Human VRK2 modulates apoptosis by interaction with Bcl-xL and regulation of BAX gene expression.
Human VRK2 modulates apoptosis by interaction with Bcl-xL and regulation of BAX gene expression.
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DOI：
10.1038/cddis.2013.40
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发表时间：
2013-02-28
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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VRK 2是一种新的丝氨酸-苏氨酸激酶，其VRK 2A亚型位于内质网和线粒体膜上。我们已经研究了VRK 2A在神经细胞介导的细胞凋亡的调节中的潜在作用。VRK 2A可以通过两种不同的方式调节内源性凋亡途径。VRK 2A蛋白直接与Bcl-xL相互作用，但不与Bcl-2、Bax、Bad、BclA或Binp-3L相互作用。VRK 2A不与Bax竞争与Bcl-xL的相互作用，并且这些蛋白质可以形成减少凋亡的复合物。因此，高VRK 2水平赋予针对细胞凋亡的保护。此外，VRK 2敲低导致由其近端启动子介导的BAX基因表达的表达增加，因此VRK 2A表现为BAX的负调节因子。低水平的VRK 2A引起线粒体Bax蛋白水平的增加，导致细胞色素C的释放和半胱天冬酶活化的增加，通过PARP处理检测。VRK 2A缺失导致细胞死亡增加，这可以通过膜联蛋白V+细胞的增加来检测。低水平的VRK 2A增加细胞对化疗药物如喜树碱或阿霉素诱导凋亡的敏感性。我们的结论是，VRK 2A蛋白是一种新的细胞凋亡的调节剂。
VRK2 is a novel Ser-Thr kinase whose VRK2A isoform is located in the endoplasmic reticulum and mitochondrial membranes. We have studied the potential role that VRK2A has in the regulation of mitochondrial-mediated apoptosis. VRK2A can regulate the intrinsic apoptotic pathway in two different ways. The VRK2A protein directly interacts with Bcl-xL, but not with Bcl-2, Bax, Bad, PUMA or Binp-3L. VRK2A does not compete with Bax for interaction with Bcl-xL, and these proteins can form a complex that reduces apoptosis. Thus, high VRK2 levels confer protection against apoptosis. In addition, VRK2 knockdown results in an increased expression of BAX gene expression that is mediated by its proximal promoter, thus VRK2A behaves as a negative regulator of BAX. Low levels of VRK2A causes an increase in mitochondrial Bax protein level, leading to an increase in the release of cytochrome C and caspase activation, detected by PARP processing. VRK2A loss results in an increase in cell death that can be detected by an increase in annexinV+ cells. Low levels of VRK2A increase cell sensitivity to induction of apoptosis by chemotherapeutic drugs like camptothecin or doxorubicin. We conclude that VRK2A protein is a novel modulator of apoptosis.
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DOI：
10.1073/pnas.0708800104
发表时间：
2007-12-18
影响因子：
11.1
作者：
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通讯作者：
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