RhoE is a pro-survival p53 target gene that inhibits ROCK I-mediated apoptosis in response to genotoxic stress (Retracted article. See vol. 29, pg. 2107, 2019)
RhoE is a pro-survival p53 target gene that inhibits ROCK I-mediated apoptosis in response to genotoxic stress (Retracted article. See vol. 29, pg. 2107, 2019)
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DOI：
10.1016/j.cub.2006.10.056
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发表时间：
2006-12-19
期刊：
影响因子：
9.2
通讯作者：
Lee, Sam W.
中科院分区：
文献类型：
--
作者：
Ongusaha, Pat P.;Kim, Hyung-Gu;Lee, Sam W.
GTP酶的Rho家族通过改变肌动蛋白细胞骨架来调节细胞行为的许多方面[1-6]。大多数Rho家族蛋白作为分子开关在活性的GTP结合构象和非活性的GDP结合构象之间循环[1-6]。与典型的Rho家族蛋白不同，Rnd亚家族成员，包括Rnd 1、Rnd 2、RhoE（也称为Rnd 3）和RhoH，是GT3缺乏的，因此预期具有组成型活性[7-10]。在这里，我们确定了一个意想不到的作用RhoE/Rnd 3在调节p53介导的应激反应。我们表明，RhoE是一个转录p53的靶基因，基因毒性应力触发肌动蛋白解聚，导致肌动蛋白应力纤维解体，通过p53依赖的RhoE诱导。沉默RhoE诱导响应于基因毒性应激维持应激纤维的形成，并显着增加细胞凋亡，这意味着RhoE在p53依赖性细胞凋亡的拮抗作用。我们发现，RhoE抑制ROCK I（Rho相关激酶1）的活性在遗传毒性应激，从而抑制细胞凋亡。我们证明，p53介导的诱导RhoE响应DNA损伤有利于细胞存活，部分通过抑制ROCK I介导的凋亡。因此，预计RhoE通过调节ROCK I信号传导来控制细胞存活和细胞死亡之间的平衡以响应遗传毒性应激而起作用。
The Rho family of GTPases regulates many aspects of cellular behavior through alterations to the actin cytoskeleton [1-6]. The majority of the Rho family proteins function as molecular switches cycling between the active, GTP-bound and the inactive, GDP-bound conformations [1-6]. Unlike typical Rho-family proteins, the Rnd subfamily members, including Rnd1, Rnd2, RhoE (also known as Rnd3), and RhoH, are GTPase deficient and are thus expected to be constitutively active [7-10]. Here, we identify an unexpected role for RhoE/Rnd3 in the regulation of the p53-mediated stress response. We show that RhoE is a transcriptional p53 target gene and that genotoxic stress triggers actin depolymerization, resulting in actin-stress-fiber disassembly through p53-dependent RhoE induction. Silencing of RhoE induction in response to genotoxic stress maintains stress fiber formation and strikingly increases apoptosis, implying an antagonistic role for RhoE in p53-dependent apoptosis. We found that RhoE inhibits ROCK I (Rho-associated kinase 1) activity during genotoxic stress and thereby suppresses apoptosis. We demonstrate that the p53-mediated induction of RhoE in response to DNA damage favors cell survival partly through inhibition of ROCK I-mediated apoptosis. Thus, RhoE is anticipated to function by regulating ROCK I signaling to control the balance between cell survival and cell death in response to genotoxic stress.