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Cell Cycle Control during Liver Development in the Rat: Evidence Indicating a Role for Cyclin D1 Posttranscriptional Regulation¹

Brown University School of Medicine, Providence, Rhode Island 02912, and Department of Pediatrics, Division of Pediatric Endocrinology and Metabolism, Rhode Island Hospital, Providence, Rhode Island 02903

Hepatocytes are capable of marked changes in proliferation in response to various physiological and pathophysiological stimuli. Although the changes in adult hepatocyte growth regulation that accompany reduction of liver mass, liver injury, and liver carcinogenesis have come under intense scrutiny, the regulation of hepatocyte growth during the latter stages of development is largely uncharacterized. We have examined hepatic cell cycle control in the developing rat. Analysis of term (fetal day 21) liver and cultured, term hepatocytes revealed G₀-G₁ growth-arrested cells relative to preterm (fetal day 19) liver and isolated hepatocytes. G₁ cyclin-dependent kinase (CDK) activity was correlated with growth arrest at term in both in vivo and in vitro studies. The decline in CDK activity at term could not be attributed to a change in CDK protein content. Rather, the decline in CDK activity was associated with a concomitant decline in cyclin D1 protein content. However, cyclin D1 mRNA levels did not correlate with protein levels. Cyclin D1 mRNA was present at a higher level in adult livers, in which cyclin D1 protein was absent, than in fetal livers. We also examined the phosphorylation (activation) state of p38 mitogen-activated protein kinase, a potential hepatocyte-growth regulator and modulator of cyclin D1 content. p38 activity was inversely related to cyclin D1 content during liver development and regeneration. These data indicate that a posttranscriptional mechanism regulating cyclin D1 content is involved in the temporary hepatocyte growth arrest seen in the perinatal period and in the maintenance of adult hepatocytes in a quiescent state. We speculate that this posttranscriptional regulation may be downstream from the p38 mitogen-activated protein kinase pathway.

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