Growth regulation via p38 mitogen-activated protein kinase in developing liver

During normal development in the rat, hepatocytes undergo marked changes in the rate of proliferation. We have previously observed transient G(1) grow th arrest at term, re-activation of proliferation immediately after birth, and a gradual transition to the quiescent adult hepatocyte phenotype after postnatal day 4. We hypothesized that these changes in proliferation are du e in part to growth inhibitory effects mediated by the p38 mitogen-activate d protein kinase pathway. p38 kinase activity measurements showed an invers e relationship with hepatocyte proliferation during the perinatal and postn atal transitions, whereas p38 content remained constant. Anisomycin activat ed the p38 pathway in fetal hepatocyte cultures while inducing growth inhib ition that was sensitive to the p38 inhibitor, SB203580. Activation of p38 in these cultures, via transient transfection with a constitutively active form of its upstream kinase MKK6, also inhibited DNA synthesis as well as r educing cyclin D1 content. Transfection with inactive MKK6 did neither. Fur thermore, MKK6-induced growth arrest was sensitive to SB203580. Finally, ad ministration of SB203580 to near-term fetal rats in utero abrogated the tra nsient hepatocyte growth arrest that occurs at term. These findings indicat e a role for the p38 mitogen-activated protein kinase pathway in the physio logical regulation of hepatocyte proliferation during normal development in the rat.