| Inactivation of p21WAF1 sensitizes cells to apoptosis via an increase of both p14ARF and p53 levels and an alteration of the Bax/Bcl-2 ratio. | |
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MedLine Citation:
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PMID: 12151395 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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p21(WAF1) appears to be a major determinant of the cell fate in response to anticancer therapy. It was shown previously that HCT116 human colon cancer cells growing in vitro enter a stable arrest upon DNA damage, whereas cells with a defective p21(WAF1) response undergo apoptosis. Here we report that the enhanced sensitivity of HCT116/p21(-/-) cells to chemotherapeutic drug-induced apoptosis correlates with an increased expression of p53 and a modification of their Bax/Bcl-2 ratio in favor of the pro-apoptotic protein Bax. Treatment of HCT116/p21(-/-) cells with daunomycin resulted in a reduction of the mitochondrial membrane potential and in activation of caspase-9, whereas no such changes were observed in HCT116/p21(+/+) cells, providing evidence that p21(WAF1) exerts an antagonistic effect on the mitochondrial pathway of apoptosis. Moreover, the role of p53 in activation of this pathway was demonstrated by the fact that inhibition of p53 activity by pifithrin-alpha reduced the sensitivity of HCT116/p21(-/-) cells to daunomycin-induced apoptosis and restored a Bax/Bcl-2 ratio similar to that observed in HCT116p21(+/+) cells. Enhancement of p53 expression after disruption of p21(WAF1) resulted from a stabilization of p53, which correlated with an increased expression of the tumor suppressor p14(ARF), an inhibitor of the ubiquitin ligase activity of Mdm2. In accordance with the role of p14(ARF) in p53 stabilization, overexpression of p14(ARF) in HCT116/p21(+/+) cells resulted in a strong increase in p53 activity. Our results identify a novel mechanism for the anti-apoptotic effect of p21(WAF1) consisting in maintenance of mitochondrial homeostasis that occurs in consequence of a negative control of p14(ARF) expression. |
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Authors:
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Delphine Javelaud; Francoise Besancon |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2002-07-31 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 277 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2002 Oct |
Date Detail:
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Created Date: 2002-09-30 Completed Date: 2002-11-20 Revised Date: 2006-11-15 |
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: 37949-54 Citation Subset: IM |
Affiliation:
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INSERM U365, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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physiology* Base Sequence Colonic Neoplasms Cyclin-Dependent Kinase Inhibitor p21 Cyclins / antagonists & inhibitors* DNA Primers Gene Deletion Genes, Reporter Humans Luciferases / genetics Proto-Oncogene Proteins / metabolism* Proto-Oncogene Proteins c-bcl-2 / metabolism* Recombinant Proteins / metabolism Tumor Cells, Cultured Tumor Suppressor Protein p14ARF / metabolism* Tumor Suppressor Protein p53 / metabolism* bcl-2-Associated X Protein |
| Chemical | |
Reg. No./Substance:
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0/BAX protein, human; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/DNA Primers; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Recombinant Proteins; 0/Tumor Suppressor Protein p14ARF; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein; EC 1.13.12.-/Luciferases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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