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Gajjar G, Huggins HP, Kim ES, Huang W, Bonnet FX, Updike DL, Keiper BD. Two eIF4E paralogs occupy separate germ granule messenger ribonucleoproteins that mediate mRNA repression and translational activation. Genetics 2025; 230:iyaf053. [PMID: 40119742 PMCID: PMC12059638 DOI: 10.1093/genetics/iyaf053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/03/2025] [Accepted: 03/10/2025] [Indexed: 03/24/2025] Open
Abstract
We studied translation factor eukaryotic initiation factor 4E (eIF4E) paralogs that regulate germline mRNAs. Translational control of mRNAs is essential for germ cell differentiation and embryogenesis. Messenger ribonucleoprotein complexes assemble on mRNAs in the nucleus, as they exit via perinuclear germ granules, and in the cytoplasm. Bound messenger ribonucleoproteins including eIF4E exert both positive and negative posttranscriptional regulation. In Caenorhabditiselegans, germ granules are surprisingly dynamic messenger ribonucleoprotein condensates that remodel during development. Two eIF4E paralogs (IFE-1 and IFE-3), their cognate eIF4E-interacting proteins, and polyadenylated mRNAs are present in germ granules. Affinity purification of IFE-1 and IFE-3 messenger ribonucleoproteins allowed mass spectrometry and mRNA-Seq to identify other proteins and the mRNAs that populate stable eukaryotic initiation factor 4E complexes. We find translationally repressed mRNAs (e.g. pos-1, mex-3, spn-4, etc.) enriched with IFE-3, but excluded from IFE-1. Identified mRNAs overlap substantially with mRNAs previously described to be IFE-1 dependent for translation. The findings suggest that oocytes and embryos utilize the 2 eukaryotic initiation factor 4E paralogs for opposite purposes on critically regulated germline mRNAs. Sublocalization within adult perinuclear germ granules suggests an architecture in which Vasa/GLH-1, PGL-1, and the IFEs are stratified, which may facilitate sequential remodeling of messenger ribonucleoproteins leaving the nucleus. Biochemical composition of isolated messenger ribonucleoproteins indicates opposing yet cooperative roles for the 2 eukaryotic initiation factor 4E paralogs. We propose that the IFEs accompany controlled mRNAs in the repressed or activated state during transit to the cytoplasm. Copurification of IFE-1 with IFE-3 suggests they may interact to move repressed mRNAs to ribosomes.
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Affiliation(s)
- Gita Gajjar
- Department of Biochemistry and Molecular Biology, Brody School of Medicine at East Carolina University, East Carolina University, Greenville, NC 27834, USA
| | - Hayden P Huggins
- Department of Biochemistry and Molecular Biology, Brody School of Medicine at East Carolina University, East Carolina University, Greenville, NC 27834, USA
| | - Eun Suk Kim
- Department of Biochemistry and Molecular Biology, Brody School of Medicine at East Carolina University, East Carolina University, Greenville, NC 27834, USA
| | - Weihua Huang
- Department of Pathology and Laboratory Medicine, Brody School of Medicine at East Carolina University, East Carolina University, Greenville, NC 27834, USA
| | - Frederic X Bonnet
- Katherine W. Davis Center for Regenerative Biology and Aging, Mount Desert Island Biological Laboratory, Bar Harbor, ME 04609, USA
| | - Dustin L Updike
- Katherine W. Davis Center for Regenerative Biology and Aging, Mount Desert Island Biological Laboratory, Bar Harbor, ME 04609, USA
| | - Brett D Keiper
- Department of Biochemistry and Molecular Biology, Brody School of Medicine at East Carolina University, East Carolina University, Greenville, NC 27834, USA
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2
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Adams-Brown SE, Reid KZ. The Central FacilitaTOR: Coordinating Transcription and Translation in Eukaryotes. Int J Mol Sci 2025; 26:2845. [PMID: 40243440 PMCID: PMC11989106 DOI: 10.3390/ijms26072845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
One of the biggest challenges to eukaryotic gene expression is coordinating transcription in the nucleus and protein synthesis in the cytoplasm. However, little is known about how these major steps in gene expression are connected. The Target of Rapamycin (TOR) signaling pathway is crucial in connecting these critical phases of gene expression. Highly conserved among eukaryotic cells, TOR regulates growth, metabolism, and cellular equilibrium in response to changes in nutrients, energy levels, and stress conditions. This review examines the extensive role of TOR in gene expression regulation. We highlight how TOR is involved in phosphorylation, remodeling chromatin structure, and managing the factors that facilitate transcription and translation. Furthermore, the critical functions of TOR extend to processing RNA, assembling RNA-protein complexes, and managing their export from the nucleus, demonstrating its wide-reaching impact throughout the cell. Our discussion emphasizes the integral roles of TOR in bridging the processes of transcription and translation and explores how it orchestrates these complex cellular processes.
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Affiliation(s)
| | - Ke Zhang Reid
- Department of Biology, Wake Forest University, Winston-Salem, NC 27109, USA
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3
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Wang R, Roiuk M, Storer F, Teleman AA, Amoyel M. Signals from the niche promote distinct modes of translation initiation to control stem cell differentiation and renewal in the Drosophila testis. PLoS Biol 2025; 23:e3003049. [PMID: 40067813 DOI: 10.1371/journal.pbio.3003049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/20/2025] [Accepted: 02/03/2025] [Indexed: 03/22/2025] Open
Abstract
Stem cells have the unique ability among adult cells to give rise to cells of different identities. To do so, they must change gene expression in response to environmental signals. Much work has focused on how transcription is regulated to achieve these changes; however, in many cell types, transcripts and proteins correlate poorly, indicating that post-transcriptional regulation is important. To assess how translational control can influence stem cell fate, we use the Drosophila testis as a model. The testis niche secretes a ligand to activate the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in two stem cell populations, germline stem cells (GSCs) and somatic cyst stem cells (CySCs). We find that global translation rates are high in CySCs and decrease during differentiation, and that JAK/STAT signaling regulates translation. To determine how translation was regulated, we knocked down translation initiation factors and found that the cap binding complex, eIF4F, is dispensable in differentiating cells, but is specifically required in CySCs for self-renewal, acting downstream of JAK/STAT activity. Moreover, we identify eIF3d1 as a key regulator of CySC fate, and show that two eIF3d1 residues subject to regulation by phosphorylation are critical to maintain CySC self-renewal. We further show that Casein Kinase II (CkII), which controls eIF3d1 phosphorylation, influences the binding of eIF3d and eIF4F in mammalian cells, and that CkII expression is sufficient to restore CySC function in the absence of JAK/STAT. We propose a model in which niche signals regulate a specific translation programme in which only some mRNAs are translated. The mechanism we identify allows stem cells to switch between modes of translation, adding a layer of regulation on top of transcription and providing cells with the ability to rapidly change gene expression upon receiving external stimuli.
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Affiliation(s)
- Ruoxu Wang
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
| | - Mykola Roiuk
- Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Heidelberg University, Heidelberg, Germany
| | - Freya Storer
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
| | - Aurelio A Teleman
- Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Heidelberg University, Heidelberg, Germany
| | - Marc Amoyel
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
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4
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Zhu Y, Yang P, Ren T, Chen Z, Tian H, Wang M, Zhang C. Integrated metabolomics and transcriptomics reveal the potential of hydroxy-alpha-sanshool in alleviating insulin resistance. Mol Med 2025; 31:76. [PMID: 39984861 PMCID: PMC11846303 DOI: 10.1186/s10020-025-01129-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 02/12/2025] [Indexed: 02/23/2025] Open
Abstract
Hydroxy-alpha-sanshool (HAS) has attracted attention because of its various biological activities, such as hypoglycemic, hypolipidemic, and antioxidant activities. In this study, we investigated the effects of HAS on insulin resistance (IR) and its mechanism. HAS reduced fasting blood glucose (FBG), promoted insulin (INS) secretion, significantly decreased levels of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP-1), and increased the IL-2 level in serum of IR model mice. HAS regulated the mRNA levels of protein kinase B (Akt), B-cell lymphoma extra-large (Bcl-xL), stearoyl-CoA desaturase-1 (SCD1), nuclear factor kappa B (NF-κB), and eukaryotic translation initiation factor 4E (eIF4E). Additionally, differentially abundant metabolites in IR model mice treated with HAS were involved in these signaling pathways including prion disease, choline metabolism in cancer, regulation of lipolysis in adipocytes and the pentose phosphate pathway and positively regulated betaine abundance. In conclusion, HAS activated the phosphatidylinositol-3 kinase (PI3K)/Akt insulin and NF-κB signaling pathways to maintain glucose homeostasis and regulate IR.
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Affiliation(s)
- Yuping Zhu
- School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Pan Yang
- School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Tingyuan Ren
- College of Brewing and Food Engineering, Guizhou University, Guiyang, 550025, China
| | - Zhuqi Chen
- School of Clinical Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Huanhuan Tian
- School of Clinical Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Mingfen Wang
- School of Clinical Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Chunlin Zhang
- School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China.
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5
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Amiri M, Mahmood N, Tahmasebi S, Sonenberg N. eIF4F-mediated dysregulation of mRNA translation in cancer. RNA (NEW YORK, N.Y.) 2025; 31:416-428. [PMID: 39809544 PMCID: PMC11874970 DOI: 10.1261/rna.080340.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025]
Abstract
Messenger RNA (mRNA) translational control plays a pivotal role in regulating cellular proteostasis under physiological and pathological conditions. Dysregulated mRNA translation is pervasive in cancer, in which protein synthesis is elevated to support accelerated cell growth and proliferation. Consequently, targeting the mRNA translation machinery has emerged as a therapeutic strategy to treat cancer. In this Perspective, we summarize the current knowledge of translation dysregulation in cancer, with emphasis on the eukaryotic translation initiation factor 4F complex. We outline recent endeavors to apply this knowledge to develop novel treatment strategies to combat cancer.
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Affiliation(s)
- Mehdi Amiri
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
| | - Niaz Mahmood
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
| | - Soroush Tahmasebi
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois 60612, USA
| | - Nahum Sonenberg
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
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6
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Zheng G, Yan Z, Zou J, Zou X, Chai K, Zhang G. AR and YAP crosstalk: impacts on therapeutic strategies in prostate cancer. Front Oncol 2025; 15:1520808. [PMID: 39963114 PMCID: PMC11830605 DOI: 10.3389/fonc.2025.1520808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 01/15/2025] [Indexed: 02/20/2025] Open
Abstract
Prostate cancer ranks as one of the most common types of cancer affecting men worldwide, and its progression is shaped by a diverse array of influencing factors. The AR signaling pathway plays a pivotal role in the pathogenesis of prostate cancer. While existing anti-androgen treatments show initial efficacy, they ultimately do not succeed in halting the advancement to CRPC. Recent studies have identified alterations in the Hippo-YAP signaling pathway within prostate cancer, highlighting intricate crosstalk with the AR signaling pathway. In this review, we examine the interactions and underlying mechanisms between AR and YAP, the key molecules in these two signaling pathways. AR regulates the stability and function of YAP by modulating its transcription, translation, and phosphorylation status, while YAP exerts both promotional and inhibitory regulatory effects on AR. Based on these findings, this paper investigates their significant roles in the onset, progression, and therapeutic resistance of prostate cancer, and discusses the clinical potential of YAP in prostate cancer treatment.
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Affiliation(s)
- Guansong Zheng
- First Clinical College, Gannan Medical University, Ganzhou, China
| | - Zhaojie Yan
- First Clinical College, Gannan Medical University, Ganzhou, China
| | - Junrong Zou
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Institute of Urology, Gannan Medical University, Ganzhou, China
- Department of Jiangxi Engineering Technology Research Center of Calculi Prevention, Gannan Medical University, Ganzhou, China
| | - Xiaofeng Zou
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Keqiang Chai
- Department of Urology, Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, China
| | - Guoxi Zhang
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
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7
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De Siqueira MK, Li G, Zhao Y, Wang S, Ahn IS, Tamboline M, Hildreth AD, Larios J, Schcolnik-Cabrera A, Nouhi Z, Zhang Z, Tol MJ, Pandey V, Xu S, O'Sullivan TE, Mack JJ, Tontonoz P, Sallam T, Wohlschlegel JA, Hulea L, Xiao X, Yang X, Villanueva CJ. PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity. Cell Rep 2024; 43:114945. [PMID: 39579770 PMCID: PMC12002411 DOI: 10.1016/j.celrep.2024.114945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 08/14/2024] [Accepted: 10/17/2024] [Indexed: 11/25/2024] Open
Abstract
Adipose tissue regulates energy homeostasis and metabolic function, but its adaptability is impaired in obesity. In this study, we investigate the impact of acute PPARγ agonist treatment in obese mice and find significant transcriptional remodeling of cells in the stromal vascular fraction (SVF). Using single-cell RNA sequencing, we profile the SVF of inguinal and epididymal adipose tissue of obese mice following rosiglitazone treatment and find an induction of ribosomal factors in both progenitor and preadipocyte populations, while expression of ribosomal factors is reduced with obesity. Notably, the expression of a subset of ribosomal factors is directly regulated by PPARγ. Polysome profiling of the epididymal SVF shows that rosiglitazone promotes translational selectivity of mRNAs that encode pathways involved in adipogenesis and lipid metabolism. Inhibition of translation using a eukaryotic translation initiation factor 4A (eIF4A) inhibitor is sufficient in blocking adipogenesis. Our findings shed light on how PPARγ agonists promote adipose tissue plasticity in obesity.
