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Title: Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
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  1. Univ. of Pittsburgh Cancer Institute, Pittsburgh, PA (United States)
  2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
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mTOR-directed 4E-BP1 phosphorylation promotes cap-dependent translation and tumorigen-esis. During mitosis, CDK1 substitutes for mTOR and fully phosphorylates 4E-BP1 at canoni-cal as well a non-canonical S83 site resulting in a mitosis-specific hyperphosphorylated δ isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. While S83 phosphorylation of 4E-BP1 does not affect in vitro cap-dependent translation, nor eIF4G/4E-BP1 cap-binding, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus (MCV) small T (sT) antigen viral oncoprotein. In contrast to inhibitory mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain-of-function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.

Research Organization:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
1322511
Report Number(s):
PNNL-SA-116951; 47765; 48171; 453040220
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 30; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 39 works
Citation information provided by
Web of Science

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Cited By (21)

Mitosis-related phosphorylation of the eukaryotic translation suppressor 4E-BP1 and its interaction with eukaryotic translation initiation factor 4E (eIF4E) journal June 2019
Effect of the Large and Small T-Antigens of Human Polyomaviruses on Signaling Pathways journal August 2019
Eukaryotic initiation factor 4E-binding protein as an oncogene in breast cancer journal May 2019
Signaling Pathways Involved in the Regulation of mRNA Translation journal April 2018
The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts journal April 2020
The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts journal April 2020
Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events journal February 2018
Beyond molecular tumor heterogeneity: protein synthesis takes control journal February 2018
Iron-dependent CDK1 activity promotes lung carcinogenesis via activation of the GP130/STAT3 signaling pathway journal April 2019
Regulation of 4E-BP1 activity in the mammalian oocyte text January 2017
Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition journal December 2019
Regulation of 4E-BP1 activity in the mammalian oocyte journal May 2017
Regulation of 4E-BP1 activity in the mammalian oocyte text January 2017
The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts journal November 2019
CDK1 couples proliferation with protein synthesis journal February 2020
CDK1 couples proliferation with protein synthesis posted_content October 2019
The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts journal April 2020
Mitosis flips the switch on autophagy control journal November 2019
The Human Polyomavirus Middle and Alternative T-Antigens; Thoughts on Roles and Relevance to Cancer journal March 2018
Stabilization of 4E-BP1 by PI3K kinase and its involvement in CHK2 phosphorylation in the cellular response to radiation journal January 2017
Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma journal January 2018

Figures / Tables (4)

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
4E-BP1
cyclin-dependent kinase 1
centrosome
mitosis