title: Glycogen synthase kinase-3β positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1.
abstract: Protein synthesis has a key role in the control of cell proliferation, and its deregulation is associated with pathological conditions, notably cancer. Rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1), was known to inhibit protein synthesis. However, it does not substantially inhibit protein synthesis and cell proliferation in many cancer types. We were interested in finding a novel target in rapamycin-resistant cancer. The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). Here, we provide evidence that glycogen synthase kinase (GSK)-3β promotes cell proliferation through positive regulation of protein synthesis. We found that GSK-3β phosphorylates and inactivates 4E-BP1, thereby increasing eIF4E-dependent protein synthesis. Considering the clinical relevance of pathways regulating protein synthesis, our study provides a promising new strategy and target for cancer therapy.
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wolgamott
authors.affiliation: Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Tcherkezian
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Vallabhapurapu
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: P P
authors.initials: PP
authors.lastname: Roux
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: S-O
authors.initials: SO
authors.lastname: Yoon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D011897:Random Allocation; D013844:Thiazoles / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D013844:Thiazoles; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3