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Affiliation(s)
- Mirian Krystel De Siqueira
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Gaoyan Li
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yutian Zhao
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Siqi Wang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China
| | - In Sook Ahn
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Mikayla Tamboline
- Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA 90025, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90025, USA
| | - Andrew D Hildreth
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jakeline Larios
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Alejandro Schcolnik-Cabrera
- Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC H1T 2M4, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Zaynab Nouhi
- Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC H1T 2M4, Canada
| | - Zhengyi Zhang
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, Division of Cardiology, Los Angeles, Los Angeles, CA 90095, USA
| | - Marcus J Tol
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Vijaya Pandey
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Shili Xu
- Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA 90025, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90025, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90025, USA
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Julia J Mack
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, Division of Cardiology, Los Angeles, Los Angeles, CA 90095, USA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Tamer Sallam
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, Division of Cardiology, Los Angeles, Los Angeles, CA 90095, USA
| | - James A Wohlschlegel
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Laura Hulea
- Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC H1T 2M4, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada; Département de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Xinshu Xiao
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90025, USA
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90025, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Claudio J Villanueva
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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8
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Yang C, Ali T, Li A, Gao R, Yu X, Li S, Li T. Ketamine reverses chronic corticosterone-induced behavioral deficits and hippocampal synaptic dysfunction by regulating eIF4E/BDNF signaling. Neuropharmacology 2024; 261:110156. [PMID: 39326783 DOI: 10.1016/j.neuropharm.2024.110156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 09/08/2024] [Accepted: 09/10/2024] [Indexed: 09/28/2024]
Abstract
Major depressive disorder (MDD) is a debilitating illness with a high global burden. While Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, offers rapid-acting antidepressant effects, its mechanism remains incompletely understood. Recent research suggests that dysregulation of mRNA translation via the Eukaryotic initiation factor 4E (eIF4E) pathway might contribute to depression pathophysiology. This study investigates whether Ketamine modulates eIF4E signaling in the hippocampus during its antidepressant action. Herein, adult male mice were exposed to Corticosterone, a well-established model for anxiety and depression, followed by behavioral testing and biochemical analysis. Corticosterone induced depression-like symptoms and disrupted synaptic function, including reduced TrkB/BDNF and eIF4E/MNK1/p-eIF2α/ubiquitin signaling. Ketamine treatment reversed these deficits. Notably, the eIF4E/MNK1 signaling inhibitor, eFT508, blocked Ketamine's antidepressant effect, leading to a return of depression-like phenotype and impaired synaptic signaling. Importantly, these effects were reversed by 7,8-DHF, a BDNF/TrkB signaling agonist. Mice treated with Corticosterone, Ketamine, and eFT508 and subsequently exposed to 7,8-DHF displayed normalized depression-like behaviors and restored synaptic signaling, including increased eIF4E phosphorylation and MNK1 expression. Besides, 7,8-DHF treatment enhanced p-eIF2α levels compared to the eFT508-treated group. These findings suggest that Ketamine exerts its antidepressant action through the regulation of the eIF4E/BDNF signaling pathway in the hippocampus. This study provides novel insights into the molecular mechanisms underlying Ketamine's therapeutic effects and highlights the potential of targeting this pathway for future MDD treatment strategies.
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Affiliation(s)
- Canyu Yang
- College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China; Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
| | - Tahir Ali
- State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; Shenzhen Bay Laboratory, Shenzhen 518055, China.
| | - Axiang Li
- College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China; Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
| | - Ruyan Gao
- State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
| | - Xiaoming Yu
- Cancer Center, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, People's Republic of China.
| | - Shupeng Li
- State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; Shenzhen Bay Laboratory, Shenzhen 518055, China; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
| | - Tao Li
- College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China; Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China; NHC Key Laboratory of Forensic Science, College of Forensic Medicine, Xi'an Jiaotong University. Xi'an, Shaanxi, People's Republic of China.
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9
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Lécuyer E, Sauvageau M, Kothe U, Unrau PJ, Damha MJ, Perreault J, Abou Elela S, Bayfield MA, Claycomb JM, Scott MS. Canada's contributions to RNA research: past, present, and future perspectives. Biochem Cell Biol 2024; 102:472-491. [PMID: 39320985 DOI: 10.1139/bcb-2024-0176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2024] Open
Abstract
The field of RNA research has provided profound insights into the basic mechanisms modulating the function and adaption of biological systems. RNA has also been at the center stage in the development of transformative biotechnological and medical applications, perhaps most notably was the advent of mRNA vaccines that were critical in helping humanity through the Covid-19 pandemic. Unbeknownst to many, Canada boasts a diverse community of RNA scientists, spanning multiple disciplines and locations, whose cutting-edge research has established a rich track record of contributions across various aspects of RNA science over many decades. Through this position paper, we seek to highlight key contributions made by Canadian investigators to the RNA field, via both thematic and historical viewpoints. We also discuss initiatives underway to organize and enhance the impact of the Canadian RNA research community, particularly focusing on the creation of the not-for-profit organization RNA Canada ARN. Considering the strategic importance of RNA research in biology and medicine, and its considerable potential to help address major challenges facing humanity, sustained support of this sector will be critical to help Canadian scientists play key roles in the ongoing RNA revolution and the many benefits this could bring about to Canada.
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Affiliation(s)
- Eric Lécuyer
- Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada
- Département de Biochimie et de Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada
- Division of Experimental Medicine, McGill University, Montréal, QC, Canada
| | - Martin Sauvageau
- Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada
- Département de Biochimie et de Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada
- Department of Biochemistry, McGill University, Montréal, QC, Canada
| | - Ute Kothe
- Department of Chemistry, University of Manitoba, Winnipeg, MB, Canada
| | - Peter J Unrau
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - Masad J Damha
- Department of Chemistry, McGill University, Montréal, QC, Canada
| | - Jonathan Perreault
- Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique (INRS), Laval, QC, Canada
| | - Sherif Abou Elela
- Département de Microbiologie et Infectiologie, Université de Sherbrooke, Sherbrooke, QC, Canada
| | | | - Julie M Claycomb
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Michelle S Scott
- Département de Biochimie et de Génomique Fonctionnelle, Université de Sherbrooke, Sherbrooke, QC, Canada
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10
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Sehrawat U. Exploiting Translation Machinery for Cancer Therapy: Translation Factors as Promising Targets. Int J Mol Sci 2024; 25:10835. [PMID: 39409166 PMCID: PMC11477148 DOI: 10.3390/ijms251910835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/26/2024] [Accepted: 10/02/2024] [Indexed: 10/20/2024] Open
Abstract
Eukaryotic protein translation has slowly gained the scientific community's attention for its advanced and powerful therapeutic potential. However, recent technical developments in studying ribosomes and global translation have revolutionized our understanding of this complex multistep process. These developments have improved and deepened the current knowledge of mRNA translation, sparking excitement and new possibilities in this field. Translation factors are crucial for maintaining protein synthesis homeostasis. Since actively proliferating cancer cells depend on protein synthesis, dysregulated protein translation is central to tumorigenesis. Translation factors and their abnormal expressions directly affect multiple oncogenes and tumor suppressors. Recently, small molecules have been used to target translation factors, resulting in translation inhibition in a gene-specific manner, opening the door for developing translation inhibitors that can lead to novel chemotherapeutic drugs for treating multiple cancer types caused by dysregulated translation machinery. This review comprehensively summarizes the involvement of translation factors in tumor progression and oncogenesis. Also, it sheds light on the evolution of translation factors as novel drug targets for developing future therapeutic drugs for treating cancer.
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Affiliation(s)
- Urmila Sehrawat
- Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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11
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Wang P, Li Z, Kim SH, Xu H, Huang H, Yang C, Snape A, Choi JH, Bermudez S, Boivin MN, Ferry N, Karamchandani J, Nagar B, Sonenberg N. PPM1G dephosphorylates eIF4E in control of mRNA translation and cell proliferation. Life Sci Alliance 2024; 7:e202402755. [PMID: 39111820 PMCID: PMC11306785 DOI: 10.26508/lsa.202402755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024] Open
Abstract
The mRNA 5'cap-binding eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in the control of mRNA translation in health and disease. One mechanism of regulation of eIF4E activity is via phosphorylation of eIF4E by MNK kinases, which promotes the translation of a subset of mRNAs encoding pro-tumorigenic proteins. Work on eIF4E phosphatases has been paltry. Here, we show that PPM1G is the phosphatase that dephosphorylates eIF4E. We describe the eIF4E-binding motif in PPM1G that is similar to 4E-binding proteins (4E-BPs). We demonstrate that PPM1G inhibits cell proliferation by targeting phospho-eIF4E-dependent mRNA translation.
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Affiliation(s)
- Peng Wang
- Department of Biochemistry and Goodman Cancer Institute, McGill University, Montreal, Canada
- Clinical Biological Imaging and Genetic (C-BIG) Repository, Montreal Neurological Institute-Hospital, Montreal, Canada
| | - Zixian Li
- Department of Biochemistry, Francesco Bellini Life Sciences Building, McGill University, Montreal, Canada
| | - Sung-Hoon Kim
- Department of Biochemistry and Goodman Cancer Institute, McGill University, Montreal, Canada
| | - Haijin Xu
- Department of Physiology, McIntyre Medical Sciences Building, McGill University, Montreal, Canada
| | - Hao Huang
- Department of Biochemistry and Goodman Cancer Institute, McGill University, Montreal, Canada
| | - Chutong Yang
- Department of Biochemistry and Goodman Cancer Institute, McGill University, Montreal, Canada
| | - Abby Snape
- Department of Biochemistry and Goodman Cancer Institute, McGill University, Montreal, Canada
| | - Jung-Hyun Choi
- Department of Biochemistry and Goodman Cancer Institute, McGill University, Montreal, Canada
| | - Sara Bermudez
- Department of Biochemistry and Goodman Cancer Institute, McGill University, Montreal, Canada
| | - Marie-Noelle Boivin
- Clinical Biological Imaging and Genetic (C-BIG) Repository, Montreal Neurological Institute-Hospital, Montreal, Canada
| | - Nicolas Ferry
- Clinical Biological Imaging and Genetic (C-BIG) Repository, Montreal Neurological Institute-Hospital, Montreal, Canada
| | - Jason Karamchandani
- Clinical Biological Imaging and Genetic (C-BIG) Repository, Montreal Neurological Institute-Hospital, Montreal, Canada
| | - Bhushan Nagar
- Department of Biochemistry, Francesco Bellini Life Sciences Building, McGill University, Montreal, Canada
| | - Nahum Sonenberg
- Department of Biochemistry and Goodman Cancer Institute, McGill University, Montreal, Canada
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12
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Levy T, Voeltzke K, Hruby L, Alasad K, Bas Z, Snaebjörnsson M, Marciano R, Scharov K, Planque M, Vriens K, Christen S, Funk CM, Hassiepen C, Kahler A, Heider B, Picard D, Lim JKM, Stefanski A, Bendrin K, Vargas-Toscano A, Kahlert UD, Stühler K, Remke M, Elkabets M, Grünewald TGP, Reichert AS, Fendt SM, Schulze A, Reifenberger G, Rotblat B, Leprivier G. mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism. Nat Commun 2024; 15:4083. [PMID: 38744825 PMCID: PMC11094136 DOI: 10.1038/s41467-024-48386-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 04/26/2024] [Indexed: 05/16/2024] Open
Abstract
Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.
