IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.
IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.
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发表时间：
2007
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影响因子：
64.5
通讯作者：
E. Varfolomeev;J. Blankenship;S. Wayson;A. Fedorova;N. Kayagaki;Parie Garg;K. Zobel;Jasmin N. Dynek;L. Elliott;H. Wallweber;J. Flygare;W. Fairbrother;K. Deshayes;V. Dixit;D. Vučić
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作者：
E. Varfolomeev;J. Blankenship;S. Wayson;A. Fedorova;N. Kayagaki;Parie Garg;K. Zobel;Jasmin N. Dynek;L. Elliott;H. Wallweber;J. Flygare;W. Fairbrother;K. Deshayes;V. Dixit;D. Vučić
凋亡抑制剂（IAP）蛋白是一种抗凋亡调节因子，可在多种刺激下阻断细胞死亡。它们在人类恶性肿瘤中表达水平升高，是开发新型癌症治疗方法的有吸引力的靶点。在此，我们证明了小分子IAP拮抗剂结合到杆状病毒IAP重复（BIR）结构域，导致显著诱导自身泛素化活性和c-IAP的快速蛋白酶体降解。IAP拮抗剂也诱导依赖于TNF信号和新生蛋白生物合成的细胞死亡。此外，c-IAP蛋白被发现作为NF-kappaB信号的调节因子。通过其泛素E3连接酶活性，c-IAP1和c-IAP2促进非典型NF-kappaB通路中中心丝氨酸/苏氨酸激酶NIK的蛋白酶体降解。
Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway.