| UVB-Induced p21 degradation promotes apoptosis of human keratinocytes. | |
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MedLine Citation:
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PMID: 20931139 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Skin cancer is the most common cancer in the United States. Ultraviolet B (UVB) radiation in sunlight is the major environmental factor causing skin cancer. p21, a p53-inducible protein, plays an important role in cell cycle, DNA repair, and apoptosis. Here we have investigated the effect of UVB radiation on p21 and its molecular mechanisms and function in human HaCaT keratinocytes, which we used as a premalignant cellular model because normal skin harbors numerous clones of p53-mutated keratinocytes. We found that in human HaCaT keratinocytes UVB induces rapid p21 down-regulation via a proteasomal degradation mechanism. In p53-defective HaCaT cells, the p21 protein levels remain decreased at a later time post-UVB, but in normal human and mouse epidermal keratinocytes with wild-type p53 the p21 levels are initially reduced but later increase post-UVB. These findings indicate that loss of p53 function leads to sustained p21 down-regulation in response to UVB damage. Degradation of p21 following UVB radiation does not require ATR, ATM, or both, because either the ATR/ATM inhibitor caffeine or siRNA knockdown of ATR, ATM, or both failed to reverse p21 degradation. However, inhibiting MDM2 or GSK3β partially reduced UVB-induced p21 degradation, while inhibiting both enzymes completely prevented it. Restoring the p21 protein levels in UVB-irradiated keratinocytes reduced apoptosis. Although at the molecular level increasing p21 expression has no effect on the protein levels of the Bcl-2 family members, it enhances the activation of AKT, a critical survival pathway to protect cells from apoptosis. Our results suggest a distinct mechanism of p21 degradation in keratinocytes by UVB, and this p21 degradation may significantly enhance UVB-induced apoptosis of premalignant keratinocytes with a p53 defect to eliminate damaged cells and therefore prevent skin cancer development. |
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Authors:
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Xia Lei; Bo Liu; Weinong Han; Mei Ming; Yu-Ying He |
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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 Date: 2010-10-08 |
Journal Detail:
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Title: Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology Volume: 9 ISSN: 1474-9092 ISO Abbreviation: Photochem. Photobiol. Sci. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-24 Completed Date: 2011-03-21 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 101124451 Medline TA: Photochem Photobiol Sci Country: England |
Other Details:
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Languages: eng Pagination: 1640-8 Citation Subset: IM |
Affiliation:
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Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis* Caffeine / pharmacology Cell Cycle Proteins / antagonists & inhibitors, genetics, metabolism Cell Line Cyclin-Dependent Kinase Inhibitor p21 / metabolism* DNA-Binding Proteins / antagonists & inhibitors, genetics, metabolism Down-Regulation Glycogen Synthase Kinase 3 / metabolism Humans Keratinocytes / metabolism, radiation effects* Protein-Serine-Threonine Kinases / antagonists & inhibitors, genetics, metabolism Proto-Oncogene Proteins c-mdm2 / metabolism RNA Interference RNA, Small Interfering Tumor Suppressor Protein p53 / genetics, metabolism Tumor Suppressor Proteins / antagonists & inhibitors, genetics, metabolism Ultraviolet Rays* |
| Grant Support | |
ID/Acronym/Agency:
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P30 CA014599/CA/NCI NIH HHS; R01 ES016936-01A2/ES/NIEHS NIH HHS; UL1 RR024999/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/DNA-Binding Proteins; 0/RNA, Small Interfering; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; 58-08-2/Caffeine; 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; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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