transcription in cells infected with viruses or transfected with plasmids. A higher number of interferon-related genes were found to be downregulated in the cells infected with DkPen compared to WSN. On the other hand, significant differences in the expression profiles of interferon response genes were observed in the cells expressing viral PA protein. In particular, avian influenza PA protein was found to cause more aggressive changes on the transcript levels. Human and avian influenza A viruses cause a substantial change in interferon response gene expression in HEK293 cells. However, a higher number of genes were downregulated in the cells infected with avian influenza DkPen compared to WSN. It has been also concluded that the viral PA protein is one of the important viral factors affecting the transcript level of host genes.
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Affiliation(s)
- Elif ÇaĞlayan
- Enstitute of Health Sciences, Marmara University, İstanbul Turkey
| | - Kadir Turan
- Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, İstanbul Turkey
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10
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Brachtendorf S, El-Hindi K, Grösch S. WITHDRAWN: Ceramide synthases in cancer therapy and chemoresistance. Prog Lipid Res 2019:100992. [PMID: 31442523 DOI: 10.1016/j.plipres.2019.100992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 04/02/2019] [Accepted: 04/02/2019] [Indexed: 10/26/2022]
Affiliation(s)
- Sebastian Brachtendorf
- Institute of Clinical Pharmacology, Faculty of Medicine, Goethe University Frankfurt, Theodor-Stern Kai 7, Frankfurt 60590, Germany
| | - Khadija El-Hindi
- Institute of Clinical Pharmacology, Faculty of Medicine, Goethe University Frankfurt, Theodor-Stern Kai 7, Frankfurt 60590, Germany
| | - Sabine Grösch
- Institute of Clinical Pharmacology, Faculty of Medicine, Goethe University Frankfurt, Theodor-Stern Kai 7, Frankfurt 60590, Germany
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11
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Brachtendorf S, El-Hindi K, Grösch S. Ceramide synthases in cancer therapy and chemoresistance. Prog Lipid Res 2019; 74:160-185. [DOI: 10.1016/j.plipres.2019.04.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 04/02/2019] [Accepted: 04/02/2019] [Indexed: 12/24/2022]
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12
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Gao Y, Zhao H, Wang P, Wang J, Zou L. The roles of SOCS3 and STAT3 in bacterial infection and inflammatory diseases. Scand J Immunol 2018; 88:e12727. [PMID: 30341772 DOI: 10.1111/sji.12727] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/11/2018] [Accepted: 10/13/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Yu Gao
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
- Department of Microbiology, Tumor and Cell Biology; Karolinska Institutet; Stockholm Sweden
| | - Honglei Zhao
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
- Department of Oncology-Pathology; Karolinska Institutet; Stockholm Sweden
| | - Peng Wang
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
| | - Jun Wang
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
| | - Lili Zou
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
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13
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The Two-Faced Cytokine IL-6 in Host Defense and Diseases. Int J Mol Sci 2018; 19:ijms19113528. [PMID: 30423923 PMCID: PMC6274717 DOI: 10.3390/ijms19113528] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 10/30/2018] [Accepted: 11/06/2018] [Indexed: 02/07/2023] Open
Abstract
Interleukein-6 (IL-6), is produced locally from infectious or injured lesions and is delivered to the whole body via the blood stream, promptly activating the host defense system to perform diverse functions. However, excessive or sustained production of IL-6 is involved in various diseases. In diseases, the IL-6 inhibitory strategy begins with the development of the anti-IL-6 receptor antibody, tocilizumab (TCZ). This antibody has shown remarkable effects on Castleman disease, rheumatoid arthritis and juvenile idiopathic arthritis. In 2017, TCZ was proven to work effectively against giant cell arteritis, Takayasu arteritis and cytokine releasing syndrome, initiating a new era for the treatment of these diseases. In this study, the defensive functions of IL-6 and various pathological conditions are compared. Further, the diseases of which TCZ has been approved for treatment are summarized, the updated results of increasing off-label use of TCZ for various diseases are reviewed and the conditions for which IL-6 inhibition might have a beneficial role are discussed. Given the involvement of IL-6 in many pathologies, the diseases that can be improved by IL-6 inhibition will expand. However, the important role of IL-6 in host defense should always be kept in mind in clinical practice.
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14
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Wang W, Li F, Xu Y, Wei J, Zhang Y, Yang H, Gao B, Yu G, Fang D. JAK1-mediated Sirt1 phosphorylation functions as a negative feedback of the JAK1-STAT3 pathway. J Biol Chem 2018; 293:11067-11075. [PMID: 29789426 DOI: 10.1074/jbc.ra117.001387] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Revised: 05/08/2018] [Indexed: 11/06/2022] Open
Abstract
The type III NAD-dependent histone deacetylase Sirt1 plays important roles in a variety of pathobiological functions through targeting either the acetylated histones or transcription factors. However, the molecular mechanisms underlying how the Sirt1 functions are regulated remain vague. Herein we identified that the Janus kinase 1 (JAK1) interacts with Sirt1 and catalyzes its phosphorylation at the tyrosine residues of 280 and 301, both of which are highly conserved and located in the histone deacetylase catalytic domain of Sirt1. IL-6 stimulation enhanced Sirt1 interaction with JAK1 and JAK1-mediated Sirt1 phosphorylation. Interestingly, JAK1-mediated Sirt1 phosphorylation did not alter Sirt1 deacetylase catalytic activity, but instead it is required for Sirt1 interaction with the downstream transcription factor STAT3. JAK1-mediated phosphorylation enhanced Sirt1 suppression of STAT3 acetylation and transcriptional activity. As a consequence, Sirt1 activation attenuates IL-6 activity in protecting cancer cells from chemotherapeutic drug-induced apoptosis. Our studies identify JAK1 as a previously unappreciated tyrosine kinase of Sirt1 and reveal a novel negative feedback of the JAK1-STAT3 pathway.
