Growth Regulation via p38 Mitogen-activated Protein Kinase in Developing Liver

Abstract

During normal development in the rat, hepatocytes undergo marked changes in the rate of proliferation. We have previously observed transient G 1 growth 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 due in part to growth inhibitory effects mediated by the p38 mitogen-activated protein kinase pathway. p38 kinase activity measurements showed an inverse relationship with hepatocyte proliferation during the perinatal and postnatal transitions, whereas p38 content remained constant. Anisomycin activated the p38 pathway in fetal hepatocyte cultures while inducing growth inhibition 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 reducing cyclin D1 content. Transfection with inactive MKK6 did neither. Furthermore, MKK6-induced growth arrest was sensitive to SB203580. Finally, administration of SB203580 to near-term fetal rats in utero abrogated the transient hepatocyte growth arrest that occurs at term. These findings indicate a role for the p38 mitogen-activated protein kinase pathway in the physiological regulation of hepatocyte proliferation during normal development in the rat.The developing liver undergoes marked changes in growth during and after the perinatal period. In the rat, a burst of hepatocyte proliferation results in the tripling of liver mass over the last 3 days prior to term (1). This is followed by a marked decrease in hepatocyte proliferation during the 1st postnatal week (2). Although late gestation fetal hepatocytes are highly proliferative both in vivo and in culture (2), the hepatocytes in adult liver are quiescent, with only 1 in 20,000 showing cell cycle activity. In addition to this fetal-to-adult transition, we have observed a period of temporary hepatocyte growth arrest that occurs just prior to parturition in the rat (2, 3). This is followed by a brief period of synchronized hepatocyte proliferation in the immediate postnatal period and a subsequent transition to the quiescent adult rat hepatocyte phenotype beyond the 1st postnatal week. The mechanisms that regulate these developmental changes in hepatocyte proliferation have not been characterized. Our work was motivated by the assumption that the elucidation of these mechanisms would contribute to understanding the pathophysiology of liver injury and carcinogenesis.The present series of experiments was based on studies demonstrating that perinatal rat hepatocytes are arrested in the G 1 phase of the cell cycle and that this cell cycle arrest coincides with a decline in cyclin D1 content. Based on evidence indicating that control of cyclin D1 abundance may be downstream from the p38 mitogen-activated protein (MAP) 1 kinase pathway (4), we examined the role of this signaling pathway in the perinatal and ...

Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1

“…Here we describe HGF/SF activation of the ATF-2 transcription factor in 37-32 mouse melanoma cells, and the implication of p38 kinase in the regulation of proliferation, but not motility. In contrast to previous studies in which p38 acted as an inhibitor of cyclin D1 in hepatocytes (Awad et al, 2000), in melanoma cells we found that HGF/SF-mediated induction of proliferation was partially blocked by the speci®c p38-kinase inhibitor SB203580, relative to the complete inhibition observed with the MEK1-speci®c inhibitor PD098059. Although p38 kinase is partially activated through P13K, and P13K has been implicated in HGF/SF-promoted motility (Nakanishi et al, 1999;Lai et al, 2000), we did not observe any e ect on motility by the speci®c p38 kinase inhibitor SB203580.…”

Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation

“…5). This is consistent with previous reports of other cell types showing inhibitory effects of p38 on cyclin D1 expression (29,30). In contrast, expression of p21 was increased in the zones of proliferating and resting chondrocytes in transgenic embryos (Fig.…”

Tissue-specific activation of mitogen-activated protein kinases for expression of transthyretin by phenylalanine and its metabolite, phenylpyruvic acid

“…Inhibition of p38 kinase activity decreases HNF4α nuclear protein levels and its phosphorylation status in vivo and in vitro, which makes the protein less stable (Xu et al, 2007). Awad et al (2000) and Mendelson et al (1996) reported that p38 MAPK is constitutively active in the liver of adult mice, which is in accordance with our results. In our study, the p38 kinase protein level was significantly decreased in the liver of phenylketonuria-affected mice regardless of age or sex.…”