Stability of p21Waf1/Cip1 CDK inhibitor protein is responsive to RhoA-mediated regulation of the actin cytoskeleton

M L Coleman, R M Densham, D R Croft, M F Olson

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2708-16
Number of pages9
JournalOncogene
Volume25
Issue number19
DOIs
Publication statusPublished - 4 May 2006

Keywords

  • 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

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