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Affiliation(s)
- Tal Levy
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Kai Voeltzke
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Laura Hruby
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Khawla Alasad
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Zuelal Bas
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Marteinn Snaebjörnsson
- Biochemistry and Molecular Biology, Theodor-Boveri-Institute, 97074, Würzburg, Germany
- Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Ran Marciano
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Katerina Scharov
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Mélanie Planque
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, 3000, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000, Leuven, Belgium
| | - Kim Vriens
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, 3000, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000, Leuven, Belgium
| | - Stefan Christen
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, 3000, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000, Leuven, Belgium
| | - Cornelius M Funk
- Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
- Hopp Children's Cancer Center (KiTZ), 69120, Heidelberg, Germany
| | - Christina Hassiepen
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Alisa Kahler
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Beate Heider
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Daniel Picard
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
- German cancer consortium (DKTK) partner site Essen/Düsseldorf, 40225, Düsseldorf, Germany
| | - Jonathan K M Lim
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Anja Stefanski
- Molecular Proteomics Laboratory, Biomedical Research Center (BMFZ), Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
| | - Katja Bendrin
- Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Andres Vargas-Toscano
- Clinic for Neurosurgery, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13125, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, 13353, Berlin, Germany
| | - Ulf D Kahlert
- Molecular and Experimental Surgery, University Clinic for General-, Visceral, Vascular- and Transplantation Surgery, Faculty of Medicine and University Medicine, Otto-von-Guericke-University, 39120, Magdeburg, Germany
| | - Kai Stühler
- Molecular Proteomics Laboratory, Biomedical Research Center (BMFZ), Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
| | - Marc Remke
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
- German cancer consortium (DKTK) partner site Essen/Düsseldorf, 40225, Düsseldorf, Germany
| | - Moshe Elkabets
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Thomas G P Grünewald
- Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
- Hopp Children's Cancer Center (KiTZ), 69120, Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, 69120, Heidelberg, Germany
| | - Andreas S Reichert
- Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
| | - Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, 3000, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000, Leuven, Belgium
| | - Almut Schulze
- Biochemistry and Molecular Biology, Theodor-Boveri-Institute, 97074, Würzburg, Germany
- Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Guido Reifenberger
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany
- German cancer consortium (DKTK) partner site Essen/Düsseldorf, 40225, Düsseldorf, Germany
| | - Barak Rotblat
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
| | - Gabriel Leprivier
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany.
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13
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Cui X, Cao Q, Li F, Jing J, Liu Z, Yang X, Schwartz GJ, Yu L, Shi H, Shi H, Xue B. The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis. JCI Insight 2024; 9:e164771. [PMID: 38713533 PMCID: PMC11382888 DOI: 10.1172/jci.insight.164771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 05/01/2024] [Indexed: 05/09/2024] Open
Abstract
Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Here we discover that histone methyltransferase suppressor of variegation 4-20 homolog 2 (Suv420h2) expression parallels that of Ucp1 in brown and beige adipocytes and that Suv420h2 knockdown significantly reduces - whereas Suv420h2 overexpression significantly increases - Ucp1 levels in brown adipocytes. Suv420h2 knockout (H2KO) mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study shows that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4e-bp1) promoter, leading to downregulated expression of 4e-bp1, a negative regulator of the translation initiation complex. This in turn upregulates PGC1α protein levels, and this upregulation is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.
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Affiliation(s)
- Xin Cui
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Qiang Cao
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Fenfen Li
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Jia Jing
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Zhixue Liu
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Xiaosong Yang
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Gary J Schwartz
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Liqing Yu
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Huidong Shi
- Georgia Cancer Center and
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Hang Shi
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Bingzhong Xue
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
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14
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Ashraf D, Khan MR, Dawson TM, Dawson VL. Protein Translation in the Pathogenesis of Parkinson's Disease. Int J Mol Sci 2024; 25:2393. [PMID: 38397070 PMCID: PMC10888601 DOI: 10.3390/ijms25042393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/15/2024] [Accepted: 02/17/2024] [Indexed: 02/25/2024] Open
Abstract
In recent years, research into Parkinson's disease and similar neurodegenerative disorders has increasingly suggested that these conditions are synonymous with failures in proteostasis. However, the spotlight of this research has remained firmly focused on the tail end of proteostasis, primarily aggregation, misfolding, and degradation, with protein translation being comparatively overlooked. Now, there is an increasing body of evidence supporting a potential role for translation in the pathogenesis of PD, and its dysregulation is already established in other similar neurodegenerative conditions. In this paper, we consider how altered protein translation fits into the broader picture of PD pathogenesis, working hand in hand to compound the stress placed on neurons, until this becomes irrecoverable. We will also consider molecular players of interest, recent evidence that suggests that aggregates may directly influence translation in PD progression, and the implications for the role of protein translation in our development of clinically useful diagnostics and therapeutics.
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Affiliation(s)
- Daniyal Ashraf
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (D.A.); (M.R.K.)
- School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Box 111, Cambridge CB2 0SP, UK
| | - Mohammed Repon Khan
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (D.A.); (M.R.K.)
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA
| | - Ted M. Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (D.A.); (M.R.K.)
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Valina L. Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (D.A.); (M.R.K.)
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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15
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Eliseeva IA, Buyan AI, Smolin EA, Kaliadzenka KS, Popov S, Kulakovskiy IV, Lyabin DN. Y-Box-Binding Proteins Have a Dual Impact on Cellular Translation. Int J Mol Sci 2024; 25:1736. [PMID: 38339016 PMCID: PMC10855678 DOI: 10.3390/ijms25031736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Y-box-binding proteins (YB proteins) are multifunctional DNA- and RNA-binding proteins that play an important role in the regulation of gene expression. The high homology of their cold shock domains and the similarity between their long, unstructured C-terminal domains suggest that Y-box-binding proteins may have similar functions in a cell. Here, we consider the functional interchangeability of the somatic YB proteins YB-1 and YB-3. RNA-seq and Ribo-seq are used to track changes in the mRNA abundance or mRNA translation in HEK293T cells solely expressing YB-1, YB-3, or neither of them. We show that YB proteins have a dual effect on translation. Although the expression of YB proteins stimulates global translation, YB-1 and YB-3 inhibit the translation of their direct CLIP-identified mRNA targets. The impact of YB-1 and YB-3 on the translation of their mRNA targets is similar, which suggests that they can substitute each other in inhibiting the translation of their mRNA targets in HEK293T cells.
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Affiliation(s)
- Irina A. Eliseeva
- Institute of Protein Research, Russian Academy of Sciences, Pushchino 142290, Russia; (I.A.E.); (A.I.B.); (E.A.S.); (K.S.K.); (I.V.K.)
| | - Andrey I. Buyan
- Institute of Protein Research, Russian Academy of Sciences, Pushchino 142290, Russia; (I.A.E.); (A.I.B.); (E.A.S.); (K.S.K.); (I.V.K.)
| | - Egor A. Smolin
- Institute of Protein Research, Russian Academy of Sciences, Pushchino 142290, Russia; (I.A.E.); (A.I.B.); (E.A.S.); (K.S.K.); (I.V.K.)
| | - Karina S. Kaliadzenka
- Institute of Protein Research, Russian Academy of Sciences, Pushchino 142290, Russia; (I.A.E.); (A.I.B.); (E.A.S.); (K.S.K.); (I.V.K.)
| | - Sergey Popov
- Endocrinology Research Center, Moscow 117036, Russia;
| | - Ivan V. Kulakovskiy
- Institute of Protein Research, Russian Academy of Sciences, Pushchino 142290, Russia; (I.A.E.); (A.I.B.); (E.A.S.); (K.S.K.); (I.V.K.)
| | - Dmitry N. Lyabin
- Institute of Protein Research, Russian Academy of Sciences, Pushchino 142290, Russia; (I.A.E.); (A.I.B.); (E.A.S.); (K.S.K.); (I.V.K.)
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16
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Murthy MHS, Jasbi P, Lowe W, Kumar L, Olaosebikan M, Roger L, Yang J, Lewinski N, Daniels N, Cowen L, Klein-Seetharaman J. Insulin signaling and pharmacology in humans and in corals. PeerJ 2024; 12:e16804. [PMID: 38313028 PMCID: PMC10838073 DOI: 10.7717/peerj.16804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 12/27/2023] [Indexed: 02/06/2024] Open
Abstract
Once thought to be a unique capability of the Langerhans islets in the pancreas of mammals, insulin (INS) signaling is now recognized as an evolutionarily ancient function going back to prokaryotes. INS is ubiquitously present not only in humans but also in unicellular eukaryotes, fungi, worms, and Drosophila. Remote homologue identification also supports the presence of INS and INS receptor in corals where the availability of glucose is largely dependent on the photosynthetic activity of the symbiotic algae. The cnidarian animal host of corals operates together with a 20,000-sized microbiome, in direct analogy to the human gut microbiome. In humans, aberrant INS signaling is the hallmark of metabolic disease, and is thought to play a major role in aging, and age-related diseases, such as Alzheimer's disease. We here would like to argue that a broader view of INS beyond its human homeostasis function may help us understand other organisms, and in turn, studying those non-model organisms may enable a novel view of the human INS signaling system. To this end, we here review INS signaling from a new angle, by drawing analogies between humans and corals at the molecular level.
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Affiliation(s)
| | - Paniz Jasbi
- School of Molecular Sciences, Arizona State University, Phoenix, AZ, USA
| | - Whitney Lowe
- Departments of Chemistry & Physics, Colorado School of Mines, Golden, CO, United States
| | - Lokender Kumar
- Departments of Chemistry & Physics, Colorado School of Mines, Golden, CO, United States
| | | | - Liza Roger
- School of Molecular Sciences, Arizona State University, Phoenix, AZ, USA
- School of Ocean Futures, Arizona State University, Tempe, AZ, United States of America
| | - Jinkyu Yang
- Department of Aeronautics & Astronautics, University of Washington, Seattle, WA, USA
| | - Nastassja Lewinski
- Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Noah Daniels
- Department of Computer Science, University of Rhode Island, Kingston, RI, USA
| | - Lenore Cowen
- Department of Computer Science, Tufts University, Medford, MA, USA
| | - Judith Klein-Seetharaman
- School of Molecular Sciences, Arizona State University, Phoenix, AZ, USA
- Departments of Chemistry & Physics, Colorado School of Mines, Golden, CO, United States
- College of Health Solutions, Arizona State University, Phoenix, AZ, United States
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17
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Cencic R, Im YK, Naineni SK, Moustafa-Kamal M, Jovanovic P, Sabourin V, Annis MG, Robert F, Schmeing TM, Koromilas A, Paquet M, Teodoro JG, Huang S, Siegel PM, Topisirovic I, Ursini-Siegel J, Pelletier J. A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer. Proc Natl Acad Sci U S A 2024; 121:e2318093121. [PMID: 38232291 PMCID: PMC10823175 DOI: 10.1073/pnas.2318093121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 12/15/2023] [Indexed: 01/19/2024] Open
Abstract
In this study, we aimed to address the current limitations of therapies for macro-metastatic triple-negative breast cancer (TNBC) and provide a therapeutic lead that overcomes the high degree of heterogeneity associated with this disease. Specifically, we focused on well-documented but clinically underexploited cancer-fueling perturbations in mRNA translation as a potential therapeutic vulnerability. We therefore developed an orally bioavailable rocaglate-based molecule, MG-002, which hinders ribosome recruitment and scanning via unscheduled and non-productive RNA clamping by the eukaryotic translation initiation factor (eIF) 4A RNA helicase. We demonstrate that MG-002 potently inhibits mRNA translation and primary TNBC tumor growth without causing overt toxicity in mice. Importantly, given that metastatic spread is a major cause of mortality in TNBC, we show that MG-002 attenuates metastasis in pre-clinical models. We report on MG-002, a rocaglate that shows superior properties relative to existing eIF4A inhibitors in pre-clinical models. Our study also paves the way for future clinical trials exploring the potential of MG-002 in TNBC and other oncological indications.
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Affiliation(s)
- Regina Cencic
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
| | - Young K. Im
- Lady Davis Institute for Medical Research, Montreal, QCH3T 1E2, Canada
| | - Sai Kiran Naineni
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
| | - Mohamed Moustafa-Kamal
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
| | - Predrag Jovanovic
- Lady Davis Institute for Medical Research, Montreal, QCH3T 1E2, Canada
- Division of Experimental Medicine, McGill University, Montreal, QCH4A 3J1, Canada
| | - Valerie Sabourin
- Lady Davis Institute for Medical Research, Montreal, QCH3T 1E2, Canada
| | - Matthew G. Annis
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
| | - Francis Robert
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
| | - T. Martin Schmeing
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
| | - Antonis Koromilas
- Lady Davis Institute for Medical Research, Montreal, QCH3T 1E2, Canada
- Division of Experimental Medicine, McGill University, Montreal, QCH4A 3J1, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QCH4A 3T2, Canada
| | - Marilène Paquet
- Département de pathologie et de microbiologie, Faculté de médecine vétérinaire, Université de Montréal, Montréal, QCH3C 3J7, Canada
| | - Jose G. Teodoro
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
| | - Sidong Huang
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
| | - Peter M. Siegel
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
- Division of Experimental Medicine, McGill University, Montreal, QCH4A 3J1, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QCH4A 3T2, Canada
- Department of Medicine, McGill University, Montreal, QCH4A 3J1, Canada
| | - Ivan Topisirovic
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Lady Davis Institute for Medical Research, Montreal, QCH3T 1E2, Canada
- Division of Experimental Medicine, McGill University, Montreal, QCH4A 3J1, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QCH4A 3T2, Canada
| | - Josie Ursini-Siegel
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Lady Davis Institute for Medical Research, Montreal, QCH3T 1E2, Canada
- Division of Experimental Medicine, McGill University, Montreal, QCH4A 3J1, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QCH4A 3T2, Canada
| | - Jerry Pelletier
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QCH3A 1A3, Canada
- Division of Experimental Medicine, McGill University, Montreal, QCH4A 3J1, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QCH4A 3T2, Canada
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18
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Yu J, Woo Y, Kim H, An S, Park SK, Jang SK. FMRP Enhances the Translation of 4EBP2 mRNA during Neuronal Differentiation. Int J Mol Sci 2023; 24:16319. [PMID: 38003508 PMCID: PMC10671300 DOI: 10.3390/ijms242216319] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/08/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
FMRP is a multifunctional protein encoded by the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1). The inactivation of the FMR1 gene results in fragile X syndrome (FXS), a serious neurodevelopmental disorder. FMRP deficiency causes abnormal neurite outgrowth, which is likely to lead to abnormal learning and memory capabilities. However, the mechanism of FMRP in modulating neuronal development remains unknown. We found that FMRP enhances the translation of 4EBP2, a neuron-specific form of 4EBPs that inactivates eIF4E by inhibiting the interaction between eIF4E and eIF4G. Depletion of 4EBP2 results in abnormal neurite outgrowth. Moreover, the impairment of neurite outgrowth upon FMRP depletion was overcome by the ectopic expression of 4EBP2. These results suggest that FMRP controls neuronal development by enhancing 4EBP2 expression at the translational level. In addition, treatment with 4EGI-1, a chemical that blocks eIF4E activity, restored neurite length in FMRP-depleted and 4EBP2-depleted cells. In conclusion, we discovered that 4EBP2 functions as a key downstream regulator of FMRP activity in neuronal development and that FMRP represses eIF4E activity by enhancing 4EBP2 translation.
