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

Croft, D.R. et al. (2011) p53-mediated transcriptional regulation and activation of the actin cytoskeleton regulatory RhoC to LIMK2 signaling pathway promotes cell survival. Cell Research, 21(4), pp. 666-682. (doi:10.1038/cr.2010.154)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bensaad, Mr Karim and Ryan, Professor Kevin and Crighton, Dr Diane and Vousden, Karen and Sansom, Professor Owen and Olson, Professor Michael
Authors: Croft, D.R., Crighton, D., Samuel, M.S., Lourenco, F.C., Munro, J., Wood, J., Bensaad, K., Vousden, K.H., Sansom, O.J., Ryan, K.M., and Olson, M.F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Research
Publisher:Nature Publishing Group
ISSN:1001-0602
ISSN (Online):1748-7838
Published Online:01 January 2010

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