Glycogen synthase kinase-3β positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1

S Shin; L Wolgamott; J Tcherkezian; S Vallabhapurapu; Y Yu; P P Roux; S-O Yoon

doi:10.1038/onc.2013.113

Glycogen synthase kinase-3β positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1

Oncogene. 2014 Mar 27;33(13):1690-9. doi: 10.1038/onc.2013.113. Epub 2013 Apr 15.

Authors

S Shin¹, L Wolgamott¹, J Tcherkezian², S Vallabhapurapu¹, Y Yu³, P P Roux², S-O Yoon¹

Affiliations

¹ Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
² Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada.
³ Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.

PMID: 23584478
DOI: 10.1038/onc.2013.113

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / biosynthesis
Adaptor Proteins, Signal Transducing / genetics*
Animals
Cell Cycle Proteins
Cell Growth Processes / physiology
Enzyme Inhibitors / pharmacology
Female
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / metabolism*
Glycogen Synthase Kinase 3 beta
Humans
Mice
Mice, Nude
Peptide Initiation Factors / genetics
Peptide Initiation Factors / metabolism
Phosphoproteins / biosynthesis
Phosphoproteins / genetics*
Phosphorylation
Protein Binding
Protein Biosynthesis
Random Allocation
Thiazoles / pharmacology
Triple Negative Breast Neoplasms / drug therapy
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / metabolism
Urea / analogs & derivatives
Urea / pharmacology
Xenograft Model Antitumor Assays

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
EIF4EBP1 protein, human
Enzyme Inhibitors
Peptide Initiation Factors
Phosphoproteins
Thiazoles
N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
Urea
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Glycogen Synthase Kinase 3