| KSR1 is required for cell cycle reinitiation following DNA damage. | |
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MedLine Citation:
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PMID: 19147494 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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KSR1 (kinase suppressor of Ras 1) is a molecular scaffold and positive regulator of the Raf/MEK/ERK phosphorylation cascade. KSR1 is required for maximal ERK activation induced by growth factors and by some cytotoxic agents. We show here that KSR1 is also required for maximal ERK activation induced by UV light, ionizing radiation, or the DNA interstrand cross-linking agent mitomycin C (MMC). We further demonstrate a role for KSR1 in the reinitiation of the cell cycle and proliferation following cell cycle arrest induced by MMC. Cells lacking KSR1 underwent but did not recover from MMC-induced G(2)/M arrest. Expression of KSR1 allowed KSR1(-/-) cells to re-enter the cell cycle following MMC treatment. However, cells expressing a mutated form of KSR1 unable to bind ERK did not recover from MMC-induced cell cycle arrest, demonstrating the requirement for the KSR1-ERK interaction. In addition, constitutive activation of ERK was not sufficient to promote cell cycle reinitiation in MMC-treated KSR1(-/-) cells. Only cells expressing KSR1 recovered from MMC-induced cell cycle arrest. Importantly, MMC-induced DNA damage was repaired in KSR1(-/-) cells, as determined by resolution of gamma-H2AX-containing foci. These data indicate that cell cycle reinitiation is not actively signaled in the absence of KSR1, even when DNA damage has been resolved. These data reveal a specific role for the molecular scaffold KSR1 and KSR1-mediated ERK signaling in the cellular response to DNA interstrand cross-links. |
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Authors:
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Gina L Razidlo; Heidi J Johnson; Scott M Stoeger; Kenneth H Cowan; Tadayoshi Bessho; Robert E Lewis |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2009-01-15 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Mar |
Date Detail:
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Created Date: 2009-03-09 Completed Date: 2009-05-04 Revised Date: 2010-09-22 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 6705-15 Citation Subset: IM |
Affiliation:
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Eppley Institute for the Research of Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Cycle / drug effects, physiology* DNA Damage / drug effects, physiology* Extracellular Signal-Regulated MAP Kinases / genetics, metabolism MAP Kinase Signaling System / drug effects, physiology* Mice Mice, Knockout Mitomycin / pharmacology Mutation Nucleic Acid Synthesis Inhibitors / pharmacology Phosphorylation / drug effects, physiology Protein Kinases / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA009476/CA/NCI NIH HHS; CA036727/CA/NCI NIH HHS; CA90400/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Nucleic Acid Synthesis Inhibitors; 50-07-7/Mitomycin; EC 2.7.-/Protein Kinases; EC 2.7.1.-/KSR-1 protein kinase; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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