RhoE Is a Pro-Survival p53 Target Gene that Inhibits ROCK I-Mediated Apoptosis in Response to Genotoxic Stress

Pat P. Ongusaha, Hyung Gu Kim, Sarah A. Boswell, Anne J. Ridley, Channing J. Der, G. Paolo Dotto, Young Bum Kim, Stuart A. Aaronson, Sam W. Lee

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

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 I) 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.

Original languageEnglish
Pages (from-to)2466-2472
Number of pages7
JournalCurrent Biology
Volume16
Issue number24
DOIs
StatePublished - 19 Dec 2006

Keywords

  • CELLBIO
  • CELLCYCLE

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