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Affiliation(s)
- Wenhui Wang
- From the Department of Oncology, Wei Fang People's Hospital, Wei Fang, Shandong Province, 261041 China.,Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and
| | - Fei Li
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and
| | - Yuanming Xu
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and
| | - Juncheng Wei
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and
| | - Yana Zhang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and.,Department of Otolaryngology-Head and Neck Surgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623 China
| | - Heeyoung Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and
| | - Beixue Gao
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and
| | - Guohua Yu
- From the Department of Oncology, Wei Fang People's Hospital, Wei Fang, Shandong Province, 261041 China,
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and
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15
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Banos G, Bramis G, Bush SJ, Clark EL, McCulloch MEB, Smith J, Schulze G, Arsenos G, Hume DA, Psifidi A. The genomic architecture of mastitis resistance in dairy sheep. BMC Genomics 2017; 18:624. [PMID: 28814268 PMCID: PMC5559839 DOI: 10.1186/s12864-017-3982-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 08/01/2017] [Indexed: 02/06/2023] Open
Abstract
Background Mastitis is the most prevalent disease in dairy sheep with major economic, hygienic and welfare implications. The disease persists in all dairy sheep production systems despite the implementation of improved management practises. Selective breeding for enhanced mastitis resistance may provide the means to further control the disease. In the present study, we investigated the genetic architecture of four mastitis traits in dairy sheep. Individual animal records for clinical mastitis occurrence and three mastitis indicator traits (milk somatic cell count, total viable bacterial count in milk and the California mastitis test) were collected monthly throughout lactation for 609 ewes of the Greek Chios breed. All animals were genotyped with a custom-made 960-single nucleotide polymorphism (SNP) DNA array based on markers located in quantitative trait loci (QTL) regions for mastitis resistance previously detected in three other distinct dairy sheep populations. Results Heritable variation and strong positive genetic correlations were estimated for clinical mastitis occurrence and the three mastitis indicator traits. SNP markers significantly associated with these mastitis traits were confirmed on chromosomes 2, 3, 5, 16 and 19. We identified pathways, molecular interaction networks and functional gene clusters for mastitis resistance. Candidate genes within the detected regions were identified based upon analysis of an ovine transcriptional atlas and transcriptome data derived from milk somatic cells. Relevant candidate genes implicated in innate immunity included SOCS2, CTLA4, C6, C7, C9, PTGER4, DAB2, CARD6, OSMR, PLXNC1, IDH1, ICOS, FYB, and LYFR. Conclusions The results confirmed the presence of animal genetic variability in mastitis resistance and identified genomic regions associated with specific mastitis traits in the Chios sheep. The conserved genetic architecture of mastitis resistance between distinct dairy sheep breeds suggests that across-breed selection programmes would be feasible. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3982-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- G Banos
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.,Scotland's Rural College, Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.,School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - G Bramis
- School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - S J Bush
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - E L Clark
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - M E B McCulloch
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - J Smith
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - G Schulze
- School of Informatics, University of Bergen, 5008, Bergen, Norway
| | - G Arsenos
- School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - D A Hume
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - A Psifidi
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK. .,Royal Veterinary College, University of London, AL9 7TA, Hatfield, UK.
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Abstract
Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance that is often due to unlimited access to food and an increasingly sedentary lifestyle on the background of a genetic and epigenetic vulnerability. Our understanding of the humoral and neuronal systems that mediate the control of energy homeostasis has improved dramatically in the past few decades. However, our ability to develop effective strategies to slow the current epidemic of obesity has been hampered, largely owing to the limited knowledge of the mechanisms underlying resistance to the action of metabolic hormones such as leptin and ghrelin. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. Intensive research over the past several years has yielded tremendous progress in our understanding of the cellular pathways that disrupt the action of leptin and ghrelin. In this Review, we discuss the molecular mechanisms underpinning resistance to leptin and ghrelin and how they can be exploited as targets for pharmacological management of obesity.
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Affiliation(s)
- Huxing Cui
- Department of Pharmacology, University of Iowa, Iowa City, Iowa 52246, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA
| | - Miguel López
- Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain
| | - Kamal Rahmouni
- Department of Pharmacology, University of Iowa, Iowa City, Iowa 52246, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA
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17
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Narazaki M, Tanaka T, Kishimoto T. The role and therapeutic targeting of IL-6 in rheumatoid arthritis. Expert Rev Clin Immunol 2017; 13:535-551. [PMID: 28494214 DOI: 10.1080/1744666x.2017.1295850] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is an autoimmune chronic disease with joint and systemic inflammation and it has been found that interleukin-6 (IL-6) plays a key role in RA. Indeed, various clinical studies have proved that the first-in-class IL-6 inhibitor, tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, showed outstanding efficacy in RA. Areas covered: We review here the role of IL-6 in the inflammatory conditions and how IL-6 contributes to pathogenesis of RA, what induces IL-6 and how IL-6 expression is regulated. Furthermore, clinical studies of tocilizumab for RA are summarized, Expert commentary: We review and discuss the prospects for future applications of IL-6 targeting therapy and new therapeutic strategies targeting IL-6. Finally, we discuss relevant issues with regard to the clinical management of IL-6 blockade in RA.
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Affiliation(s)
- Masashi Narazaki
- a Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine , Osaka University , Osaka , Japan.,b Department of Immunopathology, World Premier International Immunology Frontier Research Center , Osaka University , Osaka , Japan
| | - Toshio Tanaka
- b Department of Immunopathology, World Premier International Immunology Frontier Research Center , Osaka University , Osaka , Japan.,c Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine , Osaka University , Osaka , Japan
| | - Tadamitsu Kishimoto
- d Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center , Osaka University , Osaka , Japan
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18
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Suppressor of cytokine signaling 2 (SOCS2) contributes to encephalitis in a model of Herpes infection in mice. Brain Res Bull 2016; 127:164-170. [DOI: 10.1016/j.brainresbull.2016.09.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 09/09/2016] [Accepted: 09/15/2016] [Indexed: 11/22/2022]
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19
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Wu TH, Lee HT, Lai CC, Yang AH, Loong CC, Wang HK, Yu CL, Tsai CY. Suppressor of cytokine signaling (SOCS) 1 is down-regulated in renal transplant recipients with rejection. Transpl Immunol 2016; 38:54-9. [DOI: 10.1016/j.trim.2016.07.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 07/09/2016] [Accepted: 07/12/2016] [Indexed: 01/14/2023]
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20
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Deandrés-Galiana EJ, Fernández-Martínez JL, Saligan LN, Sonis ST. Impact of Microarray Preprocessing Techniques in Unraveling Biological Pathways. J Comput Biol 2016; 23:957-968. [PMID: 27494192 DOI: 10.1089/cmb.2016.0042] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
To better understand the impact of microarray preprocessing normalization techniques on the analysis of biological pathways in the prediction of chronic fatigue (CF) following radiation therapy, this study has compared the list of predictive genes found using the Robust Multiarray Averaging (RMA) and the Affymetrix MAS5 method, with the list that is obtained working with raw data (without any preprocessing). First, we modeled the spiked-in data set where differentially expressed genes were known and spiked-in at different known concentrations, showing that the precisions established by different gene ranking methods were higher than working with raw data. The results obtained from the spiked-in experiment were extrapolated to the CF data set to run learning and blind validation. RMA and MAS5 provided different sets of discriminatory genes that have a higher predictive accuracy in the learning phase, but lower predictive accuracy during the blind validation phase, suggesting that the genetic signatures generated using both preprocessing techniques cannot be generalizable. The pathways found using the raw data set better described what is a priori known for the CF disease. Besides, RMA produced more reliable pathways than MAS5. Understanding the strengths of these two preprocessing techniques in phenotype prediction is critical for precision medicine. Particularly, this article concludes that biological pathways might be better unraveled working with raw expression data. Moreover, the interpretation of the predictive gene profiles generated by RMA and MAS5 should be done with caution. This is an important conclusion with a high translational impact that should be confirmed in other disease data sets.
