Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2:: Role of a caspase cascade
Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2:: Role of a caspase cascade
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DOI：
10.1016/s1097-2765(00)80055-6
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发表时间：
1998-03-01
期刊：
影响因子：
16
通讯作者：
Ross, R
中科院分区：
文献类型：
--
作者：
Levkau, B;Koyama, H;Ross, R
生长因子剥夺后人内皮细胞的凋亡与细胞周期蛋白A相关的细胞周期蛋白依赖性激酶2（cdk 2）活性的快速和显著上调有关。在凋亡细胞中，cdk抑制剂p21（Cip 1/Waf 1）和p27（Kip 1）的C末端通过特异性切割而被截短。参与这种切割的酶是CPP 32和/或CPP 32样胱天蛋白酶。裂解后，p21（Cip 1/Waf 1）失去其核定位序列并离开核。p21（Cip 1/Waf 1）和p27（Kip 1）的切割导致它们与核细胞周期蛋白-cdk 2复合物的结合显著减少，导致cdk 2活性的显著诱导。显性负性cdk 2以及p21的突变体（Cip 1/Waf 1）对半胱天冬酶切割具有抗性，部分抑制细胞凋亡。这些数据表明，cdk 2的激活，通过半胱天冬酶介导的cdk抑制剂的裂解，可能是有助于在执行凋亡后半胱天冬酶激活。
Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic up-regulation of cyclin A-associated cyclin-dependent kinase 2 (cdk2) activity. In apoptotic cells, the C termini of the cdk inhibitors p21(Cip1/Waf1) and p27(Kip1) are truncated by specific cleavage. The enzyme involved in this cleavage is CPP32 and/or a CPP32-like caspase. After cleavage, p21(Cip1/Waf1) loses its nuclear localization sequence and exits the nucleus. Cleavage of p21(Cip1/Waf1) and p27(Kip1) results in, a substantial reduction in their association with nuclear cyclin-cdk2 complexes, leading to a dramatic induction of cdk2 activity. Dominant-negative cdk2, as well as a mutant of p21(Cip1/Waf1) resistant to caspase cleavage, partially suppress apoptosis. These data suggest that cdk2 activation, through caspase-mediated cleavage of cdk inhibitors, may be instrumental in the execution of apoptosis following caspase activation.