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

Abstract

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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [2];  [1];  [1]
  1. Univ. of Pittsburgh Cancer Institute, Pittsburgh, PA (United States)
  2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1322511
Report Number(s):
PNNL-SA-116951
Journal ID: ISSN 0027-8424; 47765; 48171; 453040220
Grant/Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 30; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 4E-BP1; cyclin-dependent kinase 1; centrosome; mitosis; Environmental Molecular Sciences Laboratory

Citation Formats

Velasquez, Celestino, Cheng, Erdong, Shuda, Masahiro, Lee-Oesterreich, Paula J., Pogge von Strandmann, Lisa, Gritsenko, Marina A., Jacobs, Jon M., Moore, Patrick S., and Chang, Yuan. Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation. United States: N. p., 2016. Web. doi:10.1073/pnas.1607768113.
Velasquez, Celestino, Cheng, Erdong, Shuda, Masahiro, Lee-Oesterreich, Paula J., Pogge von Strandmann, Lisa, Gritsenko, Marina A., Jacobs, Jon M., Moore, Patrick S., & Chang, Yuan. Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation. United States. doi:10.1073/pnas.1607768113.
Velasquez, Celestino, Cheng, Erdong, Shuda, Masahiro, Lee-Oesterreich, Paula J., Pogge von Strandmann, Lisa, Gritsenko, Marina A., Jacobs, Jon M., Moore, Patrick S., and Chang, Yuan. Mon . "Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation". United States. doi:10.1073/pnas.1607768113. https://www.osti.gov/servlets/purl/1322511.
@article{osti_1322511,
title = {Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation},
author = {Velasquez, Celestino and Cheng, Erdong and Shuda, Masahiro and Lee-Oesterreich, Paula J. and Pogge von Strandmann, Lisa and Gritsenko, Marina A. and Jacobs, Jon M. and Moore, Patrick S. and Chang, Yuan},
abstractNote = {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.},
doi = {10.1073/pnas.1607768113},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 30,
volume = 113,
place = {United States},
year = {Mon Jul 11 00:00:00 EDT 2016},
month = {Mon Jul 11 00:00:00 EDT 2016}
}

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