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21
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Feng Y, Sanders AJ, Morgan LD, Harding KG, Jiang WG. Potential roles of suppressor of cytokine signaling in wound healing. Regen Med 2016; 11:193-209. [PMID: 26877242 DOI: 10.2217/rme.16.4] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Wound healing is a dynamic process comprising three overlapping, highly orchestrated stages known as inflammation, proliferation and re-epithelialization, and tissue remodeling. This complex process is regulated by numerous cytokines, with dysregulation of cytokine-induced signaling leading to impaired wound healing. Suppressor of cytokine signaling (SOCS) proteins are a family of eight intracellular proteins which may hold the potential to maintain homeostasis during wound healing through their negative feedback inhibition of cytokine signaling. To date, the roles of SOCS proteins in inflammation, autoimmunity and cancer have been comprehensively illustrated; however, only a limited number of studies focused on their role in wound healing. This review demonstrates the possible links between SOCS proteins and wound healing, and also highlights the potential importance of this family in a variety of other aspects of regenerative medicine.
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Affiliation(s)
- Yi Feng
- Cardiff China Medical Research Collaborative & Wound Healing Research Unit, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
| | - Andrew J Sanders
- Cardiff China Medical Research Collaborative & Wound Healing Research Unit, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
| | - Liam D Morgan
- Cardiff China Medical Research Collaborative & Wound Healing Research Unit, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
| | - Keith G Harding
- Wound Healing Research Unit, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
| | - Wen G Jiang
- Cardiff China Medical Research Collaborative & Wound Healing Research Unit, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
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22
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Huang L, Hu B, Ni J, Wu J, Jiang W, Chen C, Yang L, Zeng Y, Wan R, Hu G, Wang X. Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:27. [PMID: 26847351 PMCID: PMC4743194 DOI: 10.1186/s13046-016-0301-7] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 01/27/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Previous studies have investigated the sustained aberrantly activated Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial for pancreatic cancer growth and metastasis. Suppressor of cytokine signaling 3 (SOCS3), as a key negative feedback regulator of this signaling pathway, is usually down-regulated in various cancers. In the present study, we aim at exploring the biological function and the underlying molecular regulation mechanisms of SOCS3 in pancreatic cancer. METHODS The expression of SOCS3 and other genes in pancreatic cancer was examined by Quantitative real-time PCR, western blotting and immunohistochemical staining. The interaction between pSTAT3 and DNA Methyltransferase 1 (DNMT1) was investigated by co-immunoprecipitation assay. Luciferase reporter assay was used to investigate the transcriptional regulation of pSTAT3 and DNMT1 on the SOCS3 gene. The effects of SOCS3 on the biological behavior of pancreatic cancer cells were assessed both in vitro and vivo. Furthermore, we performed a comprehensive analysis of the expression of SOCS3 in a pancreatic cancer tissue microarray (TMA) and correlated our findings with pathological parameters and outcomes of the patients. RESULTS We showed that SOCS3 expression was decreased in phosphorylated STAT3 (pSTAT3)-positive tumors and was negatively correlated with pSTAT3 in pancreatic cancer cells. We also found that IL-6/STAT3 promoted SOCS3 promoter hypermethylation by increasing DNMT1 activity; silencing DNMT1 or 5-aza-2-deoxycytidine (5-AZA) treatment could reverse the down-regulation of SOCS3 mediated by IL-6. Using co-immunoprecipitation and luciferase reporter assays, we found that STAT3 recruited DNMT1 to the promoter region of SOCS3 and inhibited its transcriptional activity. Overexpression of SOCS3 significantly inhibited cell proliferation, which may be due to the increase in G1-S phase arrest; overexpression of SOCS3 also inhibited cell migration and invasion as well as tumorigenicity in nude mice. Pancreatic cancer tissue microarray analysis showed that high SOCS3 expression was a good prognostic factor and negatively correlated with tumor volume and metastasis. CONCLUSION We demonstrated that activated IL-6/STAT3 signaling could induce SOCS3 methylation via DNMT1, which led to pancreatic cancer growth and metastasis. These data also provided a mechanistic link between sustained aberrantly activated IL-6/STAT3 signaling and SOCS3 down-regulation in pancreatic cancer. Thus, inhibitors of STAT3 or DNMT1 may become novel strategies for treating pancreatic cancer.
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Affiliation(s)
- Li Huang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Bin Hu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Jianbo Ni
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Jianghong Wu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Weiliang Jiang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Congying Chen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Lijuan Yang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Yue Zeng
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Rong Wan
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Guoyong Hu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
| | - Xingpeng Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 100 Haining Road, Shanghai, Hongkou District 200080 China
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23
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Miao J, Bao Y, Ye J, Shao H, Qian K, Qin A. Transcriptional Profiling of Host Gene Expression in Chicken Embryo Fibroblasts Infected with Reticuloendotheliosis Virus Strain HA1101. PLoS One 2015; 10:e0126992. [PMID: 25973612 PMCID: PMC4431687 DOI: 10.1371/journal.pone.0126992] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Accepted: 04/09/2015] [Indexed: 01/11/2023] Open
Abstract
Reticuloendotheliosis virus (REV), a member of the Gammaretrovirus genus in the Retroviridae family, causes an immunosuppressive, oncogenic and runting-stunting syndrome in multiple avian hosts. To better understand the host interactions at the transcriptional level, microarray data analysis was performed in chicken embryo fibroblast cells at 1, 3, 5, and 7 days after infection with REV. This study identified 1,785 differentially expressed genes that were classified into several functional groups including signal transduction, immune response, biological adhesion and endocytosis. Significant differences were mainly observed in the expression of genes involved in the immune response, especially during the later post-infection time points. These results revealed that differentially expressed genes IL6, STAT1, MyD88, TLRs, NF-κB, IRF-7, and ISGs play important roles in the pathogenicity of REV infection. Our study is the first to use microarray analysis to investigate REV, and these findings provide insights into the underlying mechanisms of the host antiviral response and the molecular basis of viral pathogenesis.
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Affiliation(s)
- Ji Miao
- Ministry of Education Key Laboratory for Avian Preventive Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Key Laboratory of Jiangsu Preventive Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Yanqing Bao
- Ministry of Education Key Laboratory for Avian Preventive Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Key Laboratory of Jiangsu Preventive Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Jianqiang Ye
- Ministry of Education Key Laboratory for Avian Preventive Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Key Laboratory of Jiangsu Preventive Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Hongxia Shao
- Ministry of Education Key Laboratory for Avian Preventive Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Key Laboratory of Jiangsu Preventive Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Kun Qian
- Ministry of Education Key Laboratory for Avian Preventive Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Key Laboratory of Jiangsu Preventive Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Aijian Qin
- Ministry of Education Key Laboratory for Avian Preventive Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Key Laboratory of Jiangsu Preventive Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu Province, China
- * E-mail:
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Alanazi I, Ebrahimie E, Hoffmann P, Adelson DL. Combined gene expression and proteomic analysis of EGF induced apoptosis in A431 cells suggests multiple pathways trigger apoptosis. Apoptosis 2014; 18:1291-1305. [PMID: 23892916 DOI: 10.1007/s10495-013-0887-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A431 cells, derived from epidermoid carcinoma, overexpress the epidermal growth factor receptor (EGFR) and when treated with a high dose of EGF will undergo apoptosis. We exploited microarray and proteomics techniques and network prediction to study the regulatory mechanisms of EGF-induced apoptosis in A431 cells. We observed significant changes in gene expression in 162 genes, approximately evenly split between pro-apoptotic and anti-apoptotic genes and identified 30 proteins from the proteomic data that had either pro or anti-apoptotic annotation. Our correlation analysis of gene expression and proteome modeled a number of distinct sub-networks that are associated with the onset of apoptosis, allowing us to identify specific pathways and components. These include components of the interferon signalling pathway, and down stream components, including cytokines and suppressors of cytokine signalling. A central component of almost all gene expression sub-networks identified was TP53, which is mutated in A431 cells, and was down regulated. This down regulation of TP53 appeared to be correlated with proteomic sub-networks of cytoskeletal or cell adhesion components that might induce apoptosis by triggering cytochrome C release. Of the only three genes also differentially expressed as proteins, only serpinb1 had a known association with apoptosis. We confirmed that up regulation and cleavage of serpinb1 into L-DNAaseII was correlated with the induction of apoptosis. It is unlikely that a single pathway, but more likely a combination of pathways is needed to trigger EGF induced apoptosis in A431cells.
