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

被引:62
作者
Awad, MM
Enslen, H
Boylan, JM
Davis, RJ
Gruppuso, PA [1 ]
机构
[1] Rhode Isl Hosp, Div Pediat Endocrinol & Metab, Dept Pediat, Providence, RI 02903 USA
[2] Brown Univ, Providence, RI 02903 USA
[3] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
[4] Univ Massachusetts, Sch Med, Program Mol Med, Dept Biochem & Mol Biol, Worcester, MA 01605 USA
关键词
D O I
10.1074/jbc.M008040200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:38716 / 38721
页数:6
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