| Src inhibits adriamycin-induced senescence and G2 checkpoint arrest by blocking the induction of p21waf1. | |
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MedLine Citation:
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PMID: 16204065 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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DNA-damaging drugs stop tumor cell proliferation by inducing apoptosis, necrosis, or senescence. Cyclin-dependent kinase inhibitor p21waf1 is an important regulator of these responses, promoting senescence and preventing aberrant mitosis that leads to cell death. Because tumors expressing oncogenic tyrosine kinases are relatively resistant to DNA-damaging agents, the effects of Src on cellular responses to anticancer drug Adriamycin were investigated. Src expression increased drug survival in HT1080 fibrosarcoma cells, as measured by the colony formation assay, and strongly inhibited Adriamycin-induced senescence. Src also decreased the number of apoptotic cells while increasing the fraction of cells dying through necrosis. In addition, Src inhibited the G2 and G1 tetraploidy checkpoints of Adriamycin-treated cells, permitting these cells to proceed into mitosis and subsequently double their DNA content. Inhibition of senescence and G2-G1 checkpoints in Src-expressing cells was associated with the failure of these cells to up-regulate p21waf1 in response to Adriamycin. The failure of p21waf1 induction, despite increased expression of p53 and its binding to p21waf1 promoter, was mediated by the up-regulation of c-Myc, a negative regulator of p21waf1 transcription. Conversely, ectopic expression of p21waf1 inhibited Myc transcription in Src-expressing cells, an effect that was associated with the interaction of p21waf1 with the STAT3 transcription factor at the Myc promoter. These results reveal a complex effect of Src on cellular drug responses and provide an explanation for the effect of this oncogene on cellular drug resistance. |
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Authors:
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Arnaud Vigneron; Igor B Roninson; Erick Gamelin; Olivier Coqueret |
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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, P.H.S. |
Journal Detail:
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Title: Cancer research Volume: 65 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2005 Oct |
Date Detail:
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Created Date: 2005-10-05 Completed Date: 2005-12-14 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 8927-35 Citation Subset: IM |
Affiliation:
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Institut National de la Sante et de la Recherche Medicale U564, Cancer Center Paul Papin, Angers, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antibiotics, Antineoplastic
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antagonists & inhibitors*,
pharmacology Cell Aging / drug effects Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors, biosynthesis* DNA-Binding Proteins / metabolism Down-Regulation Doxorubicin / antagonists & inhibitors*, pharmacology Drug Resistance, Neoplasm Fibrosarcoma / drug therapy*, enzymology*, metabolism, pathology G2 Phase / drug effects, physiology Humans Kruppel-Like Transcription Factors Mitosis / physiology Polyploidy Promoter Regions, Genetic Proto-Oncogene Proteins c-myc / antagonists & inhibitors, biosynthesis, genetics STAT3 Transcription Factor / metabolism Transcription Factors / metabolism Tumor Suppressor Protein p53 / metabolism src-Family Kinases / biosynthesis, genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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R01 AG17921/AG/NIA NIH HHS; R01 CA89636/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/DNA-Binding Proteins; 0/Kruppel-Like Transcription Factors; 0/MYC protein, human; 0/Proto-Oncogene Proteins c-myc; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/Transcription Factors; 0/Tumor Suppressor Protein p53; 0/ZBTB17 protein, human; 23214-92-8/Doxorubicin; EC 2.7.10.2/src-Family Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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