Cell cycle (GI phase) regulation in rat liver regeneration

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Several hepatocyte mitogens are responsible for initiating and promoting liver regeneration. To elucidate the exact mechanisms of G1 progression in vivo, we examined the expression of cyclin Dl, cyclin D1-dependent kinase activity, and the effect of cyclin-dependent kinase (CDK) inhibitors on regenerating rat liver after 70% partial hepatectomy (PH). 1. Expression of cyclin Dl mRNA and protein was drastically elevated throughout G1 after PH. 2. Although cdk4 protein gradually increased, the response was relatively small compared to cyclin Dl. 3. Marked induction of cyclin D1-dependent kinase activity was in parallel with drastic increase in cyclin Dl expression. 4. P21ィイD1CIPIィエD1 gradually increased, while p27ィイD1KIPIィエD1 was constantly expressed at high levels throughout G1. 5. The amounts of both p2lィイD1C1P1ィエD1 and 27ィイD1K1P1ィエD1 were maximal at late G1, whereas they associated with cyclin D1 at low concentrations. Recently, at these levels, they have been reported to stabilize act … More ive cyclin D-cdk4 complexes. Taken together, our findings suggest that both p21ィイD1CIPIィエD1 and p27ィイD1KIPIィエD1 may physiologically regulate the activity of cyclin Dl-cdk4 complexes throughout G1 following PH by acting as adapter proteins rather than as cdk inhibitors.We next examined the effect of PH on the levels of cyclin D1 in thioacetamide-administered cirrhotic rats. 1. To assess DNA synthesis by hepatocytes, we measured the proliferating cell nuclear antigen (PCNA) labeling index.. It showed 29% of hepatocytes in cirrhotic-liver at a maximum point, compared with 48% in normal liver at 24 hr after PH. 2. Cyclin D1 expression was elevated by 12 hr after PH in normal liver, but was markedly inhibited in cirrhotic liver.In conclusion, cyclin D1 accumulation facilitates the progressive assembly of enzymatically active cyclin D1 -cdk4 complexes as liver cells progress through G1 phase. In addition, increase of cyclin D1 throughout G1 in the regenerating liver was markedly suppressed in cirrhotic rats. Less