Bile acids up-regulate death receptor 5/TRAIL-receptor 2 expression via a c-Jun N-terminal kinase-dependent pathway involving Sp1.
Bile acids up-regulate death receptor 5 (DR5)/TRAIL-receptor 2 (TRAIL-R2) expression thereby sensitizing hepatocytes to TRAIL-mediated apoptosis. However, the precise mechanism by which bile acids enhance DR5/TRAIL-R2 expression is unknown. Although several bile acids enhanced DR5/TRAIL-R2 expression, deoxycholic acid (DCA) was the most potent. DCA stimulated JNK activation and the JNK inhibitor SP600125 blocked DCA-induced DR5/TRAIL-R2 mRNA and protein expression. Reporter gene analysis identified a 5'-flanking region containing two Sp1 binding sites within the DR5/TRAIL-R2 promoter as bile acid responsive. Sp1 binding to one of the two sites was enhanced by DCA treatment as evaluated by electrophoretic mobility shift assays and chromatin immunoprecipitation studies. JNK inhibition with SP600125 also blocked binding of Sp1 to the DR5/TRAIL-R2 promoter. Finally, point mutations of the Sp1 binding site attenuated promoter activity. In conclusion, Sp1 is a bile acid-responsive transcription factor that mediates DR5/TRAIL-R2 gene expression downstream of JNK.
Higuchi
Hajime
H
Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.
Grambihler
Annette
A
Canbay
Ali
A
Bronk
Steven F
SF
Gores
Gregory J
GJ
D000873:Anthracenes; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000494:pharmacology*; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular; D016384:Consensus Sequence; D017931:DNA Primers; D003840:Deoxycholic Acid / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000873:Anthracenes; D001647:Bile Acids and Salts; D017931:DNA Primers; D004791:Enzyme Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D016329:Sp1 Transcription Factor; C505639:TNFRSF10B protein, human; D003840:Deoxycholic Acid; C432165:pyrazolanthrone