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p18(INK4c) collaborates with other CDK-inhibitory proteins in the regenerating liver
Tom Luedde1, Maria E Rodriguez, Frank Tacke
1Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
Abstract:
p18(INK4c) belongs to the family of cyclin-dependent kinase inhibitory proteins that target the cyclin-dependent kinases and inhibit their catalytic activity. The role of p18(INK4c) for cell cycle progression in vivo is characterized poorly. Therefore, we studied the expression and physiologic relevance of p18 in quiescent and proliferating hepatocytes during liver regeneration. For our analysis we used single- (p18[INK4c], p27[KIP1], p21[CIP1/WAF1]), and double-mutant (p18/p21, p18/p27) mice. p18 expression was found in quiescent hepatocytes and a slight up-regulation was evident after partial hepatectomy (PH). p18 knockout animals showed normal cell cycle progression after PH. However, when p18/p21 and p18/p27 double-mutant mice were used, differences in cell cycle progression were evident compared with wild-type (wt) and single knockout animals. In p18/p21 knockout animals, the G1 phase was shortened as evidenced by an earlier onset of cyclin D and proliferating cell nuclear antigen (PCNA) expression and cyclin-dependent kinase (CDK) activation after PH. In contrast, in p18/p27 knockout animals, the G1 phase was unchanged, but the amount of proliferating hepatocytes (5-bromo-2'-deoxyuridine [BrdU] and PCNA positive) 48 hours after PH was elevated. In conclusion, our results suggest that p18 is involved in cell cycle progression after PH. Additionally we provide evidence that timing and strength of DNA synthesis in hepatocytes after PH is regulated tightly through the collaboration of different cell cycle inhibitors.
Insights
The cell cycle inhibitor p18 (INK4c) plays a role in liver regeneration. Its absence, particularly with other inhibitors, affects hepatocyte proliferation timing and DNA synthesis.
Area of Science:
- Cell Biology
- Molecular Biology
- Hepatology
Background:
- p18 (INK4c) is a cyclin-dependent kinase inhibitor.
- Its role in cell cycle progression in vivo is poorly understood.
- Hepatocyte proliferation is crucial for liver regeneration.
Purpose of the Study:
- To investigate the expression and physiological relevance of p18 in quiescent and proliferating hepatocytes during liver regeneration.
- To elucidate the role of p18 in cell cycle control in hepatocytes.
Main Methods:
- Utilized single- and double-mutant mice (p18, p21, p27 knockouts).
- Analyzed p18 expression in quiescent and regenerating liver tissue.
- Assessed cell cycle progression markers (cyclin D, PCNA, BrdU) after partial hepatectomy (PH).
Main Results:
- p18 was expressed in quiescent hepatocytes and slightly upregulated post-PH.
- p18 knockout mice showed normal cell cycle progression after PH.
- Double mutants revealed distinct roles: p18/p21 knockout shortened G1 phase, while p18/p27 knockout increased hepatocyte proliferation post-PH.
Conclusions:
- p18 is involved in cell cycle progression following partial hepatectomy.
- Collaborative action of cell cycle inhibitors (p18, p21, p27) tightly regulates hepatocyte DNA synthesis timing and magnitude during liver regeneration.