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p53 plays a major role in the prevention of tumour development. It responds to a range of potentially oncogenic stresses by activating protective mechanisms, most notably cell cycle arrest and apoptosis. The p53 gene is also induced during normal liver regeneration, but the purpose of this remains unclear. It has been hypothesized that p53 serve as a proliferative “brake” to control excessive proliferation. However, it has lately been shown that p53 inhibition reduces hepatocyte growth factor-induced hepatocyte proliferation. In primary rat hepatocytes, we found that epidermal growth factor (EGF) activated p53 and thus induced the cyclin-dependent kinase inhibitor p21Cip1. This induction was PI3 kinase-dependent. p53 inactivation, with a dominant negative mutant (p53V143A), attenuated EGF-induced CDK2 phosphorylation, pRb hyperphosphorylation and cell proliferation. Notably, p21Cip1 induction and nuclear translocation of CDK2 and CDK4 were inhibited. When p21Cip1 was ectopically expressed in p53-inactivated cells, activation and nuclear translocation of CDK2 were restored, and normal proliferation occured. In conclusion, our results indicated that EGF- induced expression of p53 was involved in the regulation of CDK2- and CDK4 functions, through p21Cip1 induction.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA