A novel function of caspase-8 in the regulation of androgen-receptor-driven gene expression
A novel function of caspase-8 in the regulation of androgen-receptor-driven gene expression
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DOI：
10.1038/sj.emboj.7601483
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发表时间：
2007-01-10
期刊：
影响因子：
11.4
通讯作者：
Wang, Zhengxin
中科院分区：
文献类型：
--
作者：
Qi, Wei;Wu, Hong;Wang, Zhengxin
雄激素受体（AR）的转录调节对男性性发育和前列腺癌至关重要。在这项研究中，我们使用表达克隆策略来鉴定调节AR驱动转录的分子。筛选人cDNA文库导致分离半胱天冬酶-8（Casp 8），其是介导死亡受体诱导的细胞凋亡的起始半胱天冬酶。Casp 8通过破坏AR氨基末端和羧基末端（N/C）相互作用并抑制雄激素诱导的AR核定位，独立于其凋亡蛋白酶活性抑制AR依赖性基因表达。蛋白质-蛋白质相互作用分析显示，Casp 8中的三个基序与已知参与AR N/C相互作用的基序特异性相互作用。对AR-Casp 8相互作用至关重要的氨基酸残基的取代废除了Casp 8介导的AR反式激活抑制。此外，通过RNA干扰敲低Casp 8特异性地影响LNCaP细胞中AR靶向基因的雄激素依赖性表达。这些结果表明，Casp 8具有超出其已知的介导细胞凋亡的作用的新功能。
Transcriptional regulation by the androgen receptor (AR) is critical for male sexual development and prostate cancer. In this study, we used an expression cloning strategy to identify molecules that regulate AR-driven transcription. Screening of a human cDNA library resulted in isolation of caspase-8 (Casp8), an initiator caspase that mediates death-receptor-induced apoptosis. Casp8 repressed AR-dependent gene expression independently of its apoptotic protease activity by disrupting AR amino-terminal and carboxy-terminal (N/C) interaction and inhibiting androgen-induced AR nuclear localization. Protein protein interaction analysis revealed that three motifs in Casp8 specifically interacted with the motifs that are known to be involved in AR N/C interaction. Substitutions of the amino-acid residues critical for AR-Casp8 interactions abolished the Casp8-mediated inhibition of AR transactivation. In addition, knockdown of Casp8 by RNA interference specifically affected the androgen-dependent expression of AR-targeting genes in LNCaP cells. These results indicate that Casp8 has a novel function beyond its known role in the mediation of apoptosis.