title: p53-mediated transcriptional regulation and activation of the actin cytoskeleton regulatory RhoC to LIMK2 signaling pathway promotes cell survival.
abstract: 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.
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Croft
authors.forename: Diane
authors.initials: D
authors.lastname: Crighton
authors.forename: Michael S
authors.initials: MS
authors.lastname: Samuel
authors.forename: Filipe C
authors.initials: FC
authors.lastname: Lourenco
authors.forename: June
authors.initials: J
authors.lastname: Munro
authors.forename: Jenifer
authors.initials: J
authors.lastname: Wood
authors.forename: Karim
authors.initials: K
authors.lastname: Bensaad
authors.forename: Karen H
authors.initials: KH
authors.lastname: Vousden
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Ryan
authors.forename: Michael F
authors.initials: MF
authors.lastname: Olson
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D003599:Cytoskeleton; D004249:DNA Damage; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D054461:Lim Kinases / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C102895:LIMK2 protein, human; D054461:Lim Kinases; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; C066690:RHOC protein, human; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein