期刊
CELL RESEARCH
卷 21, 期 4, 页码 666-682出版社
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2010.154
关键词
LIMK; RhoC; p53; DNA damage; actin; cofilin; cytoskeleton
类别
资金
- Cancer Research UK
- Cancer Research UK [15816, 12481] Funding Source: researchfish
The central arbiter of cell fate in response to DNA damage is p53, which regulates the expression of genes involved in cell cycle arrest, survival and apoptosis. Although many responses initiated by DNA damage have been characterized, the role of actin cytoskeleton regulators is largely unknown. We now show that RhoC and LIM kinase 2 (LIMK2) are direct p53 target genes induced by genotoxic agents. Although RhoC and LIMK2 have well-established roles in actin cytoskeleton regulation, our results indicate that activation of LIMK2 also has a pro-survival function following DNA damage. LIMK inhibition by siRNA-mediated knockdown or selective pharmacological blockade sensitized cells to radio-or chemotherapy, such that treatments that were sub-lethal when administered singly resulted in cell death when combined with LIMK inhibition. Our findings suggest that combining LIMK inhibitors with genotoxic therapies could be more efficacious than single-agent administration, and highlight a novel connection between actin cytoskeleton regulators and DNA damage-induced cell survival mechanisms.
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