J Biol Chem. 2003 Jan 3;278(1):454-61. Epub 2002 Oct 28.

Bile acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis.External

Higuchi, H., Yoon, J. H., Grambihler, A., Werneburg, N., Bronk, S. F., Gores, G. J.,
--- - Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.
Bile acids induce hepatocyte injury by enhancing death receptor-mediated apoptosis. In this study, bile acid effects on TRAIL-mediated apoptosis were examined to gain insight into bile acid potentiation of death receptor signaling. TRAIL-induced apoptosis of HuH-7 cells, stably transfected with a bile acid transporter, was enhanced by bile acids. Caspase 8 and 10 activation, bid cleavage, cytosolic cytochrome c, and caspase 3 activation by TRAIL were all increased by the bile acid glycochenodeoxycholate (GCDCA). GCDCA (100 microm) did not alter expression of TRAIL-R1/DR4, TRAIL-R2/DR5, procaspase 8, cFLIP-L, cFLIP-s, Bax, Bcl-xL, or Bax. However, both caspase 8 and caspase 10 recruitment and processing within the TRAIL death-inducing signaling complex (DISC) were greater in GCDCA-treated cells whereas recruitment of cFLIP long and short was reduced. GCDCA stimulated phosphorylation of both cFLIP isoforms, which was associated with decreased binding to GST-FADD. The protein kinase C antagonist chelerythrine prevented bile acid-stimulated cFLIP-L and -s phosphorylation, restored cFLIP binding to GST-FADD, and attenuated bile acid potentiation of TRAIL-induced apoptosis. These results provide new insights into the mechanisms of bile acid cytotoxicity and the proapoptotic effects of cFLIP phosphorylation in TRAIL signaling.
PMID: 12407100External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vitro interaction
  DD1 DD2 Reference
Family DD1 DD2 Method Species Region Expression Species Region Expression
DED Caspase10 Link FADD GST fusion protein pull-down HuH-7 lysate Not specified Full length E.coli 12407100
DED Caspase8 Link FADD GST fusion protein pull-down HuH-7 lysate Not specified Full length E.coli 12407100
DED FADD Link FLIP GST fusion protein pull-down Not specified Full length E.coli HuH-7 lysate 12407100
(Link: click this icon to show interactions only between the two corresponding DDs)