Publication Date:
2012-07-03
Description:
The transcription factor CHOP/GADD153 is induced during the unfolded protein response and is related to the induction of ER stress-mediated apoptosis. However, how CHOP is organized between the pro-survival and pro-apoptotic roles of ER stress remains largely undefined. In this study, we identified the apoptosis regulating protein suppressed by CHOP. We found that treatment of Caki cells with CHOP-inducing drugs including withaferin A, thapsigargin, brefeldin A, and silybin led to a strong reduction in cFLIP L protein levels together with a concomitant increase in the CHOP protein. Interestingly, Wit A down-regulated cFLIP L expression via both suppressing mRNA transcription and increasing cFLIPL protein instability. We also found that forced expression of CHOP dose-dependently led to a decrease of cFLIP L protein expression but did not alter cFLIP L mRNA levels. Additionally, we observed that siRNA-mediated CHOP silencing recovered the cFLIP L expression decreased by CHOP-inducing agents in Caki cells. Finally, we showed that CHOP facilitates ubiquitin/proteasome-mediated cFLIP L degradation, leading to down-regulation of cFLIP L . Finally, cFLIP L over-expression reduced cell death induced by treatment with brefeldin A, thapsigargin, and silybin. Taken together, our results provide novel evidence that cFLIP L is a CHOP control target and that CHOP-induced down-regulation of cFLIP L is due to activation of the ubiquitin/proteasome pathways. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.
Electronic ISSN:
0091-7419
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
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