Stability of p21Waf1/Cip1 CDK inhibitor protein is responsive to RhoA-mediated regulation of the actin cytoskeleton
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The proto-oncogene Ras GTPase stimulates transcription of p21Waf1/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.
|Number of pages||9|
|Publication status||Published - 4 May 2006|
- Actins, Animals, Blotting, Northern, Blotting, Western, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p21, Cytoskeleton, Enzyme Stability, Fibroblasts, MAP Kinase Kinase 4, Mice, NIH 3T3 Cells, Signal Transduction, Swiss 3T3 Cells, p38 Mitogen-Activated Protein Kinases, ras Proteins, rhoA GTP-Binding Protein