| Cellular commitment to reentry into the cell cycle after stalled DNA is determined by site-specific phosphorylation of Chk1 and PTEN. | |
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MedLine Citation:
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PMID: 18723495 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In this study, we show that depletion of Chk1 by small interfering RNA (siRNA) results in failure of reentry to the cell cycle after DNA replication has been stalled by exposure to hydroxyurea (HU). Casein kinase II (CKII) is degraded in these cells in a proteasome-dependent manner, resulting in decreased phosphorylation and PTEN levels. We show that phosphorylation of Chk1 at Ser(317) but not at Ser(345) is required for phosphorylation of PTEN at Thr(383) by CKII, making cell cycle reentry after HU treatment possible. Like Chk1 depletion, loss of PTEN due to siRNA is followed by inability to return to the cell cycle following HU. In Chk1-siRNA cells, reintroduction of wild-type PTEN but not PTEN T383A restores the ability of the cell to reenter the G(2)-M phase of the cell cycle after stalled DNA replication. We conclude that, in response to stalled DNA replication, Chk1 is phosphorylated at Ser(317) by ATR resulting in stabilization of CKII, which in turn leads to phosphorylation of PTEN at Thr(383). |
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Authors:
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Sarah A Martin; Toru Ouchi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 7 ISSN: 1535-7163 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-08-25 Completed Date: 2008-10-22 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 2509-16 Citation Subset: IM |
Affiliation:
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Department of Oncological Sciences, Mount Sinai School of Medicine, New York University, New York, NY, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Base Sequence Blotting, Western Cell Cycle* Cell Line DNA / metabolism* DNA Primers DNA Replication Flow Cytometry Mice Mutagenesis, Site-Directed PTEN Phosphohydrolase / metabolism* Phosphorylation Protein Kinases / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA 79892/CA/NCI NIH HHS; CA 90631/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA Primers; 9007-49-2/DNA; EC 2.7.-/Protein Kinases; EC 2.7.11.1/Checkpoint kinase 1; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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