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Affiliation(s)
| | | | | | | | - Sang Ki Park
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Gyeongsangbuk, Republic of Korea; (J.Y.); (Y.W.); (H.K.); (S.A.)
| | - Sung Key Jang
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Gyeongsangbuk, Republic of Korea; (J.Y.); (Y.W.); (H.K.); (S.A.)
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19
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Langer HT, Taylor SR, Ahmed M, Perrier T, Ahmed T, Goncalves MD. The proteasome regulates body weight and systemic nutrient metabolism during fasting. Am J Physiol Endocrinol Metab 2023; 325:E500-E512. [PMID: 37672249 PMCID: PMC10864006 DOI: 10.1152/ajpendo.00069.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 08/30/2023] [Accepted: 08/30/2023] [Indexed: 09/07/2023]
Abstract
The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway are the primary means of degradation in mammalian tissues. We sought to determine the individual contribution of the UPS and autophagy to tissue catabolism during fasting. Mice were overnight fasted for 15 h before regaining food access ("Fed" group, n = 6) or continuing to fast ("Fast" group, n = 7) for 3 h. In addition, to investigate the effects of autophagy on systemic metabolism and tissue degradation, one group of mice was fasted for 18 h and treated with chloroquine ("Fast + CLQ" group, n = 7) and a fourth group of mice was treated with bortezomib ("Fast + Bort" group, n = 7) to assess the contribution of the UPS. Body weight, tissue weight, circulating hormones and metabolites, intracellular signaling pathways, and protein synthesis were investigated. Fasting induced the loss of body weight, liver mass, and white adipose tissue in the Fast and the Fast + CLQ group, whereas the Fast + Bort group maintained tissue and body weight. Fasting reduced glucose and increased β hydroxybutyrate in the circulation of all mice. Both changes were most profound in the Fast + Bort group compared with the other fasting conditions. Molecular signaling indicated a successful inhibition of hepatic UPS with bortezomib and an upregulation of the PI3K/AKT/mTOR pathway. The latter was further supported by an increase in hepatic protein synthesis with bortezomib. Inhibition of the UPS through bortezomib blocks body weight loss and tissue catabolism during an acute overnight fast in mice. The effects were likely mediated through a combined effect of the drug on biomolecule degradation and synthesis.NEW & NOTEWORTHY Bortezomib treatment prevents tissue and body weight loss during fasting. The loss of proteasome activity with bortezomib exacerbates fasting-induced ketogenesis. During fasting, bortezomib increases AMPK and PI3K/AKT signaling in the liver, which promotes protein synthesis.
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Affiliation(s)
- Henning Tim Langer
- Department of Medicine, Weill Cornell Medicine, New York, New York, United States
| | - Samuel R Taylor
- Department of Medicine, Weill Cornell Medicine, New York, New York, United States
| | - Mujmmail Ahmed
- Department of Medicine, Weill Cornell Medicine, New York, New York, United States
| | - Tiffany Perrier
- Department of Medicine, Weill Cornell Medicine, New York, New York, United States
| | - Tanvir Ahmed
- Department of Medicine, Weill Cornell Medicine, New York, New York, United States
| | - Marcus D Goncalves
- Department of Medicine, Weill Cornell Medicine, New York, New York, United States
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20
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Zhang NN, Ban YJ, Wang YJ, He SY, Qi PP, Bi T, Ma YF, Dong YX, Guo B, Weng J, Li HL, Tang L, Zhang JQ. Virtual screening of novel mTOR inhibitors for the potential treatment of human colorectal cancer. Bioorg Chem 2023; 140:106781. [PMID: 37597440 DOI: 10.1016/j.bioorg.2023.106781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 08/04/2023] [Accepted: 08/08/2023] [Indexed: 08/21/2023]
Abstract
The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 μM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 μM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 μM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.
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Affiliation(s)
- Na-Na Zhang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 550025, China
| | - Yu-Juan Ban
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 550025, China
| | - Yu-Jie Wang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 550025, China
| | - Si-Yu He
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 550025, China
| | - Pan-Pan Qi
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 550025, China
| | - Ting Bi
- The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Yi-Fei Ma
- The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Yong-Xi Dong
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 550025, China
| | - Bing Guo
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang 550025, China
| | - Jiang Weng
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Hong-Liang Li
- School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming 650091, China
| | - Lei Tang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 550025, China
| | - Ji-Quan Zhang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 550025, China.
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21
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Ricciardi-Jorge T, da Rocha EL, Gonzalez-Kozlova E, Rodrigues-Luiz GF, Ferguson BJ, Sweeney T, Irigoyen N, Mansur DS. PKR-mediated stress response enhances dengue and Zika virus replication. mBio 2023; 14:e0093423. [PMID: 37732809 PMCID: PMC10653888 DOI: 10.1128/mbio.00934-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/01/2023] [Indexed: 09/22/2023] Open
Abstract
IMPORTANCE One of the fundamental features that make viruses intracellular parasites is the necessity to use cellular translational machinery. Hence, this is a crucial checkpoint for controlling infections. Here, we show that dengue and Zika viruses, responsible for nearly 400 million infections every year worldwide, explore such control for optimal replication. Using immunocompetent cells, we demonstrate that arrest of protein translations happens after sensing of dsRNA and that the information required to avoid this blocking is contained in viral 5'-UTR. Our work, therefore, suggests that the non-canonical translation described for these viruses is engaged when the intracellular stress response is activated.
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Affiliation(s)
- Taissa Ricciardi-Jorge
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
- The Pirbright Institute, Woking, United Kingdom
| | - Edroaldo Lummertz da Rocha
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
| | - Edgar Gonzalez-Kozlova
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
- Icahn School of Medicine, New York, USA
| | - Gabriela Flavia Rodrigues-Luiz
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
| | - Brian J. Ferguson
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | | | - Nerea Irigoyen
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - Daniel Santos Mansur
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
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22
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Białobrzewski MK, Klepka BP, Michaś A, Cieplak-Rotowska MK, Staszałek Z, Niedźwiecka A. Diversity of hydrodynamic radii of intrinsically disordered proteins. EUROPEAN BIOPHYSICS JOURNAL : EBJ 2023; 52:607-618. [PMID: 37831084 PMCID: PMC10618399 DOI: 10.1007/s00249-023-01683-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/08/2023] [Accepted: 09/06/2023] [Indexed: 10/14/2023]
Abstract
Intrinsically disordered proteins (IDPs) form an important class of biomolecules regulating biological processes in higher organisms. The lack of a fixed spatial structure facilitates them to perform their regulatory functions and allows the efficiency of biochemical reactions to be controlled by temperature and the cellular environment. From the biophysical point of view, IDPs are biopolymers with a broad configuration state space and their actual conformation depends on non-covalent interactions of its amino acid side chain groups at given temperature and chemical conditions. Thus, the hydrodynamic radius (Rh) of an IDP of a given polymer length (N) is a sequence- and environment-dependent variable. We have reviewed the literature values of hydrodynamic radii of IDPs determined experimentally by SEC, AUC, PFG NMR, DLS, and FCS, and complement them with our FCS results obtained for a series of protein fragments involved in the regulation of human gene expression. The data collected herein show that the values of hydrodynamic radii of IDPs can span the full space between the folded globular and denatured proteins in the Rh(N) diagram.
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Affiliation(s)
- Michał K Białobrzewski
- Laboratory of Biological Physics, Institute of Physics, Polish Academy of Sciences, Aleja Lotnikow 32/46, PL-02668, Warsaw, Poland
| | - Barbara P Klepka
- Laboratory of Biological Physics, Institute of Physics, Polish Academy of Sciences, Aleja Lotnikow 32/46, PL-02668, Warsaw, Poland
| | - Agnieszka Michaś
- Laboratory of Biological Physics, Institute of Physics, Polish Academy of Sciences, Aleja Lotnikow 32/46, PL-02668, Warsaw, Poland
| | - Maja K Cieplak-Rotowska
- Laboratory of Biological Physics, Institute of Physics, Polish Academy of Sciences, Aleja Lotnikow 32/46, PL-02668, Warsaw, Poland
- Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Pasteura 5, PL-02093, Warsaw, Poland
- The International Institute of Molecular Mechanisms and Machines, Polish Academy of Sciences, Flisa 6, PL-02247, Warsaw, Poland
| | - Zuzanna Staszałek
- Laboratory of Biological Physics, Institute of Physics, Polish Academy of Sciences, Aleja Lotnikow 32/46, PL-02668, Warsaw, Poland
| | - Anna Niedźwiecka
- Laboratory of Biological Physics, Institute of Physics, Polish Academy of Sciences, Aleja Lotnikow 32/46, PL-02668, Warsaw, Poland.
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23
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Santos JL, Petsidou E, Saraogi P, Bartsch U, Gerber AP, Seibt J. Effect of Acute Enriched Environment Exposure on Brain Oscillations and Activation of the Translation Initiation Factor 4E-BPs at Synapses across Wakefulness and Sleep in Rats. Cells 2023; 12:2320. [PMID: 37759542 PMCID: PMC10528220 DOI: 10.3390/cells12182320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Brain plasticity is induced by learning during wakefulness and is consolidated during sleep. But the molecular mechanisms involved are poorly understood and their relation to experience-dependent changes in brain activity remains to be clarified. Localised mRNA translation is important for the structural changes at synapses supporting brain plasticity consolidation. The translation mTOR pathway, via phosphorylation of 4E-BPs, is known to be activate during sleep and contributes to brain plasticity, but whether this activation is specific to synapses is not known. We investigated this question using acute exposure of rats to an enriched environment (EE). We measured brain activity with EEGs and 4E-BP phosphorylation at cortical and cerebellar synapses with Western blot analyses. Sleep significantly increased the conversion of 4E-BPs to their hyperphosphorylated forms at synapses, especially after EE exposure. EE exposure increased oscillations in the alpha band during active exploration and in the theta-to-beta (4-30 Hz) range, as well as spindle density, during NREM sleep. Theta activity during exploration and NREM spindle frequency predicted changes in 4E-BP hyperphosphorylation at synapses. Hence, our results suggest a functional link between EEG and molecular markers of plasticity across wakefulness and sleep.
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Affiliation(s)
- José Lucas Santos
- Surrey Sleep Research Centre, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XP, UK; (J.L.S.); (U.B.)
- Department of Microbial Sciences, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK;
- Department of Physiology, Development and Neuroscience, University of Cambridge, Physiological Laboratory, Downing Street, Cambridge CB2 3EG, UK
| | - Evlalia Petsidou
- Undergraduate Programme in Biological Science, University of Surrey, Guildford GU2 7XH, UK
- Postgraduate Programme in Neuroscience (MSc), Cyprus Institute of Neurology and Genetics, Iroon Avenue 6, Egkomi 2371, Cyprus
| | - Pallavi Saraogi
- Undergraduate Programme in Biological Science, University of Surrey, Guildford GU2 7XH, UK
| | - Ullrich Bartsch
- Surrey Sleep Research Centre, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XP, UK; (J.L.S.); (U.B.)
- UK Dementia Research Institute, Care Research & Technology Centre at Imperial College London and University of Surrey, Guildford GU2 7XH, UK
| | - André P. Gerber
- Department of Microbial Sciences, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK;
| | - Julie Seibt
- Surrey Sleep Research Centre, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XP, UK; (J.L.S.); (U.B.)
