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首页> 外文期刊>The FEBS journal >Dual inhibition of Cdc2 protein kinase activation during apoptosis in Xenopus egg extracts
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Dual inhibition of Cdc2 protein kinase activation during apoptosis in Xenopus egg extracts

机译：非洲爪蟾卵提取物中细胞凋亡过程中Cdc2蛋白激酶激活的双重抑制

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When intracellular damage accumulates in proliferating somatic cells, the cell cycle usually arrests in G(1) or G(2) in a checkpoint-dependent manner, either to repair the damage or to die by apoptosis. In contrast, early embryonic cells lack checkpoint-mediated cell-cycle arrest, and it is not clear whether apoptosis in early embryonic cells occurs at a specific cell cycle stage or at random points. Here, we examined the functional molecular link between the embryonic cell cycle and apoptosis using Xenopus egg extracts. When apoptosis was induced in egg extracts by addition of exogenous cytochromec during cell-cycle progression, cyclinB accumulation was inhibited, Cdc2 was not activated, and the cell cycle arrested at interphase. However, addition of recombinant cyclinB failed to activate Cdc2 due to the strong inhibitory phosphorylation of Cdc2 Tyr15 in apoptotic egg extracts. We found that endogenous Cdc25C, which activates the Cdc2-cyclinB complex by dephosphorylating Cdc2 Tyr15, was inactivated by caspase-mediated cleavage at two sites in the N-terminal regulatory domain. When the hyperactive Cdc25A catalytic fragment was added together with recombinant cyclinB to artificially dephosphorylate Cdc2 Tyr15, M-phase induction was restored in apoptotic egg extracts, indicating that the blockage of cyclinB accumulation and the caspase-mediated inactivation of Cdc25C dually inhibited Cdc2 activation. Apoptosis induction in cytostatic factor-arrested metaphase egg extracts resulted in inactivation of Cdc2 without cyclinB degradation. These results suggest that apoptotic inactivation of Cdc25C plays an important role in arresting the embryonic cell cycle at interphase during apoptosis.
机译：当细胞内损伤积累在增殖的体细胞中时，细胞周期通常以检查点依赖的方式停滞在G（1）或G（2）中，以修复损伤或因凋亡而死亡。相比之下，早期胚胎细胞缺乏检查点介导的细胞周期停滞，并且尚不清楚早期胚胎细胞中的凋亡是在特定的细胞周期阶段还是在随机点发生。在这里，我们检查了非洲爪蟾卵提取物在胚胎细胞周期与凋亡之间的功能性分子联系。当在细胞周期进程中通过添加外源细胞色素诱导卵提取物中的细胞凋亡时，cyclinB的积累受到抑制，Cdc2未激活，细胞周期停在中间期。然而，由于细胞凋亡卵提取物中Cdc2 Tyr15的强烈抑制性磷酸化，重组cyclinB的添加未能激活Cdc2。我们发现，内源性Cdc25C通过Cdc2 Tyr15的去磷酸化激活Cdc2-cyclinB复合物，在N端调节域的两个位点被caspase介导的裂解所灭活。当将高活性Cdc25A催化片段与重组cyclinB一起添加到人工去磷酸化Cdc2 Tyr15时，凋亡卵提取物中的M期诱导得以恢复，表明细胞周期蛋白B的阻滞和caspase介导的Cdc25C失活双重抑制了Cdc2C的激活。抑制细胞生长因子的中期卵提取物中的细胞凋亡诱导导致Cdc2失活，而cyclinB却没有降解。这些结果表明，Cdc25C的细胞凋亡失活在细胞凋亡的中间期阻止胚胎细胞周期中起着重要作用。

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