| Cyclin kinase inhibitor p21 potentiates bile acid-induced apoptosis in hepatocytes that is dependent on p53. | |
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MedLine Citation:
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PMID: 12085347 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Prolonged activation of the mitogen-activated protein kinase (MAPK) pathway enhances expression of the cyclin kinase inhibitor p21 that can promote growth arrest and cell survival in response to cytotoxic insults. Bile acids can also cause prolonged MAPK activation that is cytoprotective against bile acid-induced cell death. Here, we examined the impact of bile acid-induced MAPK signaling and p21 expression on the survival of primary mouse hepatocytes. Deoxycholic acid (DCA) caused prolonged activation of the MAPK pathway that weakly enhanced p21 protein expression. When DCA-induced MAPK activation was blocked using MEK1/2 inhibitors, both hepatocyte viability and expression of p21 were reduced. Surprisingly, constitutive overexpression of p21 in p21+/+ hepatocytes enhanced DCA-induced cell killing. In agreement with these findings, treatment of p21-/- hepatocytes with DCA and MEK1/2 inhibitors also caused less apoptosis than observed in wild-type p21+/+ cells. Expression of p21 in p21-/- hepatocytes did not modify basal levels of apoptosis but restored the apoptotic response of p21-/- cells to those of p21+/+ cells overexpressing p21. These findings suggest that basal expression of p21 plays a facilitating, proapoptotic role in DCA-induced apoptosis. Overexpression of p21 enhanced p53 protein levels. In agreement with a role for p53 in the enhanced apoptotic response, overexpression of p21 did not potentiate apoptosis in p53-/- hepatocytes but, instead, attenuated the death response in these cells. In conclusion, our data suggest that overexpression of p21 can promote apoptosis, leading to elevated sensitivity to proapoptotic stimuli. |
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Authors:
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Liang Qiao; Robert McKinstry; Seema Gupta; Donna Gilfor; Jolene J Windle; Philip B Hylemon; Steven Grant; Paul B Fisher; Paul Dent |
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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, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 36 ISSN: 0270-9139 ISO Abbreviation: Hepatology Publication Date: 2002 Jul |
Date Detail:
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Created Date: 2002-06-26 Completed Date: 2002-07-23 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 39-48 Citation Subset: IM |
Affiliation:
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Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, 401 College Street, Richmond, VA 23298-0058, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Bile Acids and Salts / pharmacology* Blotting, Western Caspase 3 Caspases / metabolism Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21 Cyclins / deficiency, genetics, physiology* Deoxycholic Acid / pharmacology Drug Synergism Electrophoresis, Polyacrylamide Gel Enzyme Activation / drug effects Enzyme Precursors / metabolism Gene Expression Hepatocytes / cytology*, drug effects, metabolism In Situ Nick-End Labeling Male Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinases / metabolism Receptor, Epidermal Growth Factor / metabolism Signal Transduction / drug effects Transfection Tumor Suppressor Protein p53 / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA 63753/CA/NCI NIH HHS; P01 CA 72955/CA/NCI NIH HHS; P01 DK 38030/DK/NIDDK NIH HHS; R01 CA 77141/CA/NCI NIH HHS; R01 CA 88906/CA/NCI NIH HHS; R0I DK 52825/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bile Acids and Salts; 0/Cdkn1a protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Enzyme Precursors; 0/Tumor Suppressor Protein p53; 83-44-3/Deoxycholic Acid; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
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