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24
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Mir SA, Dar A, Alshehri SA, Wahab S, Hamid L, Almoyad MAA, Ali T, Bader GN. Exploring the mTOR Signalling Pathway and Its Inhibitory Scope in Cancer. Pharmaceuticals (Basel) 2023; 16:1004. [PMID: 37513916 PMCID: PMC10384750 DOI: 10.3390/ph16071004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Mechanistic target of rapamycin (mTOR) is a protein kinase that regulates cellular growth, development, survival, and metabolism through integration of diverse extracellular and intracellular stimuli. Additionally, mTOR is involved in interplay of signalling pathways that regulate apoptosis and autophagy. In cells, mTOR is assembled into two complexes, mTORC1 and mTORC2. While mTORC1 is regulated by energy consumption, protein intake, mechanical stimuli, and growth factors, mTORC2 is regulated by insulin-like growth factor-1 receptor (IGF-1R), and epidermal growth factor receptor (EGFR). mTOR signalling pathways are considered the hallmark in cancer due to their dysregulation in approximately 70% of cancers. Through downstream regulators, ribosomal protein S6 kinase β-1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), mTORC1 influences various anabolic and catabolic processes in the cell. In recent years, several mTOR inhibitors have been developed with the aim of treating different cancers. In this review, we will explore the current developments in the mTOR signalling pathway and its importance for being targeted by various inhibitors in anti-cancer therapeutics.
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Affiliation(s)
- Suhail Ahmad Mir
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Ashraf Dar
- Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Saad Ali Alshehri
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Laraibah Hamid
- Department of Zoology, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Mohammad Ali Abdullah Almoyad
- Department of Basic Medical Sciences, College of Applied Medical Sciences in Khamis Mushyt, King Khalid University, Abha 61412, Saudi Arabia
| | - Tabasum Ali
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Ghulam Nabi Bader
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
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25
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Livingston NM, Kwon J, Valera O, Saba JA, Sinha NK, Reddy P, Nelson B, Wolfe C, Ha T, Green R, Liu J, Wu B. Bursting translation on single mRNAs in live cells. Mol Cell 2023; 83:2276-2289.e11. [PMID: 37329884 PMCID: PMC10330622 DOI: 10.1016/j.molcel.2023.05.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 03/27/2023] [Accepted: 05/14/2023] [Indexed: 06/19/2023]
Abstract
Stochasticity has emerged as a mechanism of gene regulation. Much of this so-called "noise" has been attributed to bursting transcription. Although bursting transcription has been studied extensively, the role of stochasticity in translation has not been fully investigated due to the lack of enabling imaging technology. In this study, we developed techniques to track single mRNAs and their translation in live cells for hours, allowing the measurement of previously uncharacterized translation dynamics. We applied genetic and pharmacological perturbations to control translation kinetics and found that, like transcription, translation is not a constitutive process but instead cycles between inactive and active states, or "bursts." However, unlike transcription, which is largely frequency-modulated, complex structures in the 5'-untranslated region alter burst amplitudes. Bursting frequency can be controlled through cap-proximal sequences and trans-acting factors such as eIF4F. We coupled single-molecule imaging with stochastic modeling to quantitatively determine the kinetic parameters of translational bursting.
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Affiliation(s)
- Nathan M Livingston
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jiwoong Kwon
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Oliver Valera
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - James A Saba
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Niladri K Sinha
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Pranav Reddy
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Blake Nelson
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Clara Wolfe
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Taekjip Ha
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Rachel Green
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Jian Liu
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
| | - Bin Wu
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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26
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Aria F, Pandey K, Alberini CM. Excessive Protein Accumulation and Impaired Autophagy in the Hippocampus of Angelman Syndrome Modeled in Mice. Biol Psychiatry 2023; 94:68-83. [PMID: 36764852 PMCID: PMC10276539 DOI: 10.1016/j.biopsych.2022.11.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 11/03/2022] [Accepted: 11/18/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Angelman syndrome (AS), a neurodevelopmental disorder caused by abnormalities of the 15q11.2-q13.1 chromosome region, is characterized by impairment of cognitive and motor functions, sleep problems, and seizures. How the genetic defects of AS produce these neurological symptoms is unclear. Mice modeling AS (AS mice) accumulate activity-regulated cytoskeleton-associated protein (ARC/ARG3.1), a neuronal immediate early gene (IEG) critical for synaptic plasticity. This accumulation suggests an altered protein metabolism. METHODS Focusing on the dorsal hippocampus (dHC), a brain region critical for memory formation and cognitive functions, we assessed levels and tissue distribution of IEGs, de novo protein synthesis, and markers of protein synthesis, endosomes, autophagy, and synaptic functions in AS mice at baseline and following learning. We also tested autophagic flux and memory retention following autophagy-promoting treatment. RESULTS AS dHC exhibited accumulation of IEGs ARC, FOS, and EGR1; autophagy proteins MLP3B, SQSTM1, and LAMP1; and reduction of the endosomal protein RAB5A. AS dHC also had increased levels of de novo protein synthesis, impaired autophagic flux with accumulation of autophagosome, and altered synaptic protein levels. Contextual fear conditioning significantly increased levels of IEGs and autophagy proteins, de novo protein synthesis, and autophagic flux in the dHC of normal mice, but not in AS mice. Enhancing autophagy in the dHC alleviated AS-related memory and autophagic flux impairments. CONCLUSIONS A major biological deficit of AS brain is a defective protein metabolism, particularly that dynamically regulated by learning, resulting in stalled autophagy and accumulation of neuronal proteins. Activating autophagy ameliorates AS cognitive impairments and dHC protein accumulation.
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Affiliation(s)
- Francesca Aria
- Center for Neural Science, New York University, New York, New York
| | - Kiran Pandey
- Center for Neural Science, New York University, New York, New York
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Fernandez A, Monsen PJ, Platanias LC, Schiltz GE. Medicinal chemistry approaches to target the MNK-eIF4E axis in cancer. RSC Med Chem 2023; 14:1060-1087. [PMID: 37360400 PMCID: PMC10285747 DOI: 10.1039/d3md00121k] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/08/2023] [Indexed: 06/28/2023] Open
Abstract
Aberrant translation of proteins that promote cell proliferation is an essential factor that defines oncogenic processes and cancer. The process for ribosomal translation of proteins from mRNA requires an essential initiation step which is controlled by the protein eIF4E, which binds the RNA 5'-cap and forms the eIF4F complex that subsequently translates protein. Typically, eIF4E is activated by phosphorylation on Ser209 by MNK1 and MNK2 kinases. Substantial work has shown that eIF4E and MNK1/2 are dysregulated in many cancers and this axis has therefore become an active area of interest for developing new cancer therapeutics. This review summarizes and discusses recent work to develop small molecules that target different steps in the MNK-eIF4E axis as potential cancer therapeutics. The aim of this review is to cover the breadth of different molecular approaches being taken and the medicinal chemistry basis for their optimization and testing as new cancer therapeutics.
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Affiliation(s)
- Ann Fernandez
- Department of Chemistry, Northwestern University Evanston IL 60208 USA
| | - Paige J Monsen
- Department of Chemistry, Northwestern University Evanston IL 60208 USA
| | - Leonidas C Platanias
- Robert H. Lurie Comprehensive Cancer Center Chicago IL 60611 USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago IL 60611 USA
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center Chicago IL 60612 USA
| | - Gary E Schiltz
- Department of Chemistry, Northwestern University Evanston IL 60208 USA
- Robert H. Lurie Comprehensive Cancer Center Chicago IL 60611 USA
- Department of Pharmacology, Northwestern University Feinberg School of Medicine Chicago IL 60611 USA
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Istomine R, Al-Aubodah TA, Alvarez F, Smith JA, Wagner C, Piccirillo CA. The eIF4EBP-eIF4E axis regulates CD4 + T cell differentiation through modulation of T cell activation and metabolism. iScience 2023; 26:106683. [PMID: 37187701 PMCID: PMC10176268 DOI: 10.1016/j.isci.2023.106683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 02/27/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
CD4+ T cells are critical for adaptive immunity, differentiating into distinct effector and regulatory subsets. Although the transcriptional programs underlying their differentiation are known, recent research has highlighted the importance of mRNA translation in determining protein abundance. We previously conducted genome-wide analysis of translation in CD4+ T cells revealing distinct translational signatures distinguishing these subsets, identifying eIF4E as a central differentially translated transcript. As eIF4E is vital for eukaryotic translation, we examined how altered eIF4E activity affected T cell function using mice lacking eIF4E-binding proteins (BP-/-). BP-/- effector T cells showed elevated Th1 responses ex vivo and upon viral challenge with enhanced Th1 differentiation observed in vitro. This was accompanied by increased TCR activation and elevated glycolytic activity. This study highlights how regulating T cell-intrinsic eIF4E activity can influence T cell activation and differentiation, suggesting the eIF4EBP-eIF4E axis as a potential therapeutic target for controlling aberrant T cell responses.
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Affiliation(s)
- Roman Istomine
- Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada
| | - Tho-Alfakar Al-Aubodah
- Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada
| | - Fernando Alvarez
- Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada
| | - Jacob A. Smith
- Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
| | - Carston Wagner
- Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ciriaco A. Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada
- Corresponding author
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29
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Bartish M, Abraham MJ, Gonçalves C, Larsson O, Rolny C, Del Rincón SV. The role of eIF4F-driven mRNA translation in regulating the tumour microenvironment. Nat Rev Cancer 2023; 23:408-425. [PMID: 37142795 DOI: 10.1038/s41568-023-00567-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/27/2023] [Indexed: 05/06/2023]
Abstract
Cells can rapidly adjust their proteomes in dynamic environments by regulating mRNA translation. There is mounting evidence that dysregulation of mRNA translation supports the survival and adaptation of cancer cells, which has stimulated clinical interest in targeting elements of the translation machinery and, in particular, components of the eukaryotic initiation factor 4F (eIF4F) complex such as eIF4E. However, the effect of targeting mRNA translation on infiltrating immune cells and stromal cells in the tumour microenvironment (TME) has, until recently, remained unexplored. In this Perspective article, we discuss how eIF4F-sensitive mRNA translation controls the phenotypes of key non-transformed cells in the TME, with an emphasis on the underlying therapeutic implications of targeting eIF4F in cancer. As eIF4F-targeting agents are in clinical trials, we propose that a broader understanding of their effect on gene expression in the TME will reveal unappreciated therapeutic vulnerabilities that could be used to improve the efficacy of existing cancer therapies.
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Affiliation(s)
- Margarita Bartish
- Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Segal Cancer Center, Lady Davis Institute and Jewish General Hospital, Montreal, QC, Canada
- Science for Life Laboratory, Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Madelyn J Abraham
- Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Segal Cancer Center, Lady Davis Institute and Jewish General Hospital, Montreal, QC, Canada
| | - Christophe Gonçalves
- Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Segal Cancer Center, Lady Davis Institute and Jewish General Hospital, Montreal, QC, Canada
| | - Ola Larsson
- Science for Life Laboratory, Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Charlotte Rolny
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
| | - Sonia V Del Rincón
- Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC, Canada.
- Segal Cancer Center, Lady Davis Institute and Jewish General Hospital, Montreal, QC, Canada.
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Jiang Q, Sherlock DN, Guyader J, Loor JJ. Abundance of Amino Acid Transporters and mTOR Pathway Components in the Gastrointestinal Tract of Lactating Holstein Cows. Animals (Basel) 2023; 13:ani13071189. [PMID: 37048445 PMCID: PMC10093496 DOI: 10.3390/ani13071189] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/25/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023] Open
Abstract
Data from non-ruminants indicate that amino acid (AA) transport into cells can regulate mTOR pathway activity and protein synthesis. Whether mTOR is expressed in the ruminant gastrointestinal tract (GIT) and how it may be related to AA transporters and the AA concentrations in the tissue is unknown. Ruminal papillae and the epithelia of the duodenum, jejunum, and ileum collected at slaughter from eight clinically healthy Holstein in mid-lactation were used. Metabolites and RNA were extracted from tissue for liquid chromatography–mass spectrometry and RT-qPCR analysis. The glycine and asparagine concentrations in the rumen were greater than those in the intestine (p < 0.05), but the concentrations of other AAs were greater in the small intestine than those in the rumen. Among the 20 AAs identified, the concentrations of glutamate, alanine, and glycine were the greatest. The mRNA abundances of AKT1 and MTOR were greater in the small intestine than those in the rumen (p < 0.05). Similarly, the SLC1A1, SLC6A6, SLC7A8, SLC38A1, SLC38A7, and SLC43A2 mRNA abundances were greater (p < 0.05) in the small intestine than those in the rumen. The mRNA abundances of SLC1A5, SLC3A2, and SLC7A5 were greater in the rumen than those in the small intestine (p < 0.05). Overall, the present study provides fundamental data on the relationship between mTOR pathway components and the transport of AAs in different sections of the gastrointestinal tract.
