ACTIVATION OF CYCLIN A-DEPENDENT PROTEIN-KINASES DURING APOPTOSIS
ACTIVATION OF CYCLIN A-DEPENDENT PROTEIN-KINASES DURING APOPTOSIS
复制标题
DOI：
10.1073/pnas.91.9.3754
复制
发表时间：
1994-04-26
影响因子：
11.1
通讯作者：
SCHLEGEL, R
中科院分区：
文献类型：
--
作者：
MEIKRANTZ, W;GISSELBRECHT, S;SCHLEGEL, R
用星形孢子素、咖啡因、6-二甲氨基嘌呤和冈田酸等激活M期促进因子并诱导类似处理的仓鼠细胞系过早有丝分裂，可诱导S期阻滞的HeLa细胞发生凋亡。将这些药物添加到异步化生长的HeLa细胞或用洛伐他汀阻断在G(1)早期的细胞中，效果很小或没有影响。S的细胞周期停滞也促进了肿瘤坏死因子α诱导的细胞凋亡，消除了放线菌酮同时治疗的正常要求。在所有被测试的凋亡诱导剂中，浓缩的染色质的出现伴随着周期蛋白A相关的组蛋白H1激酶活性的2-7倍的增加，水平接近有丝分裂值。在检查中，已知的与细胞周期蛋白A相关的催化亚基--CDC2和CDK2都被激活。Bcl2的稳定过表达抑制了所有受试药物的诱导凋亡活性，并减少了细胞核内的CDc2和CDk2的数量，提示bcl2抑制细胞凋亡的染色质凝集特征的可能机制。这些发现表明，有丝分裂所需的至少一个生化步骤，即激活细胞周期蛋白A依赖的蛋白激酶，也是细胞凋亡过程中的一个重要事件。
Apoptosis was induced in S-phase-arrested HeLa cells by staurosporine, caffeine, 6-dimethylaminopurine, and okadaic acid, agents that activate M-phase-promoting factor and induce premature mitosis in similarly treated hamster cell lines. Addition of these agents to asynchronously growing HeLa cells or to cells arrested in early G(1) phase with lovastatin had little or no effect. S-phase arrest also promoted tumor necrosis factor alpha-induced apoptosis, eliminating the normal requirement for simultaneous cycloheximide treatment. For all of the apoptosis-inducing agents tested, the appearance of condensed chromatin was accompanied by 2- to 7-fold increases in cyclin A-associated histone H1 kinase activity, levels approximating the mitotic value. Where examined, both Cdc2 and Cdk2, the catalytic subunits known to associate with cyclin A, were activated. Stable overexpression of bcl-2 suppressed the apoptosis-inducing activity of all agents tested and reduced the amount of Cdc2 and Cdk2 in the nucleus, suggesting a possible mechanism by which bcl-2 inhibits the chromatin condensation characteristic of apoptosis. These findings suggest that at least one of the biochemical steps required for mitosis, activation of cyclin A-dependent protein kinases, is also an important event during apoptosis.