Document Detail


CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis.
MedLine Citation:
PMID:  20430872     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Endoplasmic reticulum (ER) stress-mediated apoptosis is a key feature of hepatocyte cytotoxicity by saturated free fatty acids (FFA). This lipoapoptosis is dependent, in part, on the transcriptional upregulation of the BH3-only protein PUMA (p53 upregulated modulator of apoptosis). Although the activator protein (AP)-1 complex facilitates PUMA expression by saturated FFA, the transcription factor CAAT/enhancer binding homologous protein (CHOP) is also induced by ER stress and promotes apoptosis. To integrate the role of these two transcription factors in ER stress-induced apoptosis, we examined the relative contribution of CHOP and AP-1 in mediating PUMA induction by saturated FFA. Our results demonstrate that short-hairpin RNA-targeted knockdown of CHOP attenuates palmitate-induced apoptosis in Huh-7 cells. Loss of CHOP induction also reduced the increase in PUMA mRNA and protein levels as well as Bax activation by palmitate. No functional CHOP binding sites were identified in the PUMA promoter sequence. Rather, we observed that CHOP physically interacts with the AP-1 complex protein c-Jun upon palmitate treatment, and a CHOP:phosphorylated c-Jun heteromeric complex binds to the AP-1 consensus binding sequence within the PUMA promoter region. Finally, loss of function studies suggest that both transcription factors are necessary for maximal PUMA induction. Collectively, these data suggest that CHOP and AP-1 cooperatively mediate PUMA induction during hepatocyte lipoapoptosis.
Authors:
Sophie C Cazanave; Nafisa A Elmi; Yuko Akazawa; Steven F Bronk; Justin L Mott; Gregory J Gores
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-04-29
Journal Detail:
Title:  American journal of physiology. Gastrointestinal and liver physiology     Volume:  299     ISSN:  1522-1547     ISO Abbreviation:  Am. J. Physiol. Gastrointest. Liver Physiol.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-16     Completed Date:  2010-07-12     Revised Date:  2014-09-05    
Medline Journal Info:
Nlm Unique ID:  100901227     Medline TA:  Am J Physiol Gastrointest Liver Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  G236-43     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Apoptosis*
Apoptosis Regulatory Proteins / genetics,  metabolism*
Binding Sites
Cell Line, Tumor
Endoplasmic Reticulum / metabolism
Fatty Liver / genetics,  metabolism*,  pathology
Hepatocytes / metabolism*,  pathology
Humans
Oleic Acid / metabolism*
Palmitic Acid / metabolism*
Phosphorylation
Promoter Regions, Genetic
Proto-Oncogene Proteins / genetics,  metabolism*
Proto-Oncogene Proteins c-jun / metabolism
RNA Interference
RNA, Messenger / metabolism
Transcription Factor AP-1 / genetics,  metabolism*
Transcription Factor CHOP / genetics,  metabolism*
Transcriptional Activation
Transfection
Up-Regulation
bcl-2-Associated X Protein / metabolism
Grant Support
ID/Acronym/Agency:
DK079875/DK/NIDDK NIH HHS; DK41876/DK/NIDDK NIH HHS; DK84567/DK/NIDDK NIH HHS; K01 DK079875/DK/NIDDK NIH HHS; K01 DK079875-03/DK/NIDDK NIH HHS; P30 DK084567/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/BAX protein, human; 0/BBC3 protein, human; 0/DDIT3 protein, human; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 0/Transcription Factor AP-1; 0/bcl-2-Associated X Protein; 147336-12-7/Transcription Factor CHOP; 2UMI9U37CP/Oleic Acid; 2V16EO95H1/Palmitic Acid
Comments/Corrections

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