Interaction of a cyclin E fragment with Ku70 regulates Bax-mediated apoptosis
Interaction of a cyclin E fragment with Ku70 regulates Bax-mediated apoptosis
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DOI：
10.1128/mcb.01448-06
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发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
Almasan, Alexandru
中科院分区：
文献类型：
--
作者：
Mazumder, Suparna;Plesca, Dragos;Almasan, Alexandru
cyclin E/Cdk 2复合物在G（1）/S细胞周期转换和DNA复制中起重要作用。早期我们发现，在造血肿瘤细胞中，半胱天冬酶介导的细胞周期蛋白E裂解产生p18-细胞周期蛋白E，它不能与Cdk 2相互作用，因此发挥作用的细胞周期无关。抗切割的细胞周期蛋白E突变体的表达大大减少了细胞凋亡，表明细胞周期蛋白E切割的关键作用。p18-cyclin E表达可诱导许多细胞类型的凋亡或对凋亡刺激物的敏感性。在这里，我们确定Ku 70作为一个特定的p18-细胞周期蛋白E相互作用的合作伙伴。在造血肿瘤细胞系中，p18-cyclin E与Ku 70的结合诱导Bax从Ku 70解离，随后Bax活化。Bax激活的这一机制导致所有检测的肿瘤细胞系中凋亡信号的放大。N-末端Ku 70缺失突变体不能与p18-cyclin E结合以调节其凋亡作用。p18-cyclin E介导的凋亡扩增依赖于Bax和Ku 70在Ku 70（-/-）和Bax（-/-）小鼠胚胎成纤维细胞和造血细胞中的显著减少，其中Bax敲低通过短干扰RNA实现。p18-cyclin E/Ku 70和Bax/Ku 70相互作用提供了暴露于遗传毒性应激的细胞的凋亡和存活之间的平衡。
The cyclin E/Cdk2 complex plays an essential role in the G(1)/S cell cycle transition and DNA replication. Earlier we showed that in hematopoietic tumor cells, caspase-mediated cleavage of cyclin E generates p18-cyclin E, which is unable to interact with Cdk2 and therefore plays a role independent of the cell cycle. The expression of a cleavage-resistant cyclin E mutant greatly diminishes apoptosis, indicating the critical role of cyclin E cleavage. p18-cyclin E expression can induce apoptosis or sensitization to apoptotic stimuli in many cell types. Here we identify Ku70 as a specific p18-cyclin E-interacting partner. In hematopoietic tumor cell lines, the association of p18-cyclin E with Ku70 induces the dissociation of Bax from Ku70, followed by Bax activation. This mechanism of Bax activation leads to the amplification of the apoptosis signal in all tumor cell lines examined. N-terminal Ku70 deletion mutants are unable to bind to p18-cyclin E to regulate its apoptotic effect. p18-cyclin E-mediated amplification of apoptosis is dependent on Bax and Ku70 being greatly diminished in Ku70(-/-) and Bax(-/-) mouse embryo fibroblasts and in hematopoietic cells where Bax knockdown was achieved by short interfering RNA. The p18-cyclin E/Ku70 and Bax/Ku70 interactions provide a balance between apoptosis and the survival of cells exposed to genotoxic stress.