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Affiliation(s)
- Qianming Jiang
- Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA
| | | | - Jessie Guyader
- Evonik Operations GmbH, Hanau-Wolfgang, 63457 Essen, Germany
| | - Juan J. Loor
- Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA
- Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801, USA
- Correspondence:
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31
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Rao TJR, Mao G, Cuffari BJ, Billack B. Dysregulation of the mTOR pathway by mechlorethamine. Toxicology 2023; 486:153434. [PMID: 36708981 PMCID: PMC10266297 DOI: 10.1016/j.tox.2023.153434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 01/21/2023] [Accepted: 01/22/2023] [Indexed: 01/27/2023]
Abstract
Mechlorethamine (HN2) is a derivative of the chemical warfare agent sulfur mustard (SM) and cutaneous exposure to HN2 is associated with dermal-epidermal junction (DEJ) disruption (vesication). The primary purpose of the present study was to investigate the effect of HN2 on the mammalian target of rapamycin (mTOR) signaling pathway using an in vivo mouse ear vesicant model (MEVM). To this end, the ears of male C57BL/ 6 J mice were exposed to a single topical dose of HN2 (100 mM) or vehicle control (DMSO). Mice were then euthanized 30 min, 1 h or 24 h following exposure. Mouse ear skin exposed to HN2 and biopsied 24 h thereafter exhibited increased tissue expression of Raptor, an important member of the mTORC1 complex, relative to vehicle treated samples. HN2 reduced the downstream effectors phospho S6 (Ser 240/244) ribosomal protein and phospho 4E-BP1 (Thr 37/46) of the mTOR pathway in the epidermis at 30 min, 1 h and 24 h following HN2 exposure but not in the dermis. These results support the hypothesis that HN2-mediated cutaneous toxicity involves dysregulation of the mTOR signaling pathway in the epidermis.
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Affiliation(s)
| | - Ganming Mao
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, NY, USA
| | - Benedette J Cuffari
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, NY, USA
| | - Blase Billack
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, NY, USA.
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32
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Therapeutic targeting of eukaryotic initiation factor (eIF) 4E. Biochem Soc Trans 2023; 51:113-124. [PMID: 36661272 DOI: 10.1042/bst20220285] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/06/2023] [Accepted: 01/10/2023] [Indexed: 01/21/2023]
Abstract
Fundamental studies unraveled the role of eukaryotic initiation factor (eIF) 4E in mRNA translation and its control. Under physiological conditions, regulation of translation by eIF4E is essential to cellular homeostasis. Under stress, gene flow information is parsed by eIF4E to support adaptive mechanisms that favor cell survival. Dysregulated eIF4E activity fuels tumor formation and progression and modulates response to therapy. Thus, there has been heightened interest in understanding eIF4E function in controlling gene expression as well as developing strategies to block its activity to treat disease.
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33
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Knowles AA, Campbell SG, Cross NA, Stafford P. Dysregulation of Stress-Induced Translational Control by Porphyromonas gingivalis in Host Cells. Microorganisms 2023; 11:microorganisms11030606. [PMID: 36985180 PMCID: PMC10057856 DOI: 10.3390/microorganisms11030606] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/15/2023] [Accepted: 02/21/2023] [Indexed: 03/04/2023] Open
Abstract
Porphyromonas gingivalis contributes to the chronic oral disease periodontitis, triggering the activation of host inflammatory responses, inducing cellular stresses such as oxidation. During stress, host cells can activate the Integrated Stress Response (ISR), a pathway which determines cellular fate, by either downregulating protein synthesis and initiating a stress–response gene expression program, or by initiating programmed cell death. Recent studies have implicated the ISR within both host antimicrobial defenses and the pathomechanism of certain microbes. In this study, using a combination of immunofluorescence confocal microscopy and immunoblotting, the molecular mechanisms by which P. gingivalis infection alters translation attenuation during oxidative stress-induced activation of the ISR in oral epithelial cells were investigated. P. gingivalis infection alone did not result in ISR activation. In contrast, infection coupled with stress caused differential stress granule formation and composition. Infection heightened stress-induced translational repression independently of core ISR mediators. Heightened translational repression during stress was observed with both P. gingivalis–conditioned media and outer membrane vesicles, implicating a secretory factor in this exacerbated translational repression. The effects of gingipain inhibitors and gingipain-deficient P. gingivalis mutants confirmed these pathogen-specific proteases as the effector of exacerbated translational repression. Gingipains are known to degrade the mammalian target of rapamycin (mTOR) and the findings of this study implicate the gingipain-mTOR axis as the effector of host translational dysregulation during stress.
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Christie M, Igreja C. eIF4E-homologous protein (4EHP): a multifarious cap-binding protein. FEBS J 2023; 290:266-285. [PMID: 34758096 DOI: 10.1111/febs.16275] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/29/2021] [Accepted: 11/09/2021] [Indexed: 02/05/2023]
Abstract
The cap-binding protein 4EHP/eIF4E2 has been a recent object of interest in the field of post-transcriptional gene regulation and translational control. From ribosome-associated quality control, to RNA decay and microRNA-mediated gene silencing, this member of the eIF4E protein family regulates gene expression through numerous pathways. Low in abundance but ubiquitously expressed, 4EHP interacts with different binding partners to form multiple protein complexes that regulate translation in a variety of biological contexts. Documented functions of 4EHP primarily relate to its role as a translational repressor, but recent findings indicate that it might also participate in the activation of translation in specific settings. In this review, we discuss the known functions, properties and mechanisms that involve 4EHP in the control of gene expression. We also discuss our current understanding of how 4EHP processes are regulated in eukaryotic cells, and the diseases implicated with dysregulation of 4EHP-mediated translational control.
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Affiliation(s)
- Mary Christie
- School of Life and Environmental Sciences, The University of Sydney, NSW, Australia
| | - Cátia Igreja
- Department for Integrative Evolutionary Biology, Max Planck Institute for Developmental Biology, Tübingen, Germany
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35
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Kamble VS, Pachpor TA, Khandagale SB, Wagh VV, Khare SP. Translation initiation and dysregulation of initiation factors in rare diseases. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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36
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Scarpin MR, Simmons CH, Brunkard JO. Translating across kingdoms: target of rapamycin promotes protein synthesis through conserved and divergent pathways in plants. JOURNAL OF EXPERIMENTAL BOTANY 2022; 73:7016-7025. [PMID: 35770874 PMCID: PMC9664230 DOI: 10.1093/jxb/erac267] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/16/2022] [Indexed: 06/15/2023]
Abstract
mRNA translation is the growth rate-limiting step in genome expression. Target of rapamycin (TOR) evolved a central regulatory role in eukaryotes as a signaling hub that monitors nutrient availability to maintain homeostasis and promote growth, largely by increasing the rate of translation initiation and protein synthesis. The dynamic pathways engaged by TOR to regulate translation remain debated even in well-studied yeast and mammalian models, however, despite decades of intense investigation. Recent studies have firmly established that TOR also regulates mRNA translation in plants through conserved mechanisms, such as the TOR-LARP1-5'TOP signaling axis, and through pathways specific to plants. Here, we review recent advances in our understanding of the regulation of mRNA translation in plants by TOR.
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Affiliation(s)
- M Regina Scarpin
- Laboratory of Genetics, University of Wisconsin, Madison, WI, USA
- Department of Plant and Microbial Biology, University of California, Berkeley,CA, USA
- Plant Gene Expression Center, USDA Agricultural Research Service, Albany, CA, USA
| | - Carl H Simmons
- Laboratory of Genetics, University of Wisconsin, Madison, WI, USA
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Born LI, Andree T, Frank S, Hübner J, Link S, Langheine M, Charlet A, Esser JS, Brehm R, Moser M. eif4ebp3l-A New Affector of Zebrafish Angiogenesis and Heart Regeneration? Int J Mol Sci 2022; 23:ijms231710075. [PMID: 36077472 PMCID: PMC9456460 DOI: 10.3390/ijms231710075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/29/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
The eukaryotic initiation factor 4E binding protein (4E-BP) family is involved in translational control of cell proliferation and pro-angiogenic factors. The zebrafish eukaryotic initiation factor 4E binding protein 3 like (eif4ebp3l) is a member of the 4E-BPs and responsible for activity-dependent myofibrillogenesis, but whether it affects cardiomyocyte (CM) proliferation or heart regeneration is unclear. We examined eif4ebp3l during zebrafish vascular development and heart regeneration post cryoinjury in adult zebrafish. Using morpholino injections we induced silencing of eif4ebp3l in zebrafish embryos, which led to increased angiogenesis at 94 h post fertilization (hpf). For investigation of eif4ebp3l in cardiac regeneration, zebrafish hearts were subjected to cryoinjury. Regenerating hearts were analyzed at different time points post-cryoinjury for expression of eif4ebp3l by in situ hybridization and showed strongly decreased eif4ebp3l expression in the injured area. We established a transgenic zebrafish strain, which overexpressed eif4ebp3l under the control of a heat-shock dependent promotor. Overexpression of eif4ebp3l during zebrafish heart regeneration caused only macroscopically a reduced amount of fibrin at the site of injury. Overall, these findings demonstrate that silencing of eif4ebp3l has pro-angiogenic properties in zebrafish vascular development and when eif4ebp3l is overexpressed, fibrin deposition tends to be altered in zebrafish cardiac regeneration after cryoinjury.
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Affiliation(s)
- Lisa I. Born
- Department of Cardiology and Angiology, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Institute of Anatomy, University of Veterinary Medicine of Hannover, Foundation, 30173 Hannover, Germany
- Correspondence:
| | - Theresa Andree
- Department of Cardiology and Angiology, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Svenja Frank
- Department of Cardiology and Angiology, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Judith Hübner
- Department of Cardiology and Angiology, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Sandra Link
- Department of Cardiology and Angiology, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Marion Langheine
- Institute of Anatomy, University of Veterinary Medicine of Hannover, Foundation, 30173 Hannover, Germany
| | - Anne Charlet
- Department of Cardiology and Angiology, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Jennifer S. Esser
- Department of Cardiology and Angiology, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Ralph Brehm
- Institute of Anatomy, University of Veterinary Medicine of Hannover, Foundation, 30173 Hannover, Germany
| | - Martin Moser
- Department of Cardiology and Angiology, University Heart Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
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Wang Y, Wu X, Yang K, Liu Q, Jiang B, Yang R, Xiao P, He C. Integrating network pharmacology analysis and pharmacodynamic evaluation for exploring the active components and molecular mechanism of moutan seed coat extract to improve cognitive impairment. Front Pharmacol 2022; 13:952876. [PMID: 36034803 PMCID: PMC9411852 DOI: 10.3389/fphar.2022.952876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
Paeonia suffruticosa (Moutan) is a traditional medicinal plant in China. Its seed coat is rich in resveratrol oligomer, especially suffruticosol B (SB). Previous studies had shown that the seed coat extracts of Paeonia suffruticosa (PSCE) had good cholinesterase inhibitory activity and neuroprotective effect, but the effective dose range was unknown, and the pharmacodynamic components and molecular mechanism of PSCE had not been discussed. The current study aimed to screen the pharmacodynamic components in PSCE and investigate the improvement effect of PSCE and the selected SB on scopolamine-induced cognitive dysfunction in mice and its mechanism. The results of high-throughput sequencing and bioinformatics analysis showed that suffruticosol B (SB) and trans-gnetin H (GH) might be the main active components of PSCE; PSCE might improve cognitive dysfunction through p53, HIF-1, MAPK, and PI3K-Akt signaling pathways, while SB and GH might improve cognitive dysfunction through HIF-1 signaling pathway. SB and GH had good molecular docking activity with the target of HIF-1 signaling pathway. The pharmacodynamic activities of PSCE and SB were further verified by behavioral experiments. PSCE and SB could improve the recognition ability of familiar and new objects and shorten the escape latency in the Morris Water Maze test (PSCE 120 mg∙kg-1, p < 0.05; SB 60 mg∙kg-1, p < 0.01); PSCE and SB could increase Ach and GSH levels, enhance the activities of ChAT, SOD and CAT, decrease the levels of IL-1β, IL-6, and TNF-α, and decrease the activity of AChE. In conclusion, the results indicated that PSCE might exert pharmacodynamic activity through multiple components, targets, and pathways, and SB and GH might be the main active components of PSCE. PSCE and SB might improve cognitive dysfunction by regulating cholinergic, antioxidant, and anti-inflammatory effects. These results indicated that PSCE and SB might be potential anti-AD drug candidates, providing a scientific basis for the development and utilization of Moutan bark.
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O-GlcNAc Modification and Its Role in Diabetic Retinopathy. Metabolites 2022; 12:metabo12080725. [PMID: 36005597 PMCID: PMC9415332 DOI: 10.3390/metabo12080725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
Diabetic retinopathy (DR) is a leading complication in type 1 and type 2 diabetes and has emerged as a significant health problem. Currently, there are no effective therapeutic strategies owing to its inconspicuous early lesions and complex pathological mechanisms. Therefore, the mechanism of molecular pathogenesis requires further elucidation to identify potential targets that can aid in the prevention of DR. As a type of protein translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification is involved in many diseases, and increasing evidence suggests that dysregulated O-GlcNAc modification is associated with DR. The present review discusses O-GlcNAc modification and its molecular mechanisms involved in DR. O-GlcNAc modification might represent a novel alternative therapeutic target for DR in the future.
