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

Oncogene volume 25, pages 2708–2716 (2006)Cite this article

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.

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Acknowledgements

We thank S. Sebti (University of South Florida, Tampa, Florida) for the gift of GGTI-298. This study was supported by Cancer Research UK and a National Cancer Institute grant R01 CA030721 to M. Olson.

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Authors and Affiliations

  1. The Wellcome Trust Centre for Human Genetics, Oxford, UK

    M L Coleman

  2. The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK

    R M Densham, D R Croft & M F Olson

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  1. M L Coleman
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  2. R M Densham
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  3. D R Croft
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Correspondence to M F Olson.

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Coleman, M., Densham, R., Croft, D. et al. Stability of p21Waf1/Cip1 CDK inhibitor protein is responsive to RhoA-mediated regulation of the actin cytoskeleton. Oncogene 25, 2708–2716 (2006). https://doi.org/10.1038/sj.onc.1209322

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Keywords

  • signal transduction
  • cellular
  • molecular and tumour biology
  • guanine nucleotide binding proteins and effectors

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