半胱天冬酶3介导的Rac GTP酶失活促进人淋巴瘤细胞中的药物诱导凋亡。
Caspase 3-mediated inactivation of rac GTPases promotes drug-induced apoptosis in human lymphoma cells.
作者信息
Zhang Baolin, Zhang Yaqin, Shacter Emily
机构信息
Laboratory of Biochemistry, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
出版信息
Mol Cell Biol. 2003 Aug;23(16):5716-25. doi: 10.1128/MCB.23.16.5716-5725.2003.
The Rac members of the Rho family GTPases control signaling pathways that regulate diverse cellular activities, including cytoskeletal organization, gene transcription, and cell transformation. Rac is implicated in apoptosis, but little is known about the mechanism by which it responds to apoptotic stimuli. Here we demonstrate that endogenous Rac GTPases are caspase 3 substrates that are cleaved in human lymphoma cells during drug-induced apoptosis. Cleavage of Rac1 occurs at two unconventional caspase 3 sites, VVGD11/G and VMVD47/G, and results in inactivation of the GTPase and effector functions of the protein (binding to the p21-activated protein kinase PAK1). Expression of caspase 3-resistant Rac1 mutants in the cells suppresses drug-induced apoptosis. Thus, proteolytic inactivation of Rac GTPases represents a novel, irreversible mechanism of Rac downregulation that allows maximal cell death following drug treatment.
Rho家族GTP酶的Rac成员控制着调节多种细胞活动的信号通路，包括细胞骨架组织、基因转录和细胞转化。Rac与细胞凋亡有关，但对其响应凋亡刺激的机制了解甚少。在这里，我们证明内源性Rac GTP酶是caspase 3的底物，在药物诱导的人淋巴瘤细胞凋亡过程中被切割。Rac1的切割发生在两个非常规的caspase 3位点，VVGD11/G和VMVD47/G，导致GTP酶失活和该蛋白的效应功能（与p21激活的蛋白激酶PAK1结合）丧失。细胞中抗caspase 3的Rac1突变体的表达抑制了药物诱导的细胞凋亡。因此，Rac GTP酶的蛋白水解失活代表了一种新的、不可逆的Rac下调机制，使药物治疗后细胞最大限度地死亡。
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