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Activation of the p53–p21Cip1 pathway is required for CDK2 activation and S-phase entry in primary rat hepatocytes

Oncogene volume 27, pages 2763–2771 (2008)Cite this article

Abstract

p53 plays a major role in the prevention of tumor 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, and 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 DNA synthesis of primary hepatocytes. Here we show that epidermal growth factor (EGF) activated p53 in a phosphatidylinositol-3 kinase-dependent way, and thus induced the cyclin-dependent kinase inhibitor p21Cip1 in primary rat hepatocytes. p53 inactivation with a dominant-negative mutant (p53V143A) attenuated EGF-induced DNA synthesis and was associated with reduced CDK2 phosphorylation and retinoblastoma protein hyperphosphorylation. When p21Cip1 was ectopically expressed in p53-inactivated cells, these effects were neutralized. In conclusion, our results demonstrate that in normal hepatocytes, EGF-induced expression of p53 is involved in regulating CDK2- and CDK4 activity, through p21Cip1 expression.

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Acknowledgements

We thank Heidi K Blomhoff for generously providing the p21Cip wild-type plasmid. This work was supported by grant 134720/310 from the Research Council of Norway and from the Norwegian Cancer Society.

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Authors and Affiliations

  1. Laboratory for Toxicopathology, Institute of Pathology, Rikshospitalet Radiumhospitalet Medical Centre, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway

    L Wierød, C M Rosseland, M P Oksvold, H Grøsvik, E Skarpen & H S Huitfeldt

  2. Center for Cellular Stress Responses, University of Oslo, Oslo, Norway

    L Wierød, C M Rosseland, M P Oksvold, H Grøsvik, E Skarpen & H S Huitfeldt

  3. The Norwegian Institute of Public Health, Oslo, Norway

    B Lindeman

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  1. L Wierød
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Correspondence to L Wierød.

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Wierød, L., Rosseland, C., Lindeman, B. et al. Activation of the p53–p21Cip1 pathway is required for CDK2 activation and S-phase entry in primary rat hepatocytes. Oncogene 27, 2763–2771 (2008). https://doi.org/10.1038/sj.onc.1210937

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