Okada Hitoshi, Suh Woong-Kyung, Jin Jianping, Woo Minna, Du Chunying, Elia Andrew, Duncan Gordon S, Wakeham Andrew, Itie Annick, Lowe Scott W, Wang Xiaodong, Mak Tak W
Amgen Institute and Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada M5G 2C1.
Mol Cell Biol. 2002 May;22(10):3509-17. doi: 10.1128/MCB.22.10.3509-3517.2002.
The mitochondrial proapoptotic protein Smac/DIABLO has recently been shown to potentiate apoptosis by counteracting the antiapoptotic function of the inhibitor of apoptosis proteins (IAPs). In response to apoptotic stimuli, Smac is released into the cytosol and promotes caspase activation by binding to IAPs, thereby blocking their function. These observations have suggested that Smac is a new regulator of apoptosis. To better understand the physiological function of Smac in normal cells, we generated Smac-deficient (Smac(-/-)) mice by using homologous recombination in embryonic stem (ES) cells. Smac(-/-) mice were viable, grew, and matured normally and did not show any histological abnormalities. Although the cleavage in vitro of procaspase-3 was inhibited in lysates of Smac(-/-) cells, all types of cultured Smac(-/-) cells tested responded normally to all apoptotic stimuli applied. There were also no detectable differences in Fas-mediated apoptosis in the liver in vivo. Our data strongly suggest the existence of a redundant molecule or molecules capable of compensating for a loss of Smac function.
线粒体促凋亡蛋白Smac/DIABLO最近被证明可通过对抗凋亡抑制蛋白（IAPs）的抗凋亡功能来增强细胞凋亡。在凋亡刺激下，Smac释放到细胞质中，并通过与IAPs结合促进半胱天冬酶激活，从而阻断其功能。这些观察结果表明Smac是细胞凋亡的一种新调节因子。为了更好地理解Smac在正常细胞中的生理功能，我们通过在胚胎干细胞（ES）中进行同源重组，培育出了Smac缺陷（Smac(-/-)）小鼠。Smac(-/-)小鼠能够存活、生长并正常成熟，且未表现出任何组织学异常。尽管在Smac(-/-)细胞裂解物中，procaspase-3的体外切割受到抑制，但所有测试的培养Smac(-/-)细胞类型对施加的所有凋亡刺激均有正常反应。在体内肝脏中，Fas介导的细胞凋亡也没有可检测到的差异。我们的数据强烈表明存在一种或多种能够补偿Smac功能丧失的冗余分子。
