| Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells. | |
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MedLine Citation:
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PMID: 12545164 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Many stimuli causing 'stress' or DNA damage in cells can produce phenotypes that overlap with telomere-based replicative senescence. In epithelial systems, the p16/RB pathway may function as a stress senescence-signaling pathway independent of telomere shortening. Overexpressing cyclin-dependent kinase 4 (Cdk4) in human epidermal keratinocytes and human mammary epithelial cells not only prevents the p16(INK4a)-associated premature growth arrest due to telomere-independent stress (e.g., inadequate culture conditions), but also bypasses the ensuing telomere-dependent senescence (M1). Overexpressed Cdk4 in epithelial cells induces a dramatic upregulation of p16(INK4a) and milder upregulation of p53 and p21(WAF1), which become unresponsive to UV irradiation. Despite the high levels of these checkpoint factors, Cdk4-overexpressing cells divide in an apparently normal regulated fashion, are able to respond to changes in calcium levels, retain the stem cell phenotype, and fully differentiate and stratify. These results suggest that the differentiation pathways in Cdk4-overexpressing cells remain intact. |
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Authors:
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Ruben D Ramirez; Brittney-Shea Herbert; Melville B Vaughan; Ying Zou; Kenia Gandia; Carmela P Morales; Woodring E Wright; Jerry W Shay |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Oncogene Volume: 22 ISSN: 0950-9232 ISO Abbreviation: Oncogene Publication Date: 2003 Jan |
Date Detail:
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Created Date: 2003-01-24 Completed Date: 2003-02-12 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 433-44 Citation Subset: IM |
Affiliation:
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Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA. ruben.ramirez@utsouthwestern.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Calcium / metabolism Cell Aging Cell Differentiation Cell Division Cells, Cultured Chromosome Aberrations Cyclin D Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor p16 / genetics, metabolism Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinases / genetics, metabolism* Cyclins / metabolism DNA Replication DNA-Binding Proteins Epithelial Cells / metabolism*, radiation effects Female Humans Keratinocytes / metabolism Proto-Oncogene Proteins* Reference Values Telomerase / genetics, metabolism Telomere / metabolism* Tumor Suppressor Protein p53 / metabolism Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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AG01228/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CDKN1A protein, human; 0/Cyclin D; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/DNA-Binding Proteins; 0/Proto-Oncogene Proteins; 0/Tumor Suppressor Protein p53; 7440-70-2/Calcium; EC 2.7.1.37/CDK4 protein, human; EC 2.7.11.22/Cyclin-Dependent Kinase 4; EC 2.7.11.22/Cyclin-Dependent Kinases; EC 2.7.7.49/Telomerase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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