Stability of p21(Waf1)/(Cip1) CDK inhibitor protein is responsive to RhoA- mediated regulation of the actin cytoskeleton

Coleman, M., Densham, R., Croft, D. and Olson, M. (2006) Stability of p21(Waf1)/(Cip1) CDK inhibitor protein is responsive to RhoA- mediated regulation of the actin cytoskeleton. Oncogene, 25(19), pp. 2708-2716. (doi:10.1038/sj.onc.1209322)

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Abstract

The proto-oncogene Ras GTPase stimulates transcription of p21(Waf1/Cip1) (p21), which is repressed by the RhoA GTPase. We previously showed that Ras also elevates p21 protein levels by reducing its proteasome-mediated degradation. Therefore, we investigated whether RhoA also influenced p21 protein degradation. Pulse-chase analysis of p21 protein stability revealed that inhibitors of Rho function, which disrupt filamentous actin (F-actin), drastically slowed p21 degradation. Direct F-actin disruption mimicked Rho inhibition to stabilize p21. We found that Rho inhibition, or F-actin disruption, activated the JNK stress-activated protein kinase, and that interfering with JNK signalling, but not p38, abrogated p21 stabilization by Rho inhibition or F-actin-disrupting drugs. In addition, Ras-transformation led to increased constitutive JNK activity that contributed to the elevated p21 protein levels. These data suggest that p21 stability is influenced by a mechanism that monitors F-actin downstream of Rho, and which acts through a pathway involving activation of JNK. These results may have significant implications for therapies that target Rho-signalling pathways to induce p21-mediated cell-cycle arrest.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Olson, Professor Michael
Authors: Coleman, M., Densham, R., Croft, D., and Olson, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncogene
ISSN:0950-9232

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