Open AccessActivation of the p53–p21Cip1 pathway is required for CDK2 activation and S-phase entry in primary rat hepatocytes
Author(s) -
Lene Wierød,
Carola M. Rosseland,
Birgitte Lindeman,
Morten P. Oksvold,
H. Grøsvik,
Ellen Skarpen,
Henrik S. Huitfeldt
Publication year - 2007
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/sj.onc.1210937
Subject(s) - biology , hyperphosphorylation , cyclin dependent kinase 2 , microbiology and biotechnology , cell cycle , hepatocyte , retinoblastoma protein , epidermal growth factor , kinase , cyclin dependent kinase 1 , dna synthesis , cancer research , apoptosis , cell growth , protein kinase a , cell culture , biochemistry , dna , genetics , in vitro
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 p21(Cip1) in primary rat hepatocytes. p53 inactivation with a dominant-negative mutant (p53(V143A)) attenuated EGF-induced DNA synthesis and was associated with reduced CDK2 phosphorylation and retinoblastoma protein hyperphosphorylation. When p21(Cip1) 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 p21(Cip1) expression.