Estrogen-induced proliferation in cultured hepatocytes involves cyclin D1, p21(Cip1) and p27(Kip1)

The purpose of this study was to establish if estrogen-induced hepatocyte proliferation in vitro involves the cell cycle regulators cyclin D1, p21Cip1, and p27Kip1. Male rat hepatocytes were cultured in presence of 17-β-estradiol (E2) ± ICI-182780, a pure estrogen antagonist, and [3H]-thymidine, as required. DNA synthesis as well as p21Cip1, p27Kip1, and cyclin D1mRNA and protein levels were evaluated at different times (12, 24, 36, and 48 hours) of incubation. E2-increased DNA synthesis was correlated with cyclin D1 and p21Cip1 (mRNA and protein) variations that were reversed by the addition of ICI-182780. p27Kip1protein levels progressively increased regardless of the presence of E2 or ICI-182780. Our data confirm that estrogens’ stimulatory effect is related to their ability to increase cyclin D1 levels. The increase of p21Cip1 is probably related to the reentry of hepatocytes in the quiescent state. p27Kip1protein is not able to arrest hepatocyte proliferation.