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Affiliation(s)
- Ibrahim Alanazi
- School of Molecular & Biomedical Science, The University of Adelaide, Adelaide, SA, Australia
| | - Esmaeil Ebrahimie
- School of Molecular & Biomedical Science, The University of Adelaide, Adelaide, SA, Australia
| | - Peter Hoffmann
- School of Molecular & Biomedical Science, The University of Adelaide, Adelaide, SA, Australia
| | - David L Adelson
- School of Molecular & Biomedical Science, The University of Adelaide, Adelaide, SA, Australia.
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25
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Matsushita K, Itoh S, Ikeda S, Yamamoto Y, Yamauchi Y, Hayashi M. LIF/STAT3/SOCS3 Signaling Pathway in Murine Bone Marrow Stromal Cells Suppresses Osteoblast Differentiation. J Cell Biochem 2014; 115:1262-8. [DOI: 10.1002/jcb.24777] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Accepted: 01/22/2014] [Indexed: 12/26/2022]
Affiliation(s)
- Kenta Matsushita
- Department of Restorative Dentistry and Endodontology; Osaka University Graduate School of Dentistry; Osaka Japan
| | - Shousaku Itoh
- Department of Restorative Dentistry and Endodontology; Osaka University Graduate School of Dentistry; Osaka Japan
| | - Shun Ikeda
- Department of Restorative Dentistry and Endodontology; Osaka University Graduate School of Dentistry; Osaka Japan
| | - Yumiko Yamamoto
- Department of Restorative Dentistry and Endodontology; Osaka University Graduate School of Dentistry; Osaka Japan
| | - Yukako Yamauchi
- Department of Restorative Dentistry and Endodontology; Osaka University Graduate School of Dentistry; Osaka Japan
| | - Mikako Hayashi
- Department of Restorative Dentistry and Endodontology; Osaka University Graduate School of Dentistry; Osaka Japan
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The role of suppressors of cytokine signalling in human neoplasms. Mol Biol Int 2014; 2014:630797. [PMID: 24757565 PMCID: PMC3976820 DOI: 10.1155/2014/630797] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 02/02/2014] [Accepted: 02/04/2014] [Indexed: 12/28/2022] Open
Abstract
Suppressors of cytokine signalling 1-7 (SOCS1-7) and cytokine-inducible SH2-containing protein (CIS) are a group of intracellular proteins that are well known as JAK-STAT and several other signalling pathways negative feedback regulators. More recently several members have been identified as tumour suppressors and dysregulation of their biological roles in controlling cytokine and growth factor signalling may contribute to the development of many solid organ and haematological malignancies. This review explores their biological functions and their possible tumour suppressing role in human neoplasms.
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27
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Carow B, Rottenberg ME. SOCS3, a Major Regulator of Infection and Inflammation. Front Immunol 2014; 5:58. [PMID: 24600449 PMCID: PMC3928676 DOI: 10.3389/fimmu.2014.00058] [Citation(s) in RCA: 393] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 01/31/2014] [Indexed: 12/18/2022] Open
Abstract
In this review, we describe the role of suppressor of cytokine signaling-3 (SOCS3) in modulating the outcome of infections and autoimmune diseases as well as the underlying mechanisms. SOCS3 regulates cytokine or hormone signaling usually preventing, but in some cases aggravating, a variety of diseases. A main role of SOCS3 results from its binding to both the JAK kinase and the cytokine receptor, which results in the inhibition of STAT3 activation. Available data also indicate that SOCS3 can regulate signaling via other STATs than STAT3 and also controls cellular pathways unrelated to STAT activation. SOCS3 might either act directly by hampering JAK activation or by mediating the ubiquitination and subsequent proteasome degradation of the cytokine/growth factor/hormone receptor. Inflammation and infection stimulate SOCS3 expression in different myeloid and lymphoid cell populations as well as in diverse non-hematopoietic cells. The accumulated data suggest a relevant program coordinated by SOCS3 in different cell populations, devoted to the control of immune homeostasis in physiological and pathological conditions such as infection and autoimmunity.
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Affiliation(s)
- Berit Carow
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden
| | - Martin E Rottenberg
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden
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Zhang L, Li J, Li L, Zhang J, Wang X, Yang C, Li Y, Lan F, Lin P. IL-23 selectively promotes the metastasis of colorectal carcinoma cells with impaired Socs3 expression via the STAT5 pathway. Carcinogenesis 2014; 35:1330-40. [PMID: 24464786 DOI: 10.1093/carcin/bgu017] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Interleukin-23 (IL-23) is a conventional proinflammatory IL related to colorectal carcinoma (CRC). The signal transducer and activator of transcription (STAT) and suppressors of cytokine signaling (Socs) molecules, respectively, serve as agonists and antagonists of IL-23-associated inflammation. However, it remains unknown whether IL-23 directly affects CRC metastasis. In this study, we measured the metastasis of several human CRC cell lines stimulated by IL-23 in vitro and in vivo. Interestingly, the prometastasis effect of IL-23 was observed only in SW-620 cells. IL-23-associated migration and invasion was mediated by the phosphorylation of STAT5. The expression of Socs3 in SW-620 was impaired by IL-23 via DNA methylation and DNA methyltransferase-1 (DNMT-1)-dependent way. The DNMT-1-associated regulation was not observed in the other three cells. Socs3 was further confirmed to inhibit the prometastatic function of IL-23 both in vitro and in vivo. We analyzed the clinical correlation between the level of IL-23 in tumors and the metastasis of CRC and found that higher IL-23 levels along with lower Socs3 in CRC tissues accounted for more metastatic cases. In conclusion, it was demonstrated that IL-23, assisted by STAT5, might only promote the metastasis of CRC with deficient Socs3 expression in which IL-23-induced DNMT-1 was involved. It was elucidated that Socs3 seemed to be one of the important factors that mediate the selectivity of IL-23. Taken together, these discoveries give rise to new insights into the role of IL-23 in cancer biology and provide additional preclinical data regarding IL-23-associated therapy for CRC.
