Document Detail

Activator protein-1 and CCAAT/enhancer-binding protein mediated GADD153 expression is involved in deoxycholic acid-induced apoptosis.
MedLine Citation:
PMID:  12069855     Owner:  NLM     Status:  MEDLINE    
Studies have demonstrated bile acids, principally deoxycholic acid (DCA), to be colon tumor promoters. DCA is cytotoxic and increasing evidence suggests a role for DCA-induced apoptosis in colon tumorigenesis. Although the precise mechanism by which DCA induces apoptosis remains unclear, DCA may affect cell growth and cell death via altering intracellular signaling and gene expression. In this study, we examined the effect of DCA on the GADD153 (growth arrest- and DNA damage-inducible gene 153) proapoptotic gene and its role in DCA-induced apoptosis in a human colon cancer cell line, HCT116. Our results showed that GADD153 expression was strongly stimulated by DCA and disruption of this with an antisense GADD153 transcript could significantly suppress DCA-induced apoptosis, suggesting GADD153 is essential for DCA induction of apoptosis. Further studies were conducted to investigate the upstream regulatory factors that participated in DCA mediated GADD153 expression. Activator protein-1 (AP-1) was activated by DCA and an AP-1 regulatory element was identified in the human GADD153 promoter in our previous studies. However, inhibition of the AP-1 activation by the dominant negative mutant c-Jun, Tam67, caused only a partial suppression of both DCA-induced GADD153 expression and apoptosis, indicating AP-1 plays an important but not exclusive role in DCA mediated GADD153 pathway. By further promoter analyses, a novel DCA response element, which is located downstream of the AP-1 binding site in the human GADD153 promoter, was determined and identified as C/EBP regulatory element. These results suggest that GADD153 expression is critical for DCA-induced apoptosis and that multiple signaling pathways that include AP-1 and C/EBP transcription factors are involved in DCA-induced GADD153 expression.
Dianhua Qiao; Eunok Im; Wenqing Qi; Jesse D Martinez
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1583     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2002 Jun 
Date Detail:
Created Date:  2002-06-18     Completed Date:  2002-08-06     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  108-16     Citation Subset:  IM    
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 53792-8550, USA.
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MeSH Terms
Apoptosis / drug effects*
Base Sequence
Binding Sites
CCAAT-Enhancer-Binding Proteins / genetics*,  physiology*
DNA Primers
Deoxycholic Acid / pharmacology*
Gene Expression Regulation / physiology*
Promoter Regions, Genetic
Transcription Factor AP-1 / physiology*
Transcription Factor CHOP
Transcription Factors / genetics*
Transcription, Genetic
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/CCAAT-Enhancer-Binding Proteins; 0/DDIT3 protein, human; 0/DNA Primers; 0/Transcription Factor AP-1; 0/Transcription Factors; 147336-12-7/Transcription Factor CHOP; 83-44-3/Deoxycholic Acid

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