| Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). | |
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MedLine Citation:
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PMID: 15149599 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cellular senescence can be triggered by telomere shortening as well as a variety of stresses and signaling imbalances. We used multiparameter single-cell detection methods to investigate upstream signaling pathways and ensuing cell cycle checkpoint responses in human fibroblasts. Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 and causing G1 phase arrest. Inhibition of ATM expression or activity resulted in cell cycle reentry, indicating that stable arrest requires continuous signaling. ATR kinase appears to play a minor role in normal cells but in the absence of ATM elicited a delayed G2 phase arrest. These pathways do not affect expression of p16, which was upregulated in a telomere- and DNA damage-independent manner in a subset of cells. Distinct senescence programs can thus progress in parallel, resulting in mosaic cultures as well as individual cells responding to multiple signals. |
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Authors:
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Utz Herbig; Wendy A Jobling; Benjamin P C Chen; David J Chen; John M Sedivy |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Molecular cell Volume: 14 ISSN: 1097-2765 ISO Abbreviation: Mol. Cell Publication Date: 2004 May |
Date Detail:
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Created Date: 2004-05-19 Completed Date: 2004-07-13 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 9802571 Medline TA: Mol Cell Country: United States |
Other Details:
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Languages: eng Pagination: 501-13 Citation Subset: IM |
Affiliation:
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Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Aging
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genetics* Cell Cycle Proteins / genetics, metabolism Cell Death / genetics Cell Line Cyclin-Dependent Kinase Inhibitor p16 / genetics, metabolism Cyclin-Dependent Kinase Inhibitor p21 Cyclins / genetics, metabolism* DNA Damage / genetics DNA-Binding Proteins G1 Phase / genetics G2 Phase / genetics Genes, cdc / physiology Humans Protein-Serine-Threonine Kinases / genetics, metabolism* Signal Transduction / genetics* Stress, Physiological / genetics, metabolism Telomere / genetics* Telomeric Repeat Binding Protein 2 / genetics, metabolism Tumor Suppressor Protein p53 / genetics, metabolism* Tumor Suppressor Proteins Up-Regulation / genetics |
| Grant Support | |
ID/Acronym/Agency:
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F32 CA099388/CA/NCI NIH HHS; P20 RR-15578/RR/NCRR NIH HHS; R01 AG16694/AG/NIA NIH HHS; R01 AG18949/AG/NIA NIH HHS; R01 CA50519/CA/NCI NIH HHS; T32 GM-07601/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CDKN1A protein, human; 0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/DNA-Binding Proteins; 0/Telomeric Repeat Binding Protein 2; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; EC 2.7.1.-/ATR protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein |
| Comments/Corrections | |
Comment In:
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Mol Cell. 2004 May 21;14(4):420-1
[PMID:
15149591
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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