Document Detail


Cyclin kinase inhibitor p21 potentiates bile acid-induced apoptosis in hepatocytes that is dependent on p53.
MedLine Citation:
PMID:  12085347     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
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:
Title:  Hepatology (Baltimore, Md.)     Volume:  36     ISSN:  0270-9139     ISO Abbreviation:  Hepatology     Publication Date:  2002 Jul 
Date Detail:
Created Date:  2002-06-26     Completed Date:  2002-07-23     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  39-48     Citation Subset:  IM    
Affiliation:
Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, 401 College Street, Richmond, VA 23298-0058, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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:
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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