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Affiliation(s)
- Le Zhang
- Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Jun Li
- Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Li Li
- Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Jie Zhang
- Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Xiaodong Wang
- Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Chuanhua Yang
- Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Yanyan Li
- Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Feng Lan
- Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Ping Lin
- Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
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Müller P, Pugazhendhi D, Zeidler MP. Modulation of human JAK-STAT pathway signaling by functionally conserved regulators. JAKSTAT 2013; 1:34-43. [PMID: 24058749 PMCID: PMC3670133 DOI: 10.4161/jkst.18006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Revised: 08/26/2011] [Accepted: 09/06/2011] [Indexed: 12/21/2022] Open
Abstract
Both the core JAK-STAT pathway components and their in vivo roles have been widely conserved between vertebrates and invertebrate models such as Drosophila melanogaster. Misregulation of JAK-STAT pathway activity has also been identified as a key factor in the development of multiple human malignancies. Recently, whole genome RNA interference (RNAi) screens in cultured Drosophila cells have identified both positively and negatively acting JAK-STAT pathway regulators. Here, we describe the analysis of 73 human genes representing homologs of 56 Drosophila genes originally identified by genome-wide RNAi screening as regulators of JAK-STAT signaling. Using assays for human STAT1 and STAT3 protein levels and phosphorylation status, as well as assays measuring the expression of endogenous STAT1 and STAT3 transcriptional targets, we have tested siRNAs targeting these 73 human genes and have identified potential JAK-STAT pathway regulatory roles in 69 (95%) of these. The genes identified represent a wide range of human JAK-STAT pathway regulators and include genes not previously known to modulate this signaling cascade. These results underline the value of model system based approaches for the identification of pathway regulators and have led to the identification of loci whose misregulation may ultimately be implicated in JAK-STAT pathway-mediated human disease.
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Affiliation(s)
- Patrick Müller
- Department of Molecular and Cellular Biology; Harvard University; Cambridge, MA USA
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31
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Cycloheximide stimulates suppressor of cytokine signaling-3 gene expression in 3T3-L1 adipocytes via the extracellular signal-regulated kinase pathway. Toxicol Lett 2013; 217:42-9. [DOI: 10.1016/j.toxlet.2012.12.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 11/30/2012] [Accepted: 12/03/2012] [Indexed: 12/20/2022]
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32
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Inhibitory Mechanism of Signal Transduction through Chicken Leptin Receptor by Suppressor of Cytokine Signaling 3 (SOCS3). J Poult Sci 2013. [DOI: 10.2141/jpsa.0120166] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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33
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Turan T, Şanlı-Mohamed G, Baran Y. Changes in protein profiles of multiple myeloma cells in response to bortezomib. Leuk Lymphoma 2012; 54:1061-8. [DOI: 10.3109/10428194.2012.735668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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34
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Chang HH, Huang YM, Wu CP, Tang YC, Liu CW, Huang CH, Ho LT, Wu LY, Kuo YC, Kao YH. Endothelin-1 stimulates suppressor of cytokine signaling-3 gene expression in adipocytes. Gen Comp Endocrinol 2012; 178:450-8. [PMID: 22766240 DOI: 10.1016/j.ygcen.2012.06.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 06/07/2012] [Accepted: 06/22/2012] [Indexed: 01/20/2023]
Abstract
Endothelin (ET)-1 and suppressor of cytokine signaling (SOCS)-3 were respectively found to regulate energy metabolism and hormone signaling in fat cells. Although ET-1 can also regulate the expression of SOCS-3-stimulating hormones, it is still unknown whether ET-1 regulates SOCS-3 gene expression. This study investigated the pathways involved in ET-1's modulation of SOCS-3 gene expression in 3T3-L1 adipocytes. ET-1 upregulated SOCS-3 mRNA and protein expression in dose- and time-dependent manners. The concentration of ET-1 that increased SOCS-3 mRNA levels by 250-400% was ∼100nM with 2-4h of treatment. Treatment with actinomycin D prevented ET-1-stimulated SOCS-3 mRNA expression, suggesting that the effect of ET-1 requires new mRNA synthesis. Pretreatment with the ET type A receptor (ET(A)R) antagonist, BQ-610, but not the ET type B receptor (ET(B)R) antagonist, BQ-788, prevented the stimulatory effect of ET-1 on SOCS-3 gene expression. The specific inhibitors of either MEK1 (U-0126 and PD-98059), JAK (AG-490), JNK (SP-600125), or PI3K (LY-294002 and wortmannin) reduced ET-1-increased levels of SOCS-3 mRNA and respectively inhibited ET-1-stimulated activities of MEK1, JAK, JNK, and PI3K. These results imply that the ET(A)R, ERK, JAK, JNK, and PI3K are functionally necessary for ET-1's stimulation of SOCS-3 gene expression. Moreover, ET-1 was observed to upregulate expressions of SOCS-1, -2, -3, -4, -5, and -6 mRNAs, but not SOCS-7 or cytokine-inducible SH2-containing protein-1 mRNAs. This suggests that ET-1 selectively affects particular types of SOCS family members. Changes in SOCS gene expressions induced by ET-1 may help explain the mechanism by which ET-1 modulates hormone signaling of adipocytes.
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Affiliation(s)
- Hsin-Huei Chang
- Department of Life Sciences, National Central University, Jhongli, Taoyuan, Taiwan
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35
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Suppression of the interferon and NF-κB responses by severe fever with thrombocytopenia syndrome virus. J Virol 2012; 86:8388-401. [PMID: 22623799 DOI: 10.1128/jvi.00612-12] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, multiorgan dysfunction, and a high fatality rate between 12 and 30%. It is caused by SFTS virus (SFTSV), a novel Phlebovirus in family Bunyaviridae. Although the viral pathogenesis remains largely unknown, hemopoietic cells appear to be targeted by the virus. In this study we report that human monocytes were susceptible to SFTSV, which replicated efficiently, as shown by an immunofluorescence assay and real-time reverse transcription-PCR. We examined host responses in the infected cells and found that antiviral interferon (IFN) and IFN-inducible proteins were induced upon infection. However, our data also indicated that downregulation of key molecules such as mitochondrial antiviral signaling protein (MAVS) or weakened activation of interferon regulatory factor (IRF) and NF-κB responses may contribute to a restricted innate immunity against the infection. NSs, the nonstructural protein encoded by the S segment, suppressed the beta interferon (IFN-β) and NF-κB promoter activities, although NF-κB activation appears to facilitate SFTSV replication in human monocytes. NSs was found to be associated with TBK1 and may inhibit the activation of downstream IRF and NF-κB signaling through this interaction. Interestingly, we demonstrated that the nucleoprotein (N), also encoded by the S segment, exhibited a suppressive effect on the activation of IFN-β and NF-κB signaling as well. Infected monocytes, mainly intact and free of apoptosis, may likely be implicated in persistent viral infection, spreading the virus to the circulation and causing primary viremia. Our findings provide the first evidence in dissecting the host responses in monocytes and understanding viral pathogenesis in humans infected with a novel deadly Bunyavirus.
