Hepatocytes undergo marked changes in proliferation during normal liver development. In order to elucidate the mechanism for these changes, we examined the ontogeny of expression for the known cyclin-dependent kinase inhibitors (CKIs), p15Ink4b, p16Ink4a, p18Ink4c, p19Ink4d, p21Cip1, p27Kip1 and p57Kip2. All except p16Ink4a were expressed at some time between late gestation and adulthood. The mRNA and protein expression patterns for p15Ink4b and p57Kip2 were consistent with a role for these CKIs in the regulation of hepatocyte proliferation. Specifically, p57Kip2 may contribute to hepatocyte growth arrest that occurs in term fetuses, while p15Ink4b may contribute to the maintenance of adult hepatocytes in a quiescent state. These results assign a possible role to two CKIs not previously identified as involved in hepatocyte cell cycle control.
