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Expression of G1 cell cycle regulators in rat liver upon repeated exposure to thioacetamide
Kyoung-Tae Kim1, Sang-Young Han, Jin-Sook Jeong
1Department of Internal Medicine, Dong-A University College of Medicine, Pusan, Korea.
Background And 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.
Insights
Thioacetamide (TA) treatment in rats promotes liver cell cycle progression by increasing cyclin D1, CDK4, CDK6, and p21(CIP1) expression. Inactive p16(INK4a) also contributes to G1 phase entry in quiescent hepatocytes.
Area of Science:
- Hepatology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Eukaryotic cell cycle control involves cyclin-dependent kinases (CDKs), cyclins, and CDK inhibitors.
- Thioacetamide (TA) is a known hepatocarcinogen that induces liver damage and malignant transformation in a dose-dependent manner.
Purpose of the Study:
- To investigate alterations in cell cycle regulator expression in rat liver during thioacetamide (TA) administration.
- To understand the role of specific cell cycle proteins in G1 phase entry and progression following TA exposure.
Main Methods:
- Daily intraperitoneal injection of low-dose TA (50 mg/kg) to rats for 7 days.
- Western blot and immunohistochemistry were used to analyze the expression and localization of cyclin D1, CDK4, CDK6, p21(CIP1), and p16(INK4a).
Main Results:
- Expression of cyclin D1, CDK4, CDK6, and p21(CIP1) increased significantly within days of TA administration, peaking around day 2-3.
- Nuclear translocation of cyclin D1 and p21(CIP1) was observed, suggesting a role in cell cycle progression.
- p16(INK4a) expression increased with cytoplasmic localization, indicating an inactive form, while TA treatment promoted G1 progression in quiescent hepatocytes.
Conclusions:
- Low-dose TA administration facilitates liver cell cycle opening and G1 progression.
- The observed effects are likely mediated by increased cyclin D1, CDK4, CDK6, and p21(CIP1), alongside an inactive p16(INK4a).
- These changes occur in quiescent hepatocytes, not stem cells, highlighting a specific mechanism of TA-induced liver alterations.