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36
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Wang X, Liu Q, Ihsan A, Huang L, Dai M, Hao H, Cheng G, Liu Z, Wang Y, Yuan Z. JAK/STAT Pathway Plays a Critical Role in the Proinflammatory Gene Expression and Apoptosis of RAW264.7 Cells Induced by Trichothecenes as DON and T-2 Toxin. Toxicol Sci 2012; 127:412-24. [DOI: 10.1093/toxsci/kfs106] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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37
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Lopez-Rodriguez R, Trapero-Marugan M, Borque MJ, Roman M, Hernandez-Bartolome A, Rodriguez-Muñoz Y, Martin-Vilchez S, Abad-Santos F, Muñoz de Rueda P, Vidal-Castiñeira JR, Rodrigo L, Salmeron J, Moreno-Otero R, Sanz-Cameno P. Genetic variants of interferon-stimulated genes and IL-28B as host prognostic factors of response to combination treatment for chronic hepatitis C. Clin Pharmacol Ther 2011; 90:712-21. [PMID: 21993426 DOI: 10.1038/clpt.2011.189] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Chronic hepatitis C (CHC) is a worldwide health problem that is highly related to liver fibrosis, cirrhosis, and hepatocellular carcinoma. The achievement of response to the current standard of care-pegylated interferon plus ribavirin-has recently been described to be associated with single-nucleotide polymorphisms (SNPs) near the IL-28B gene. Additionally, baseline expression levels of genes involved in interferon (IFN)-stimulated genes (ISGs) have been found to be related to treatment outcome. In the present study, 285 patients were genotyped for 63 SNPs within genes of the IFN signaling pathway (IPGs) and ISGs. Two ISG polymorphisms-OASL rs12819210 (odds ratio (OR)=2.1, P=0.03) and IFIT1 rs304478 (OR=2.5, P=0.01)-were found to be independent predictive factors of sustained virological response (SVR) after adjusting for other clinical covariates. Furthermore, the predictive value of IL-28B SNP was notably improved by simultaneous genotyping of rs12819210 and rs304478, particularly in patients with the worst prognosis (viral genotype 1, area under the curve (AUC)=0.74). In conclusion, ISG SNPs could constitute a valuable tool for individualizing CHC therapy.
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Affiliation(s)
- R Lopez-Rodriguez
- Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitario Princesa, Universidad Autónoma de Madrid, Madrid, Spain
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38
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Nara H, Onoda T, Rahman M, Araki A, Juliana FM, Tanaka N, Asao H. WSB-1, a novel IL-21 receptor binding molecule, enhances the maturation of IL-21 receptor. Cell Immunol 2011; 269:54-9. [PMID: 21463857 DOI: 10.1016/j.cellimm.2011.03.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2010] [Revised: 12/06/2010] [Accepted: 03/13/2011] [Indexed: 12/13/2022]
Abstract
Interleukin-21 (IL-21) is a pleiotropic cytokine that regulates T-cell, B-cell, NK-cell, and myeloid-cell functions. IL-21 binds with its cognate receptor complex, which consists of the IL-21 receptor (IL-21R) and the common gamma chain. We identified a novel IL-21R-binding molecule, WSB-1, which contains WD-40 repeats and a SOCS-box domain. WSB-1 associates with the middle part of intracytoplasmic region of IL-21R and enhances the maturation of IL-21R from N-linked glycosylated form to fully glycosylated mature form. Furthermore, WSB-1 moderates IL-21R degradation. Taken together, our present study suggests that WSB-1 has a role in the tuning of the maturation and degradation of IL-21R.
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Affiliation(s)
- Hidetoshi Nara
- Department of Immunology, Yamagata University, Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
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39
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Lisowski P, Juszczak GR, Goscik J, Wieczorek M, Zwierzchowski L, Swiergiel AH. Effect of chronic mild stress on hippocampal transcriptome in mice selected for high and low stress-induced analgesia and displaying different emotional behaviors. Eur Neuropsychopharmacol 2011; 21:45-62. [PMID: 20961740 DOI: 10.1016/j.euroneuro.2010.08.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2010] [Revised: 08/13/2010] [Accepted: 08/18/2010] [Indexed: 12/18/2022]
Abstract
There is increasing evidence that mood disorders may derive from the impact of environmental pressure on genetically susceptible individuals. Stress-induced hippocampal plasticity has been implicated in depression. We studied hippocampal transcriptomes in strains of mice that display high (HA) and low (LA) swim stress-induced analgesia and that differ in emotional behaviors and responses to different classes of antidepressants. Chronic mild stress (CMS) affected expression of a number of genes common for both strains. CMS also produced strain specific changes in expression suggesting that hippocampal responses to stress depend on genotype. Considerably larger number of genes, biological processes, molecular functions, biochemical pathways, and gene networks were affected by CMS in LA than in HA mice. The results suggest that potential drug targets against detrimental effects of stress include glutamate transporters, and cholinergic, cholecystokinin (CCK), glucocorticoids, and thyroid hormones receptors. Furthermore, some biological processes evoked by stress and different between the strains, such as apoptosis, neurogenesis and chromatin modifications, may be responsible for the long-term, irreversible effects of stress and suggest a role for epigenetic regulation of mood related stress responses.
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Affiliation(s)
- Pawel Lisowski
- Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Poland
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40
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A genetic perspective on coeliac disease. Trends Mol Med 2010; 16:537-50. [PMID: 20947431 DOI: 10.1016/j.molmed.2010.09.003] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Revised: 09/05/2010] [Accepted: 09/08/2010] [Indexed: 02/06/2023]
Abstract
Coeliac disease is an inflammatory disorder of the small intestine with an autoimmune component and strong heritability. Genetic studies have confirmed strong association to HLA and identified 39 nonHLA risk genes, mostly immune-related. Over 50% of the disease-associated single nucleotide polymorphisms are correlated with gene expression. Most of the coeliac disease-associated regions are shared with other immune-related diseases, as well as with metabolic, haematological or neurological traits, or cancer. We review recent progress in the genetics of coeliac disease and describe the pathways these genes are in, the functional consequences of the associated markers on gene expression and the genes shared between coeliac disease and other traits.
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Milet J, Nuel G, Watier L, Courtin D, Slaoui Y, Senghor P, Migot-Nabias F, Gaye O, Garcia A. Genome wide linkage study, using a 250K SNP map, of Plasmodium falciparum infection and mild malaria attack in a Senegalese population. PLoS One 2010; 5:e11616. [PMID: 20657648 PMCID: PMC2904701 DOI: 10.1371/journal.pone.0011616] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Accepted: 06/06/2010] [Indexed: 12/22/2022] Open
Abstract
Multiple factors are involved in the variability of host's response to P. falciparum infection, like the intensity and seasonality of malaria transmission, the virulence of parasite and host characteristics like age or genetic make-up. Although admitted nowadays, the involvement of host genetic factors remains unclear. Discordant results exist, even concerning the best-known malaria resistance genes that determine the structure or function of red blood cells. Here we report on a genome-wide linkage and association study for P. falciparum infection intensity and mild malaria attack among a Senegalese population of children and young adults from 2 to 18 years old. A high density single nucleotide polymorphisms (SNP) genome scan (Affimetrix GeneChip Human Mapping 250K-nsp) was performed for 626 individuals: i.e. 249 parents and 377 children out of the 504 ones included in the follow-up. The population belongs to a unique ethnic group and was closely followed-up during 3 years. Genome-wide linkage analyses were performed on four clinical and parasitological phenotypes and association analyses using the family based association tests (FBAT) method were carried out in regions previously linked to malaria phenotypes in literature and in the regions for which we identified a linkage peak. Analyses revealed three strongly suggestive evidences for linkage: between mild malaria attack and both the 6p25.1 and the 12q22 regions (empirical p-value = 5×10−5 and 9×10−5 respectively), and between the 20p11q11 region and the prevalence of parasite density in asymptomatic children (empirical p-value = 1.5×10−4). Family based association analysis pointed out one significant association between the intensity of plasmodial infection and a polymorphism located in ARHGAP26 gene in the 5q31–q33 region (p-value = 3.7×10−5). This study identified three candidate regions, two of them containing genes that could point out new pathways implicated in the response to malaria infection. Furthermore, we detected one gene associated with malaria infection in the 5q31–q33 region.
