A death receptor-associated anti-apoptotic protein, BRE, inhibits mitochondrial apoptotic pathway
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摘要BRE, brain and reproductive organ-expressed protein, was found previously to bind the intracellular juxtamembrane domain of a ubiquitous death receptor, tumor necrosis factor receptor 1 (TNF-R1), and to downregulate TNF-alpha-induced activation of NF-kappaB. Here we show that BRE also binds to another death receptor, Fas, and upon overexpression conferred resistance to apoptosis induced by TNF-alpha, anti-Fas agonist antibody, cycloheximide, and a variety of stress-related stimuli. However, down-regulation of the endogenous BRE by small interfering RNA increased apoptosis to TNF-alpha, but nottoetoposide, indicating that the physiological antiapoptotic role of this protein is specific to death receptor-mediated apoptosis. We further demonstrate that BRE mediates antiapoptosis by inhibiting the mitochondrial apoptotic machinery but without translocation to the mitochondria or nucleus or down-regulation of the cellular level of truncated Bid. Dissociation of BRE rapidly from TNF-R1, but not from Fas, upon receptor ligation suggests that this protein interacts with the death inducing signaling complex during apoptotic induction. Increased association of BRE with phosphorylated, sumoylated, and ubiquitinated proteins after death receptor stimulation was also detected. We conclude that in contrast to the truncated Bid that integrates mitochondrial apoptosis to death receptor-triggered apoptotic cascade, BRE inhibits the integration. We propose that BRE inhibits, by ubiquitination-like activity, components in or proximal to the death-inducing signaling complexes that are necessary for activation of the mitochondria.
著者Li Q, Ching AKK, Chan BCL, Chow SKY, Lim PL, Ho TCY, Ip WK, Wong CK, Lam CWK, Lee KKH, Chan JYH, Chui YL
期刊名稱Journal of Biological Chemistry
出版年份2004
月份12
日期10
卷號279
期次50
出版社AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
頁次52106 - 52116
國際標準期刊號0021-9258
電子國際標準期刊號1083-351X
語言英式英語
Web of Science 學科類別Biochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY

上次更新時間 2020-19-10 於 02:34