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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kwun, Hyun Jin Moore, Patrick S. Shuda, Masahiro Cordek, Daniel G. Chang, Yuan Cheng, Erdong Velásquez, Celestino |
| Description | Author Affiliation: Shuda M ( Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213.); Velásquez C ( Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213.); Cheng E ( Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213.); Cordek DG ( Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213.); Kwun HJ ( Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213.); Chang Y ( Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 psm9@pitt.edu yc70@pitt.edu.); Moore PS ( Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 psm9@pitt.edu yc70@pitt.edu.); |
| Abstract | Mitosis is commonly thought to be associated with reduced cap-dependent protein translation. Here we show an alternative control mechanism for maintaining cap-dependent translation during mitosis revealed by a viral oncoprotein, Merkel cell polyomavirus small T (MCV sT). We find MCV sT to be a promiscuous E3 ligase inhibitor targeting the anaphase-promoting complex, which increases cell mitogenesis. MCV sT binds through its Large T stabilization domain region to cell division cycle protein 20 (Cdc20) and, possibly, cdc20 homolog 1 (Cdh1) E3 ligase adapters. This activates cyclin-dependent kinase 1/cyclin B1 (CDK1/CYCB1) to directly hyperphosphorylate eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP1) at authentic sites, generating a mitosis-specific, mechanistic target of rapamycin (mTOR) inhibitor-resistant δ phospho-isoform not present in G1-arrested cells. Recombinant 4E-BP1 inhibits capped mRNA reticulocyte translation, which is partially reversed by CDK1/CYCB1 phosphorylation of 4E-BP1. eIF4G binding to the $eIF4E–m^{7}GTP$ cap complex is resistant to mTOR inhibition during mitosis but sensitive during interphase. Flow cytometry, with and without sT, reveals an orthogonal $pH3^{S10+}$ mitotic cell population having higher inactive $p4E-BP1^{T37/T46+}$ saturation levels than $pH3^{S10–}$ interphase cells. Using a Click-iT flow cytometric assay to directly measure mitotic protein synthesis, we find that most new protein synthesis during mitosis is cap-dependent, a result confirmed using the eIF4E/4G inhibitor drug 4E1RCat. For most cell lines tested, cap-dependent translation levels were generally similar between mitotic and interphase cells, and the majority of new mitotic protein synthesis was cap-dependent. These findings suggest that mitotic cap-dependent translation is generally sustained during mitosis by CDK1 phosphorylation of 4E-BP1 even under conditions of reduced mTOR signaling. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 19 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adaptor Proteins, Signal Transducing Metabolism Antigens, Polyomavirus Transforming Cyclin-Dependent Kinases Neoplasms Phosphoproteins Protein Biosynthesis TOR Serine-Threonine Kinases Cell Proliferation HEK293 Cells HeLa Cells Interphase Mitosis Nocodazole Chemistry Phosphorylation Protein Binding Protein Structure, Tertiary Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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