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Affiliation(s)
- Jacqueline Milet
- UMR 216 - Mère et Enfant face aux infections tropicales, Institut de Recherche pour le Développement (IRD), Paris, France
- Laboratoire de parasitologie, Université Paris Descartes, Paris, France
| | - Gregory Nuel
- UMR CNRS 8145 - Mathématiques Appliquées Paris 5 (MAP5), Université Paris Descartes, Paris, France
| | - Laurence Watier
- U 657, Institut National de la Santé et de la Recherche Médicale (INSERM), Garches, France
| | - David Courtin
- UMR 216 - Mère et Enfant face aux infections tropicales, Institut de Recherche pour le Développement (IRD), Paris, France
- Laboratoire de parasitologie, Université Paris Descartes, Paris, France
| | - Yousri Slaoui
- UMR CNRS 8145 - Mathématiques Appliquées Paris 5 (MAP5), Université Paris Descartes, Paris, France
| | - Paul Senghor
- Laboratoire de Parasitologie et de Mycologie, Département de Biologie et d'Explorations fonctionnelles, Faculté de Médecine, Université Cheikh Anta Diop, Dakar, Sénégal
| | - Florence Migot-Nabias
- UMR 216 - Mère et Enfant face aux infections tropicales, Institut de Recherche pour le Développement (IRD), Paris, France
- Laboratoire de parasitologie, Université Paris Descartes, Paris, France
| | - Oumar Gaye
- Laboratoire de Parasitologie et de Mycologie, Département de Biologie et d'Explorations fonctionnelles, Faculté de Médecine, Université Cheikh Anta Diop, Dakar, Sénégal
| | - André Garcia
- UMR 216 - Mère et Enfant face aux infections tropicales, Institut de Recherche pour le Développement (IRD), Paris, France
- Laboratoire de parasitologie, Université Paris Descartes, Paris, France
- * E-mail:
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Nara H, Onoda T, Rahman M, Araki A, Juliana FM, Tanaka N, Asao H. Regulation of interleukin-21 receptor expression and its signal transduction by WSB-2. Biochem Biophys Res Commun 2010; 392:171-7. [DOI: 10.1016/j.bbrc.2010.01.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Accepted: 01/04/2010] [Indexed: 11/16/2022]
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43
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Frizzell KM, Gamble MJ, Berrocal JG, Zhang T, Krishnakumar R, Cen Y, Sauve AA, Kraus WL. Global analysis of transcriptional regulation by poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in MCF-7 human breast cancer cells. J Biol Chem 2009; 284:33926-38. [PMID: 19812418 DOI: 10.1074/jbc.m109.023879] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG) are enzymes that modify target proteins by the addition and removal, respectively, of ADP-ribose polymers. Although a role for PARP-1 in gene regulation has been well established, the role of PARG is less clear. To investigate how PARP-1 and PARG coordinately regulate global patterns of gene expression, we used short hairpin RNAs to stably knock down PARP-1 or PARG in MCF-7 cells followed by expression microarray analyses. Correlation analyses showed that the majority of genes affected by the knockdown of one factor were similarly affected by the knockdown of the other factor. The most robustly regulated common genes were enriched for stress-response and metabolic functions. In chromatin immunoprecipitation assays, PARP-1 and PARG localized to the promoters of positively and negatively regulated target genes. The levels of chromatin-bound PARG at a given promoter generally correlated with the levels of PARP-1 across the subset of promoters tested. For about half of the genes tested, the binding of PARP-1 at the promoter was dependent on the binding of PARG. Experiments using stable re-expression of short hairpin RNA-resistant catalytic mutants showed that PARP-1 and PARG enzymatic activities are required for some, but not all, target genes. Collectively, our results indicate that PARP-1 and PARG, nuclear enzymes with opposing enzymatic activities, localize to target promoters and act in a similar, rather than antagonistic, manner to regulate gene expression.
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Affiliation(s)
- Kristine M Frizzell
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA
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44
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Park KK, Hu Y, Muhling J, Pollett MA, Dallimore EJ, Turnley AM, Cui Q, Harvey AR. Cytokine-induced SOCS expression is inhibited by cAMP analogue: impact on regeneration in injured retina. Mol Cell Neurosci 2009; 41:313-24. [PMID: 19394427 DOI: 10.1016/j.mcn.2009.04.002] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2008] [Revised: 03/25/2009] [Accepted: 04/17/2009] [Indexed: 12/09/2022] Open
Abstract
Injured adult retinal ganglion cells (RGCs) regrow axons into peripheral nerve (PN) grafted onto cut optic nerve. Survival and regeneration of RGCs is increased by intraocular injections of ciliary neurotrophic factor (CNTF) and axonal regeneration is further enhanced by co-injection of a cyclic AMP analogue (CPT-cAMP). Based on these data, and because cytokine signaling is negatively regulated by suppressor of cytokine signaling (SOCS) proteins, we set out to determine whether CNTF injections increase retinal SOCS expression and whether any changes are attenuated by co-injection with CPT-cAMP. Using quantitative PCR we found increased SOCS1, SOCS2 and SOCS3 mRNA levels at various times after a single CNTF injection. Expression remained high for many days. SOCS protein levels were also increased. In situ hybridization revealed that RGCs express SOCS3 mRNA, and SOCS expression in cultured RGCs was increased by CNTF. Co-injection of CPT-cAMP reduced CNTF induced expression of SOCS1 and SOCS3 mRNA and decreased SOCS3 protein expression. CNTF injection also transiently increased retinal leukemia inhibitory factor (LIF) expression, an effect that was also moderated by CPT-cAMP. We propose that, along with known reparative effects of elevated cAMP on neurons, reducing SOCS upregulation may be an additional way in which cyclic nucleotides augment cytokine-induced regenerative responses in the injured CNS.
