| Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence. | |
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MedLine Citation:
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PMID: 20703098 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Genotoxic stress triggers the p53 tumor suppressor network to activate cellular responses that lead to cell cycle arrest, DNA repair, apoptosis or senescence. This network functions mainly through transactivation of different downstream targets, including cell cycle inhibitor p21, which is required for short-term cell cycle arrest or long-term cellular senescence, or proapoptotic genes such as p53 upregulated modulator of apoptosis (PUMA) and Noxa. However, the mechanism that switches from cell cycle arrest to apoptosis is still unknown. In this study, we found that mice harboring a hypomorphic mutant p53, R172P, a mutation that abrogates p53-mediated apoptosis while keeping cell cycle control mostly intact, are more susceptible to ultraviolet-B (UVB)-induced skin damage, inflammation and immunosuppression than wild-type mice. p53(R172P) embryonic fibroblasts (MEFs) are hypersensitive to UVB and prematurely senesce after UVB exposure, in stark contrast to wild-type MEFs, which undergo apoptosis. However, these mutant cells are able to repair UV-induced DNA lesions, indicating that the UV hypersensitive phenotype results from the subsequent damage response. Mutant MEFs show an induction of p53 and p21 after UVR, while wild-type MEFs additionally induce PUMA and Noxa. Importantly, p53(R172P) MEFs failed to downregulate anti-apoptotic protein Bcl-2, which has been shown to play an important role in p53-dependent apoptosis. Taken together, these data demonstrate that in the absence of p53-mediated apoptosis, cells undergo cellular senescence to prevent genomic instability. Our results also indicate that p53-dependent apoptosis may play an active role in balancing cellular growth. |
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Authors:
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Omid Tavana; Cara L Benjamin; Nahum Puebla-Osorio; Mei Sang; Stephen E Ullrich; Honnavara N Ananthaswamy; Chengming Zhu |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-08-16 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 9 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-09-20 Completed Date: 2011-01-18 Revised Date: 2012-04-10 |
Medline Journal Info:
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Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States |
Other Details:
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Languages: eng Pagination: 3328-36 Citation Subset: IM |
Affiliation:
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Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Apoptosis Regulatory Proteins / metabolism Cell Aging* Cell Line Cyclin-Dependent Kinase Inhibitor p21 / genetics, metabolism DNA Damage Fibroblasts / metabolism, radiation effects Hypersensitivity / genetics, metabolism Immune Tolerance* Mice Mutation Photosensitivity Disorders / etiology Proto-Oncogene Proteins c-bcl-2 / metabolism Radiation Tolerance* Skin / pathology, radiation effects Tumor Suppressor Protein p53 / genetics, metabolism* Tumor Suppressor Proteins / metabolism Ultraviolet Rays* |
| Grant Support | |
ID/Acronym/Agency:
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CA 112660/CA/NCI NIH HHS; CA116933/CA/NCI NIH HHS; CA131207/CA/NCI NIH HHS; ES07784/ES/NIEHS NIH HHS; P50 CA093459/CA/NCI NIH HHS; R01 CA131207-04/CA/NCI NIH HHS; R01 CA131207-05/CA/NCI NIH HHS; R01 ES007327-03/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Apoptosis Regulatory Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/PUMA protein, mouse; 0/Pmaip1 protein, mouse; 0/Proto-Oncogene Proteins c-bcl-2; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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