Cleavage of PITSLRE kinases by ICE/CASP-1 and CPP32/CASP-3 during apoptosis induced by tumor necrosis factor
Cleavage of PITSLRE kinases by ICE/CASP-1 and CPP32/CASP-3 during apoptosis induced by tumor necrosis factor
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DOI：
10.1074/jbc.272.18.11694
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发表时间：
1997-05-02
影响因子：
4.8
通讯作者：
Fiers, W
中科院分区：
文献类型：
--
作者：
Beyaert, R;Kidd, VJ;Fiers, W
越来越多的证据表明，多种天冬氨酸特异性半胱氨酸蛋白酶（caspases, CASPs）在程序性细胞死亡中起着至关重要的作用。许多细胞蛋白已被确定为它们的底物，并作为在死亡过程中测定CASPs激活的标记物。然而，还没有底物被明确地确定为细胞凋亡的效应分子。PITSLRE激酶是cdc2样激酶的一个超家族，与凋亡信号传导和肿瘤发生有关。在本文中，我们报道了肿瘤坏死因子（TNF）介导的细胞凋亡与CrmA-和bcl -2抑制的PITSLRE激酶裂解有关，表明CASPs的作用。7种小鼠casp体外切割p110 PITSLRE激酶α - 2-1的能力测试表明，只有CASP-1 （ICE（白细胞介素-1 β转换酶））和CASP-3 （CPP32）能够在tnf诱导的细胞凋亡中产生相同的43-kDa切割产物。突变分析显示，p110 PITSLRE激酶α - 2-1的裂解发生在YVPDS序列的Asp（393）处，这与casp -1介导的原白介素-1 β的裂解相似。在GASP-1（0/0）小鼠成纤维细胞中仍观察到tnf诱导的PITSLRE激酶的蛋白水解。这些数据表明CASP-3是一种潜在的重要CASP家族蛋白酶，在tnf诱导的细胞凋亡过程中负责PITSLRE激酶的切割。
Emerging evidence suggests that multiple aspartate-specific cysteine proteases (caspases (CASPs)) play a crucial role in programmed cell death. Many cellular proteins have been identified as their substrates and serve as markers to assay the activation of CASPs during the death process. However, no substrate has yet been unambiguously identified as an effector molecule in apoptosis. PITSLRE kinases are a superfamily of Cdc2-like kinases that have been implicated in apoptotic signaling and tumorigenesis. In this paper we report that tumor necrosis factor (TNF)-mediated apoptosis is associated with a CrmA- and Bcl-2-inhibitable cleavage of PITSLRE kinases, indicating a role for CASPs. Testing of seven murine CASPs for their ability to cleave p110 PITSLRE kinase alpha 2-1 in vitro revealed that only CASP-1 (ICE (interleukin-1 beta-converting enzyme)) and CASP-3 (CPP32) were able to produce the same 43-kDa cleavage product as observed in cells undergoing TNF-induced apoptosis. Mutational analysis revealed that cleavage of p110 PITSLRE kinase alpha 2-1 occurred at Asp(393) within the sequence YVPDS, which is similar to that involved in the CASP-1-mediated cleavage of prointerleukin-1 beta. TNF-induced proteolysis of PITSLRE kinases was still observed in fibroblasts from GASP-1(0/0) mice. These data implicate CASP-3 as a potentially important CASP family protease responsible for the cleavage of PITSLRE kinases during TNF-induced apoptosis.