XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage
XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage
复制标题
DOI：
10.1074/jbc.m910231199
复制
发表时间：
2000-10-13
影响因子：
4.8
通讯作者：
Kufe, D
中科院分区：
文献类型：
--
作者：
Datta, R;Oki, E;Kufe, D
IAP（细胞凋亡抑制剂）家族的抗细胞凋亡蛋白调节程序性细胞死亡。在六种已知的人类IAP相关蛋白中，XIAP是最有效的抑制剂。为了研究XIAP对DNA损伤诱导的细胞凋亡的作用机制，我们制备了稳定过表达XIAP的U-937细胞。结果表明，XIAP抑制1-[β-D-阿拉伯呋喃糖基]胞嘧啶（ara-C）和其他遗传毒性剂诱导的细胞凋亡。XIAP对阿糖胞苷诱导的线粒体细胞色素c的释放和半胱氨酸蛋白酶原-9的衰减裂解没有可检测的影响。此外，我们表明，阿糖胞苷诱导协会XIAP与半胱天冬酶-9的裂解片段，从而抑制半胱天冬酶-9活性。结果还表明，ara-C诱导的半胱天冬酶-8依赖性机制的半胱天冬酶原-3的切割和XIAP抑制半胱天冬酶-3的活性。这些结果表明，XIAP作为蛋白水解加工的半胱天冬酶-9和-3在细胞对遗传毒性应激的反应中的抑制剂，在半胱天冬酶原-9切割的下游起作用。
The IAP (inhibitor of apoptosis) family of anti-apoptotic proteins regulates programmed cell death. Of the six known human IAP-related proteins, XIAP is the most potent inhibitor. To study the mechanistic effects of XIAP on DNA damage-induced apoptosis, we prepared U-937 cells that stably overexpress XIAP. The results demonstrate that XIAP inhibits apoptosis induced by 1-[beta-D-arabinofuranosyl]cytosine (ara-C) and other genotoxic agents. XIAP had no detectable effect on ara-C-induced release of mitochondrial cytochrome c and attenuated cleavage of procaspase-9. In addition, we show that ara-C induces the association of XIAP with the cleaved fragments of caspase-9 and thereby inhibition of caspase-9 activity. The results also demonstrate that ara-C induces cleavage of procaspase-3 by a caspase-8-dependent mechanism and that XIAP inhibits caspase-3 activity. These results demonstrate that XIAP functions downstream of procaspase-9 cleavage as an inhibitor of both proteolytically processed caspase-9 and -3 in the cellular response to genotoxic stress.