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Yan D, Hao Q, Chen Y, Li Z, Zhang H, Yuan K, Li R, Li R, Zhao Y, Wang K, Peng H, Zhang D, Chen X, Zhao Y. mTOR-FABP4 signal is activated in brain arteriovenous malformations in humans. J Mol Med (Berl) 2022; 100:1287-1297. [PMID: 35876909 DOI: 10.1007/s00109-022-02237-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 07/05/2022] [Accepted: 07/13/2022] [Indexed: 10/16/2022]
Abstract
Arteriovenous malformations (AVMs) are the most common types of cerebral vascular malformations, which are dynamic lesions with de novo growth potentials. The dysfunction of endothelial cells has been postulated to play a role in the pathogenesis of brain AVMs. mTOR-FABP4 signal enhances the angiogenic responses of endothelial cells and is not activated in the normal cerebral vasculature. Herein, we investigated the hypothesis that the mTOR-FABP4 signal may be activated in brain AVMs. The abundance of molecules in mTOR-FABP4 signal expression was detected by immunohistochemistry and Western blotting; special expressing cells were further characterized by double immunofluorescence using antibodies against various cell-specific markers. Next, several functional assays were performed to analyze the influence of the mTOR-FABP4 signal on proliferation, apoptosis, migration, and vascular tube formation of endothelial cells in human umbilical vein endothelial cells (HUVECs) using rapamycin and L-leucine. The expression of mTOR, p-mTOR, and FABP4 was increased in endothelial cells of human brain AVMs. Endothelial cell mTOR and p-mTOR expression were present in 70% and 55% of brain AVMs, respectively. Moreover, a population of FABP4-positive endothelial cells was detected in 80% of brain AVMs. The mTOR-FABP4 signal was activated and inhibited by L-leucine and rapamycin in HUVECs. The proliferation, apoptosis, migration, and vascular tube formation of endothelial cells could be inhibited by rapamycin. The mTOR-FABP4 signal was activated in human brain AVMs, and the mTOR-FABP4 signal was involved in proliferation, apoptosis, migration, and the vascular tube formation of endothelial cells. Taken together, whether rapamycin has therapeutic potential for treating human brain AVMs is worthy of further study. KEY MESSAGES : We confirmed that the mTOR- FABP4 pathway is activated in human brain arteriovenous malformations. We confirmed that mTOR signaling pathway affects endothelial cell function by regulating proliferation, migration, apoptosis, and tube formation of endothelial cell. Our study can provide theoretical support for mTOR pathway inhibitors in the treatment of human brain arteriovenous malformations.
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Affiliation(s)
- Debin Yan
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qiang Hao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yu Chen
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhipeng Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Haibin Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Kexin Yuan
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Runting Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Ruinan Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yahui Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Ke Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Hao Peng
- Hainan General Hospital, Hainan, China
| | - Dong Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Xiaolin Chen
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Yuanli Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. .,Department of Neurosurgery, Peking University International Hospital, Peking University, Beijing, China. .,China National Clinical Research Center for Neurological Diseases, Beijing, China. .,Stroke Center, Beijing Institute for Brain Disorders, Beijing, China. .,Beijing Key Laboratory of Translation Medicine for Cerebrovascular Disease, Beijing, China. .,Beijing Translational Engineering Enter for 3D Printer in Clinical Neuroscience, Beijing, China.
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Narayan S, Raza A, Mahmud I, Koo N, Garrett TJ, Law ME, Law BK, Sharma AK. Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A. iScience 2022; 25:104518. [PMID: 35754740 PMCID: PMC9218363 DOI: 10.1016/j.isci.2022.104518] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 05/16/2022] [Accepted: 05/30/2022] [Indexed: 12/04/2022] Open
Abstract
The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells.
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Affiliation(s)
- Satya Narayan
- Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610, USA
| | - Asif Raza
- Department of Pharmacology, Penn State University College of Medicine, Penn State Cancer Institute, Hershey, PA 17033, USA
| | - Iqbal Mahmud
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Nayeong Koo
- Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610, USA
| | - Timothy J. Garrett
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Mary E. Law
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA
| | - Brian K. Law
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA
| | - Arun K. Sharma
- Department of Pharmacology, Penn State University College of Medicine, Penn State Cancer Institute, Hershey, PA 17033, USA
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Zheng Z, Xu T, Liu Z, Tian W, Jiang ZH, Zhu GY, Li T, Gao J, Bai LP. Cryptolepine suppresses breast adenocarcinoma via inhibition of HIF-1 mediated glycolysis. Biomed Pharmacother 2022; 153:113319. [PMID: 35753261 DOI: 10.1016/j.biopha.2022.113319] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 11/19/2022] Open
Abstract
As a characteristic transcription factor in solid tumors, hypoxia inducible factor-1 (HIF-1) acts as a master regulator in breast cancer progression. Cryptolepine, as a natural alkaloid, noticeably inhibited HIF-1 transcriptional activity and decreased the protein expression of hypoxia-induced HIF-1α in breast cancer cells. Further study showed that cryptolepine blocked HIF-1-mediated glycolysis and suppressed the expression of multiple glycolysis enzymes, resulting in a decrease in ATP production in hypoxic T47D and 4T1 cells. Meanwhile, cryptolepine displayed potent suppressive effect on tumor growth in a dose-dependent manner. In 4T1 tumor xenografts, cryptolepine reduced HIF-1α protein expression, and thus decreased the levels of both lactate acid and ATP productions. The mechanistic study revealed that cryptolepine could effectively suppress the process of HIF-1α mRNA translation rather than transcription, which was attributed to the inhibition on the phosphorylation of eIF4E regulated by both MAPK and mTOR signaling pathways. Collectively, current findings suggested that cryptolepine possesses the potential to treat breast cancers by modulating HIF-1 both in vitro and in vivo.
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Affiliation(s)
- Zhiyuan Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, 999078, Macau, People's Republic of China
| | - Ting Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, 999078, Macau, People's Republic of China
| | - Zhiyan Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, 999078, Macau, People's Republic of China
| | - Wenyue Tian
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, 999078, Macau, People's Republic of China
| | - Zhi-Hong Jiang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, 999078, Macau, People's Republic of China; Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease (Macau University of Science and Technology), 999078, Macau, People's Republic of China
| | - Guo-Yuan Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, 999078, Macau, People's Republic of China; Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease (Macau University of Science and Technology), 999078, Macau, People's Republic of China
| | - Ting Li
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, 999078, Macau, People's Republic of China
| | - Jin Gao
- IncreasePharm (Hengqin) Institute Co., Ltd, Zhu Hai, Guangdong 519031, People's Republic of China
| | - Li-Ping Bai
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, 999078, Macau, People's Republic of China; Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease (Macau University of Science and Technology), 999078, Macau, People's Republic of China.
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Yang M, Lu Y, Piao W, Jin H. The Translational Regulation in mTOR Pathway. Biomolecules 2022; 12:biom12060802. [PMID: 35740927 PMCID: PMC9221026 DOI: 10.3390/biom12060802] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/23/2022] [Accepted: 05/30/2022] [Indexed: 12/12/2022] Open
Abstract
The mechanistic/mammalian target of rapamycin (mTOR) plays a master role in cell proliferation and growth in response to insulin, amino acids, energy levels, and oxygen. mTOR can coordinate upstream signals with downstream effectors, including transcriptional and translational apparatuses to regulate fundamental cellular processes such as energy utilization, protein synthesis, autophagy, cell growth, and proliferation. Of the above, protein synthesis is highly energy-consuming; thus, mRNA translation is under the tight and immediate control of mTOR signaling. The translational regulation driven by mTOR signaling mainly relies on eukaryotic translation initiation factor 4E (eIF4E)-binding protein (4E-BP), ribosomal protein S6 kinase (S6K), and its downstream players, which are significant in rapid cellular response to environmental change. mTOR signaling not only controls the general mRNA translation, but preferential mRNA translation as well. This means that mTOR signaling shows the stronger selectivity to particular target mRNAs. Some evidence has supported the contribution of 4E-BP and La-related proteins 1 (LARP1) to such translational regulation. In this review, we summarize the mTOR pathway and mainly focus on mTOR-mediated mRNA translational regulation. We introduce the major components of mTOR signaling and their functions in translational control in a general or particular manner, and describe how the specificity of regulation is coordinated. Furthermore, we summarize recent research progress and propose additional ideas for reference. Because the mTOR pathway is on the center of cell growth and metabolism, comprehensively understanding this pathway will contribute to the therapy of related diseases, including cancers, type 2 diabetes, obesity, and neurodegeneration.
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Affiliation(s)
| | | | | | - Hua Jin
- Correspondence: (W.P.); (H.J.)
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Saviuk N, Chong Y, Wang P, Bermudez S, Zhao Z, Bhaskaran AA, Bowie D, Sonenberg N, Cooper E, Haghighi AP. Loss of 4E-BP converts cerebellar long-term depression to long-term potentiation. Cell Rep 2022; 39:110911. [PMID: 35675781 DOI: 10.1016/j.celrep.2022.110911] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 10/31/2021] [Accepted: 05/12/2022] [Indexed: 11/17/2022] Open
Abstract
Genetic perturbances in translational regulation result in defects in cerebellar motor learning; however, little is known about the role of translational mechanisms in the regulation of cerebellar plasticity. We show that genetic removal of 4E-BP, a translational suppressor and target of mammalian target of rapamycin complex 1, results in a striking change in cerebellar synaptic plasticity. We find that cerebellar long-term depression (LTD) at parallel fiber-Purkinje cell synapses is converted to long-term potentiation in 4E-BP knockout mice. Biochemical and pharmacological experiments suggest that increased phosphatase activity largely accounts for the defects in LTD. Our results point to a model in which translational regulation through the action of 4E-BP plays a critical role in establishing the appropriate kinase/phosphatase balance required for normal synaptic plasticity in the cerebellum.
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Affiliation(s)
- Natasha Saviuk
- Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada; Department of Physiology, McGill University, Montréal, QC, Canada
| | - Yumaine Chong
- Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada; Department of Physiology, McGill University, Montréal, QC, Canada
| | - Peng Wang
- Biochemistry, McGill University, Montréal, QC, Canada
| | - Sara Bermudez
- Biochemistry, McGill University, Montréal, QC, Canada
| | - Zhe Zhao
- Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada
| | - Arjun A Bhaskaran
- Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada; Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
| | - Derek Bowie
- Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada; Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
| | | | - Ellis Cooper
- Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada; Department of Physiology, McGill University, Montréal, QC, Canada.
| | - A Pejmun Haghighi
- Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada; Department of Physiology, McGill University, Montréal, QC, Canada; Buck Institute for Research on Aging, Novato, CA, USA.
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Martin A, Castells J, Allibert V, Emerit A, Zolotoff C, Cardot-Ruffino V, Gallot YS, Vernus B, Chauvet V, Bartholin L, Schaeffer L, Durieux AC, Hourdé C, Favier FB, Mazelin L, Freyssenet D. Hypothalamic-pituitary-adrenal axis activation and glucocorticoid-responsive gene expression in skeletal muscle and liver of Apc mice. J Cachexia Sarcopenia Muscle 2022; 13:1686-1703. [PMID: 35277933 PMCID: PMC9178358 DOI: 10.1002/jcsm.12939] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 01/05/2022] [Accepted: 01/17/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Cancer patients at advanced stages experience a severe depletion of skeletal muscle compartment together with a decrease in muscle function, known as cancer cachexia. Cachexia contributes to reducing quality of life, treatment efficiency, and lifespan of cancer patients. However, the systemic nature of the syndrome is poorly documented. Here, we hypothesize that glucocorticoids would be important systemic mediators of cancer cachexia. METHODS To explore the role of glucocorticoids during cancer cachexia, biomolecular analyses were performed on several tissues (adrenal glands, blood, hypothalamus, liver, and skeletal muscle) collected from ApcMin/+ male mice, a mouse model of intestine and colon cancer, aged of 13 and 23 weeks, and compared with wild type age-matched C57BL/6J littermates. RESULTS Twenty-three-week-old Apc mice recapitulated important features of cancer cachexia including body weight loss (-16%, P < 0.0001), muscle atrophy (gastrocnemius muscle: -53%, P < 0.0001), and weakness (-50% in tibialis anterior muscle force, P < 0.0001), increased expression of atrogens (7-fold increase in MuRF1 transcript level, P < 0.0001) and down-regulation of Akt-mTOR pathway (3.3-fold increase in 4EBP1 protein content, P < 0.0001), together with a marked transcriptional rewiring of hepatic metabolism toward an increased expression of gluconeogenic genes (Pcx: +90%, Pck1: +85%), and decreased expression of glycolytic (Slc2a2: -40%, Gk: -30%, Pklr: -60%), ketogenic (Hmgcs2: -55%, Bdh1: -80%), lipolytic/fatty oxidation (Lipe: -50%, Mgll: -60%, Cpt2: -60%, Hadh: -30%), and lipogenic (Acly: -30%, Acacb: -70%, Fasn: -45%) genes. The hypothalamic pituitary-adrenal axis was activated, as evidenced by the increase in the transcript levels of genes encoding corticotropin-releasing hormone in the hypothalamus (2-fold increase, P < 0.01), adrenocorticotropic hormone receptor (3.4-fold increase, P < 0.001), and steroid biosynthesis enzymes (Cyp21a1, P < 0.0001, and Cyp11b1, P < 0.01) in the adrenal glands, as well as by the increase in corticosterone level in the serum (+73%, P < 0.05), skeletal muscle (+17%, P < 0.001), and liver (+24%, P < 0.05) of cachectic 23-week-old Apc mice. A comparative transcriptional analysis with dexamethasone-treated C57BL/6J mice indicated that the activation of the hypothalamic-pituitary-adrenal axis in 23-week-old ApcMin/+ mice was significantly associated with the transcription of glucocorticoid-responsive genes in skeletal muscle (P < 0.05) and liver (P < 0.001). The transcriptional regulation of glucocorticoid-responsive genes was also observed in the gastrocnemius muscle of Lewis lung carcinoma tumour-bearing mice and in KPC mice (tibialis anterior muscle and liver). CONCLUSIONS These findings highlight the role of the hypothalamic-pituitary-adrenal-glucocorticoid pathway in the transcriptional regulation of skeletal muscle catabolism and hepatic metabolism during cancer cachexia. They also provide the paradigm for the design of new therapeutic strategies.
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Affiliation(s)
- Agnès Martin
- Univ Lyon, UJM-Saint-Etienne, Laboratoire Interuniversitaire de Biologie de la Motricité, EA7424, F-42023, Saint-Etienne, France
| | - Josiane Castells
- Univ Lyon, UJM-Saint-Etienne, Laboratoire Interuniversitaire de Biologie de la Motricité, EA7424, F-42023, Saint-Etienne, France
| | - Valentine Allibert
- Univ Lyon, UJM-Saint-Etienne, Laboratoire Interuniversitaire de Biologie de la Motricité, EA7424, F-42023, Saint-Etienne, France
| | - Andréa Emerit
- Institut NeuroMyoGene (INMG), Univ Lyon, Université Lyon 1, CNRS UMR 5310, INSERM U 1217, Lyon, France
| | - Cindy Zolotoff
- Univ Lyon, UJM-Saint-Etienne, Laboratoire Interuniversitaire de Biologie de la Motricité, EA7424, F-42023, Saint-Etienne, France
| | - Victoire Cardot-Ruffino
- Centre Léon Bérard, Centre de recherche en cancérologie de Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Yann S Gallot
- LBEPS, Univ Evry, IRBA, Université Paris Saclay, Evry, France
| | - Barbara Vernus
- Dynamique Musculaire et Métabolisme, Univ Montpellier, INRA, Montpellier, France
| | - Véronique Chauvet
- Centre Léon Bérard, Centre de recherche en cancérologie de Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Laurent Bartholin
- Centre Léon Bérard, Centre de recherche en cancérologie de Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Laurent Schaeffer
- Institut NeuroMyoGene (INMG), Univ Lyon, Université Lyon 1, CNRS UMR 5310, INSERM U 1217, Lyon, France
| | - Anne-Cécile Durieux
- Univ Lyon, UJM-Saint-Etienne, Laboratoire Interuniversitaire de Biologie de la Motricité, EA7424, F-42023, Saint-Etienne, France
| | - Christophe Hourdé
- Laboratoire Interuniversitaire de Biologie de la Motricité, Université Savoie Mont Blanc, Le Bourget du Lac, France
| | - François B Favier
- Dynamique Musculaire et Métabolisme, Univ Montpellier, INRA, Montpellier, France
| | - Laetitia Mazelin
- Institut NeuroMyoGene (INMG), Univ Lyon, Université Lyon 1, CNRS UMR 5310, INSERM U 1217, Lyon, France
| | - Damien Freyssenet
- Univ Lyon, UJM-Saint-Etienne, Laboratoire Interuniversitaire de Biologie de la Motricité, EA7424, F-42023, Saint-Etienne, France
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mTOR substrate phosphorylation in growth control. Cell 2022; 185:1814-1836. [PMID: 35580586 DOI: 10.1016/j.cell.2022.04.013] [Citation(s) in RCA: 223] [Impact Index Per Article: 74.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 12/20/2022]
Abstract
The target of rapamycin (TOR), discovered 30 years ago, is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2. TOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. With emphasis on mammalian TOR (mTOR), we comprehensively reviewed the literature and identified all reported direct substrates. In the context of recent structural information, we discuss how mTORC1 and mTORC2, despite having a common catalytic subunit, phosphorylate distinct substrates. We conclude that the two complexes recruit different substrates to phosphorylate a common, minimal motif.
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Zhuo Y, Li S, Hu W, Zhang Y, Shi Y, Zhang F, Zhang J, Wang J, Liao M, Chen J, Qian H, Li D, Sun C. Targeting SNORA38B attenuates tumorigenesis and sensitizes immune checkpoint blockade in non-small cell lung cancer by remodeling the tumor microenvironment via regulation of GAB2/AKT/mTOR signaling pathway. J Immunother Cancer 2022; 10:e004113. [PMID: 35577506 PMCID: PMC9115109 DOI: 10.1136/jitc-2021-004113] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/28/2022] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Non-coding RNAs (ncRNAs), including small nucleolar RNAs (snoRNAs), are widely involved in the physiological and pathological processes of human beings. While up to date, although considerable progress has been achieved in ncRNA-related pathogenesis of non-small cell lung cancer (NSCLC), the underlying mechanisms and biological significance of snoRNAs in NSCLC still need to be further clarified. METHODS Quantitative real-time polymerase chain reaction or RNAscope was performed to verify the expression of Small Nucleolar RNA, H/ACA Box 38B (SNORA38B) in NSCLC cell lines or clinical samples. BALB/c nude mice xenograft model or C57BL/6J mice syngeneic tumor model were estimated to detect the effects of SNORA38B in tumor growth or tumor immune microenvironment in vivo. Cytometry by time of flight, enzyme-linked immunosorbent assay and flow cytometry assay were conducted to clarify the effects and mechanisms of SNORA38B-mediated tumor immunosuppressive microenvironment. The binding activity between SNORA38B and E2F transcription factor 1(E2F1) was detected by RNA immunoprecipitation and RNA pull-down assays. Then, bioinformatics analysis and chromatin immunoprecipitation were utilized to demonstrate the regulation of GRB2-associated-binding protein 2 (GAB2) by E2F1. Moreover, the combinatorial treatment of SNORA38B locked nucleic acid (LNA) and immune checkpoint blockade (ICB) was used to treat murine Lewis lung carcinoma-derived tumor burden C57BL/6J mice to clarify the effectiveness of targeting SNORA38B in NSCLC immunotherapy. RESULTS SNORA38B was found highly expressed in NSCLC tissues and cell lines, and associated with worse prognosis. Further results showed that SNORA38B functioned as an oncogene via facilitating cell proliferation, migration, invasion, and inhibiting cell apoptosis in vitro and promoting tumorigenesis of NSCLC cells in vivo. SNORA38B could also recruit the CD4+FOXP3+ regulatory T cells by triggering tumor cells to secrete interleukin 10, which in turn reduced the infiltration of CD3+CD8+ T cells in NSCLC tumor microenvironment (TME), favoring tumor progression and poorer immune efficacy. Mechanistically, SNORA38B mainly distributed in the nucleus, and promoted NSCLC progression by regulating GAB2 transcription to activate protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway through directly binding with E2F1. Moreover, we found that SNORA38B LNAs were able to ameliorate CD3+CD8+ T cell infiltration in TME, which sensitized NSCLC to the treatment of ICB. CONCLUSIONS In conclusion, our data demonstrated that SNORA38B functioned as an oncogene in NSCLC both in vitro and in vivo at least in part by regulating the GAB2/AKT/mTOR pathway via directly binding to E2F1. SNORA38B could also sensitize NSCLC to immunotherapy, which may be a critical therapeutic target for NSCLC.
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Affiliation(s)
- Yue Zhuo
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Shujun Li
- Department of Physical Examination, Wuhan Hospital for the Prevention and Treatment of Occupational Diseases, Wuhan, Hubei, People's Republic of China
| | - Wei Hu
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
| | - Yu Zhang
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Yufan Shi
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Faxue Zhang
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Jian Zhang
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Juan Wang
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Meijuan Liao
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Jiahao Chen
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Huiling Qian
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Dejia Li
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Chengcao Sun
- Department of Occupational and Environmental Health, Wuhan University, Wuhan, Hubei, People's Republic of China
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Simcox J, Lamming DW. The central moTOR of metabolism. Dev Cell 2022; 57:691-706. [PMID: 35316619 PMCID: PMC9004513 DOI: 10.1016/j.devcel.2022.02.024] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/20/2022] [Accepted: 02/24/2022] [Indexed: 12/21/2022]
Abstract
The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the current state of knowledge regarding the regulation of mTOR signaling and the metabolic regulation of the four macromolecular building blocks of the cell: carbohydrate, nucleic acid, lipid, and protein by mTOR. We review the role of mTOR in the control of organismal physiology and aging through its action in key tissues and discuss the potential for clinical translation of mTOR inhibition for the treatment and prevention of diseases of aging.
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Affiliation(s)
- Judith Simcox
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
| | - Dudley W Lamming
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
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49
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Foxo3a tempers excessive glutaminolysis in activated T cells to prevent fatal gut inflammation in the murine IL-10 -/- model of colitis. Cell Death Differ 2022; 29:585-599. [PMID: 34588632 PMCID: PMC8901686 DOI: 10.1038/s41418-021-00876-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 02/08/2023] Open
Abstract
Mutations in susceptibility alleles correlate with gut-inflammatory diseases, such as Crohn's disease; however, this does not often impact the disease progression indicating the existence of compensatory genes. We show that a reduction in Foxo3a expression in IL-10-deficient mice results in a spontaneous and aggressive Crohn's- like disease with 100% penetrance, which is rescued by deletion of myeloid cells, T cells and inhibition of mTORC1. In Foxo3a-/- IL-10-/- mice, there is poor cell death of myeloid cells in the gut, leading to increased accumulation of myeloid and T cells in the gut. Myeloid cells express high levels of inflammatory cytokines, and regulatory T cells are dysfunctional despite increased abundance. Foxo3a signaling represses the transcription of glutaminase (GLS/GLS2) to prevent over-consumption of glutamine by activated T cells and its conversion to glutamate that contributes to the TCA cycle and mTORC1 activation. Finally, we show that Foxo3a restricts the abundance of colitogenic microbiota in IL-10-deficient mice. Thus, by suppressing glutaminolysis in activated T cells Foxo3a mediates a critical checkpoint that prevents the development of fulminant gut inflammatory disease.
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50
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Rapaka D, Bitra VR, Challa SR, Adiukwu PC. mTOR signaling as a molecular target for the alleviation of Alzheimer's disease pathogenesis. Neurochem Int 2022; 155:105311. [PMID: 35218870 DOI: 10.1016/j.neuint.2022.105311] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/12/2022] [Accepted: 02/20/2022] [Indexed: 10/19/2022]
Abstract
Mechanistic/mammalian target of rapamycin (mTOR) belongs to the phosphatidylinositol kinase-related kinase (PIKK) family. mTOR signaling is required for the commencement of essential cell functions including autophagy. mTOR primarily governs cell growth in response to favourable nutrients and other growth stimuli. However, it also influences aging and other aspects of nutrient-related physiology such as protein synthesis, ribosome biogenesis, and cell proliferation in adults with very limited growth. The major processes for survival such as synaptic plasticity, memory storage and neuronal recovery involve a significant mTOR activity. mTOR dysregulation is becoming a prevalent motif in a variety of human diseases, including cancer, neurological disorders, and other metabolic syndromes. The use of rapamycin to prolong life in different animal models may be attributable to the multiple roles played by mTOR signaling in various processes involved in ageing, protein translation, autophagy, stem cell pool turnover, inflammation, and cellular senescence. mTOR activity was found to be altered in AD brains and rodent models, supporting the notion that aberrant mTOR activity is one of the key events contributing to the onset and progression of AD hallmarks This review assesses the molecular association between the mTOR signaling pathway and pathogenesis of Alzheimer's disease. The research data supporting this theme are also reviewed.
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Affiliation(s)
- Deepthi Rapaka
- A.U. College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, 530003, India.
| | | | - Siva Reddy Challa
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, 61614, USA.
| | - Paul C Adiukwu
- School of Pharmacy, University of Botswana, Gaborone, 0022, Botswana.
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