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Molecular and Cellular Biology, February 2004, p. 1426-1438, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1426-1438.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Involvement of Rho Family GTPases in p19Arf- and p53-Mediated Proliferation of Primary Mouse Embryonic Fibroblasts

Division of Experimental Hematology, Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, Ohio 45229

Received 1 October 2003/ Returned for modification 29 October 2003/ Accepted 30 October 2003

The Rho family GTPases Rac1, RhoA, and Cdc42 function as molecular switches that transduce intracellular signals regulating gene expression and cell proliferation as well as cell migration. p19^Arf and p53, on the other hand, are tumor suppressors that act both independently and sequentially to regulate cell proliferation. To investigate the functional interaction and cooperativeness of Rho GTPases with the p19^Arf-p53 pathway, we examined the contribution of Rho GTPases to the gene transcription and cell proliferation unleashed by deletion of p19Arf or p53 in primary mouse embryo fibroblasts. We found that (i) p19^Arf or p53 deficiency led to a significant increase in PI 3-kinase activity, which in turn upregulated RhoA and Rac1 activities; (ii) deletion of p19Arf or p53 led to an increase in cell growth rate that was in part dependent on RhoA, Rac1, and Cdc42 activities; (iii) p19^Arf or p53 deficiency caused an enhancement of the growth-related transcription factor NF-B and cyclin D1 activities that are partly dependent on RhoA or Cdc42 but not on Rac1; (iv) forced expression of the activating mutants of Rac1, RhoA, or Cdc42 caused a hyperproliferative phenotype of the p19Arf^-/- and p53^-/- cells and promoted transformation of both cells; (v) RhoA appeared to contribute to p53-regulated cell proliferation by modulating cell cycle machinery, while hyperactivation of RhoA further suppressed a p53-independent apoptotic signal; and (vi) multiple pathways regulated by RhoA, including that of Rho-kinase, were required for RhoA to fully promote the transformation of p53^-/- cells. Taken together, these results provide strong evidence indicating that signals through the Rho family GTPases can both contribute to cell growth regulation by p19Arf and p53 and cooperate with p19Arf or p53 deficiency to promote primary cell transformation.

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