Cdk2 phosphorylation of Bcl-xL after stress converts it to a pro-apoptotic protein mimicking Bax/Bak.
Cdk2 phosphorylation of Bcl-xL after stress converts it to a pro-apoptotic protein mimicking Bax/Bak.
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DOI：
10.1038/cddiscovery.2015.66
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发表时间：
2016
影响因子：
7
通讯作者：
Price PM
中科院分区：
文献类型：
--
作者：
Megyesi J;Tarcsafalvi A;Seng N;Hodeify R;Price PM
细胞凋亡是一种受调控的细胞死亡形式，通过确定的生化途径进行。大多数细胞凋亡是由促生存和促凋亡Bcl-2家族蛋白之间的相互作用控制的，其中死亡通常是线粒体外膜通透性的结果。许多药物影响这种平衡以促进细胞凋亡，但这一过程尚不完全清楚。我们发现化疗药物顺铂通过细胞周期蛋白依赖性激酶2磷酸化促生存Bcl-2家族成员Bcl-xL，从而启动凋亡途径。磷酸化发生在以前未报道的位点，其生物学意义通过Bcl-xL的拟磷修饰得到证实，该修饰能够在不添加顺铂的情况下诱导细胞凋亡。诱导细胞死亡的机制与促凋亡的Bcl-2家族蛋白相似，即磷酸化的Bcl-xL易位到线粒体膜上，并在膜上形成孔。这引发了细胞色素c的释放和半胱天冬酶的激活，导致细胞死亡。
Apoptosis is a regulated form of cell death that proceeds by defined biochemical pathways. Most apoptosis is controlled by interactions between pro-survival and pro-apoptotic Bcl-2 family proteins in which death is often the consequence of permeabilization of the mitochondrial outer membrane. Many drugs affect this equilibrium to favor apoptosis but this process is not completely understood. We show that the chemotherapeutic drug cisplatin initiates an apoptotic pathway by phosphorylation of a pro-survival Bcl-2 family member, Bcl-xL, by cyclin-dependent kinase 2. The phosphorylation occurred at a previously unreported site and its biologic significance was demonstrated by a phosphomimetic modification of Bcl-xL that was able to induce apoptosis without addition of cisplatin. The mechanism of cell death induction was similar to that initiated by pro-apoptotic Bcl-2 family proteins, that is, phosphorylated Bcl-xL translocated to the mitochondrial membrane, and formed pores in the membrane. This initiated cytochrome c release and caspase activation that resulted in cell death.