p53-mediated transcriptional regulation and activation of the actin cytoskeleton regulatory RhoC to LIMK2 signaling pathway promotes cell survival

• Published in: Cell research 2011-04, Vol.21 (4), p.666-682
• Main Authors: Croft, Daniel R, Crighton, Diane, Samuel, Michael S, Lourenco, Filipe C, Munro, June, Wood, Jenifer, Bensaad, Karim, Vousden, Karen H, Sansom, Owen J, Ryan, Kevin M, Olson, Michael F
• Format: Article
• Language: English
• Subjects: 631/337/1427; 631/80/128; 631/80/86; Actin; Actins - metabolism; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biomedical and Life Sciences; Cell Biology; Cell cycle; Cell fate; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Chemotherapy; Chromatin Immunoprecipitation; Cytoskeleton; Deoxyribonucleic acid; DNA; DNA Damage; Fluorescent Antibody Technique; Gene Expression Regulation; Gene Knockdown Techniques; Gene regulation; Genotoxicity; Humans; Immunoblotting; Life Sciences; LIM kinase; Lim Kinases - metabolism; Mice; Microarray Analysis; Original; original-article; p53; p53 protein; rho GTP-Binding Proteins - metabolism; rho-Associated Kinases - metabolism; rhoC GTP-Binding Protein; RNA, Small Interfering; RNA介导; Signal transduction; Signal Transduction - drug effects; Survival; Transcription activation; Transcription, Genetic; Tumor Suppressor Protein p53 - metabolism; 信号转导通路; 激活; 监管机构; 细胞存活; 肌动蛋白细胞骨架; 转录调控
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2010.154

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.