title: CHOP down-regulates cFLIP(L)  expression by promoting ubiquitin/proteasome-mediated cFLIP(L)  degradation.
abstract: 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.
authors: Department of Anatomy, College of Medicine, Yeungnam University, Daegu 705-717, Korea.
authors: Hyo-Jeong
authors: HJ
authors: Noh
authors: Sung-Jun
authors: SJ
authors: Lee
authors: Eon-Gi
authors: EG
authors: Sung
authors: In-Hwan
authors: IH
authors: Song
authors: Joo-Young
authors: JY
authors: Kim
authors: Chang-Hoon
authors: CH
authors: Woo
authors: Taeg Kyu
authors: TK
authors: Kwon
authors: Tae-Jin
authors: TJ
authors: Lee
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007976:Leupeptins / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D055550:Protein Stability; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination; D056811:Unfolded Protein Response; D054358:Withanolides / Q000494:pharmacology
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C497249:DDIT3 protein, human; D007976:Leupeptins; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012838:Silymarin; D025801:Ubiquitin; D054358:Withanolides; D051742:Transcription Factor CHOP; D020126:Brefeldin A; D000077385:Silybin; D019284:Thapsigargin; D046988:Proteasome Endopeptidase Complex; C009684:withaferin A; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde