Expression of G1 Cell Cycle Regulators in Rat Liver upon Repeated Exposure to Thioacetamide

Korean J Hepatol > Volume 13(1); 2007 > Article

The Korean Journal of Hepatology 2007;13(1): 81-90.

Expression of G1 Cell Cycle Regulators in Rat Liver upon Repeated Exposure to Thioacetamide

Kyoung-Tae Kim, M.D., Sang-Young Han, M.D., Ph.D., Jin-Sook Jeong, M.D., Ph.D.1

Department of Internal Medicine and Pathology1, Dong-A University College of Medicine, Pusan, Korea

ABSTRACT

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, p21^CIP1 and p16^INK4a 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 p21^CIP1 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 p21^CIP1 was evident within 1 day and prominent at 2 and 7 day. Expression of p16^INK4a 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 p21^CIP1 and cyclin D1, different with p16^INK4a suggests that p21^CIP1 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 p21^CIP1, and inactive p16^INK4a, which occur at quiescent hepatocytes, not stem cells. (Korean J Hepatol 2007;13:81-90)

KeyWords: Thioacetamide; Rats; Liver; Cyclins; Cyclin dependent kinases