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Affiliation(s)
- Kevin K Park
- School of Anatomy and Human Biology M309, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA 6009, Australia
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HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFN{gamma} signaling. Blood 2009; 113:5192-201. [PMID: 19279332 DOI: 10.1182/blood-2008-10-183525] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
HIV infection remains a worldwide threat. HIV-1 transactivator protein Tat is one of the retroviral proteins identified as a key immunomodulator in AIDS pathogenesis. Although the primary function of Tat is to regulate HIV-1 replication in the infected cell, it also dysregulates cytokine production resulting in perturbation of the host immune response and enhancement of the retrovirus survival. Because interferon-gamma (IFNgamma) is a pleiotropic cytokine with potent antiviral and immunoregulatory effects, we investigated whether Tat interferes with the IFNgamma signal transduction in primary monocytes. We demonstrated that Tat impaired the IFNgamma-receptor signaling pathway at the level of STAT1 activation, possibly via Tat-dependent induction of suppressor of cytokine signaling-2 (SOCS-2) activity. We delineated the inhibitory role of SOCS-2 in IFNgamma signaling pathway by overexpression of exogenous SOCS-2 in HEK293 cell. The results showed that SOCS-2 suppressed the IFNgamma-activated STAT1 phosphorylation and consequent IFNgamma-regulated transcription of specific genes. To confirm the role of SOCS2 in the Tat-induced process, we demonstrated that SOCS-2 siRNA in human blood monocytes abrogated the Tat-dependent inhibition of IFNgamma signaling. Our data suggested a possible mechanism implicating the role of SOCS-2 in mediating HIV-1-induced immune evasion and dysregulation of IFNgamma signaling in primary human monocytes.
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Abstract
Cytokines are powerful mediators of the immune response that, following initial release by components of the innate system, drive effector functions as well as stimulate the additional arms of the response. Their individual functions are diverse, with stimulatory and inhibitory actions, with the resultant systemic immune response a summation of these actions. The frequently opposing effects of cytokines determine that the blockade of one results in the functional augmentation of the other. Thus, the differential regulation of cytokines profoundly influences the character of the immune response. The suppressor of cytokine signaling proteins are a family of molecules pivotal to this critical regulation. In this review, we will discuss their structural components and functions and our understanding of their impact on the systemic immune response.
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Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia 2008; 22:686-707. [DOI: 10.1038/leu.2008.26] [Citation(s) in RCA: 293] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Miyanaka Y, Ueno Y, Tanaka S, Yoshioka K, Hatakeyama T, Shimamoto M, Sumii M, Chayama K. Clinical significance of mucosal suppressors of cytokine signaling 3 expression in ulcerative colitis. World J Gastroenterol 2007; 13:2939-44. [PMID: 17589943 PMCID: PMC4171145 DOI: 10.3748/wjg.v13.i21.2939] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the clinical significance of mucosal expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 in human ulcerative colitis (UC).
METHODS: Biopsy specimens for histological analysis and mRNA detection were obtained endoscopically from the rectum of 62 patients with UC (36 men; age 13-76 years). The patients were classified endoscopically according to Matts’ grade (grade 1 to 4). Expression of SOCS1 and SOCS3 mRNAs was quantified in samples by competitive reverse transcription-polymerase chain reaction (RT-PCR). GAPDH was used as an internal control for efficiency of RT-PCR and amount of RNA.
RESULTS: SOCS3 mRNA expression was significantly higher in inflamed mucosa of UC than in inactive mucosa. The level of expression was well correlated with the degree of both endoscopic and histologic inflammation. Interestingly, among the patients in remission, the group with relatively low expression of SOCS3 showed a higher rate of remission maintenance over a 12-mo period. In contrast, SOCS1 mRNA was expressed in both inflamed and non-inflamed colonic mucosa and was not correlated with the activity of colonic mucosa or prognosis.
CONCLUSION: These observations suggest that increased expression of mucosal SOCS3, but not of SOCS1, may play a critical role in the development of the colonic inflammation of UC.
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Affiliation(s)
- Yoshihiro Miyanaka
- Department of Medicine and Molecular Science, Hiroshima University, Hiroshima, Japan
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Lv W, Liu Z, Jin H, Yu X, Zhang L, Zhang L. Three-dimensional structure of HIV-1 VIF constructed by comparative modeling and the function characterization analyzed by molecular dynamics simulation. Org Biomol Chem 2007; 5:617-26. [PMID: 17285170 DOI: 10.1039/b612050d] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
VIF is one of the six accessory proteins of HIV-1. It has been shown to be necessary for the survival of HIV-1 in the human body and for the retention of viral infectivity. It is strongly expected that a new therapeutic strategy against HIV-1 infection could be realized by blocking the biological pathway to VIF. In this paper, a three-dimensional model of VIF was constructed by comparative modeling based on two templates, VHL and NarL, which were used to construct the C-terminal domain and N-terminal domain of VIF, respectively. A model of the VIF-ElonginB-ElonginC complex was constructed, and molecular dynamics simulations were used to investigate the interactions between VIF and ElonginB-ElonginC. Mutagenesis was used to identify the function of some conserved residues in the putative SOCS-box. The results showed that the mutations of the critical residues led to the disruption of the interactions between VIF and ElonginB-ElonginC, consistent with experimental observations. These novel models of VIF and its complex has therefore provided structural information for investigating the function of VIF at the molecular level.
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Affiliation(s)
- Wei Lv
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China
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Nishigaki K, Hanson C, Ohashi T, Spadaccini A, Ruscetti S. Erythroblast transformation by the friend spleen focus-forming virus is associated with a block in erythropoietin-induced STAT1 phosphorylation and DNA binding and correlates with high expression of the hematopoietic phosphatase SHP-1. J Virol 2006; 80:5678-85. [PMID: 16731906 PMCID: PMC1472600 DOI: 10.1128/jvi.02651-05] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Infection of mice with Friend spleen focus-forming virus (SFFV) results in a multistage erythroleukemia. In the first stage, the SFFV envelope glycoprotein interacts with the erythropoietin receptor and a short form of the receptor tyrosine kinase sf-Stk, resulting in constitutive activation of signal transducing molecules and the development of erythropoietin (Epo)-independent erythroid hyperplasia and polycythemia. The second stage results from the outgrowth of a rare virus-infected erythroid cell that expresses nonphysiological levels of the myeloid transcription factor PU.1. These cells exhibit a differentiation block and can be grown as murine erythroleukemia (MEL) cell lines. In this study, we examined SFFV MEL cells to determine whether their transformed phenotype was associated with a block in the activation of any Epo signal-transducing molecules. Our studies indicate that Epo- or SFFV-induced activation of STAT1/3 DNA binding activity is blocked in SFFV MEL cells. The block is at the level of tyrosine phosphorylation of STAT1, although Jak2 phosphorylation is not blocked in these cells. In contrast to Epo, alpha interferon can induce STAT1 phosphorylation and DNA binding in SFFV MEL cells. The SFFV-transformed cells were shown to express elevated levels of the hematopoietic phosphatase SHP-1, and treatment of the cells with a phosphatase inhibitor restored STAT1 tyrosine phosphorylation. MEL cells derived from Friend murine leukemia virus (MuLV) or ME26 MuLV-infected mice, which do not express PU.1, express lower levels of SHP-1 and are not blocked in STAT1/3 DNA-binding activity. Our studies suggest that SFFV-infected erythroid cells become transformed when differentiation signals activated by STAT1/3 are blocked due to high SHP-1 levels induced by inappropriate expression of the PU.1 protein.
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Affiliation(s)
- Kazuo Nishigaki
- Laboratory of Cancer Prevention, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA
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