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1 Hopital Pontchaillou, INSERM U522, Rennes, France
* To whom correspondence should be addressed. E-mail: guennadi.iline{at}rennes.inserm.fr.
Unlike a large number of cell types that undergo terminal differentiation associated with permanent withdrawal from cell cycle, mature quiescent hepatocytes retain high proliferative potential. We report here a specific behavior of members of the Cip/Kip family of cyclin-dependent kinase (cdk) inhibitors during development of the rat liver and proliferation of normal hepatocytes. Expression of p21, p27 and p57 transcripts and proteins was down-regulated during the differentiation process to low or undetectable levels in adult liver. In contrast to p27, p21 protein increased in mitogen-dependent manner in isolated hepatocytes and its expression pattern correlated with that of cyclin D1. In proliferating hepatocytes p21 was predominantly associated with cyclin D1, these proteins were co-localised in the nucleus and p21-associated pRb kinase activity increased in parallel with that of cyclin D1. Overexpression of p21 in mitogen-stimulated hepatocytes reduced DNA synthesis; in contrast, inhibition of p21 expression by antisense or siRNAs oligonucleotides accelerated S phase entry. Finally, expression of p21 and cyclin D1, but not p27 proteins was regulated by MEK/ERK and PI3K-FRAP/mTOR signal transduction pathways. In conclusion, these results demonstrate a specific and differential regulation of p21 and p27 during hepatocyte differentiation and proliferation that may contribute to the control of quiescent differentiated hepatic cell proliferating activity.
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