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KMID : 1103920070130010081
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Korean Journal of Hepatology
2007 Volume.13 No. 1 p.81 ~ p.90
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Expression of G1 Cell Cycle Regulators in Rat Liver upon Repeated Exposure to Thioacetamide
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Kim Kyoung-Tae
Han Sang-Young
Jeong Jin-Sook
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Abstract
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Background/Aims: Eukaryotic cell cycle is regulated by signal transduction pathways mediated by complexes of cyclin dependent kinases (CDKs) and their partner cyclins, or by interaction with CDK inhibitors. Thioacetamide (TA) is a weak hepatocarcinogen causing several types of liver damage in a dose dependent manner and ultimately producing malignant transformation. We investigated alterations of expression of cell cycle regulators in the rat liver, involved in G1 entry and progression during TA administration.
Methods: We studied expression patterns of cyclin D1, CDK4, CDK6, p21CIP1 and p16INK4a during daily intraperitoneal injection of low dose TA (50 mg/kg) till 7 day. We used western blot and immunohistochemistry for detection.
Results: Expression of cyclin D1, CDK4, CDK6 and p21CIP1 increased from 6 hour and peaked at 2, 3 day, then
decreased next 2 days, and re-increased at 6 day. Cytoplasmo-nuclear translocation of cyclin D1 and p21CIP1 was evident within 1 day and prominent at 2 and 7 day. Expression of p16INK4a increased immediately after TA treatment and remarkably increased from 3 day and progressed till 7 day, showing cytoplasmic location, suggestive of inactive form. Most of in situ immunoreactions occurred at the centrilobular hepatocytes. Concomitant nuclear translocation of p21CIP1 and cyclin D1, different with p16INK4a suggests that p21CIP1 might be a transporter for nuclear translocation rather than cell cycle inhibitor.
Conclusions: Daily administration of low dose TA makes cell cycle open and G1 progress, possibly due to cyclin D1, CDK4 and CDK 6, their transporter p21CIP1, and inactive p16INK4a, which occur at quiescent hepatocytes, not stem cells.
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KEYWORD
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Thioacetamide, Rats, Liver, Cyclins, Cyclin dependent kinases
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