p18(INK4c) collaborates with other CDK-inhibitory proteins in the regenerating liver.
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.
Luedde
Tom
T
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
Rodriguez
Maria E
ME
Tacke
Frank
F
Xiong
Yue
Y
Brenner
David A
DA
Trautwein
Christian
C
D000818:Animals; D016203:CDC2 Protein Kinase / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology*; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016213:Cyclins / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors; D016193:G1 Phase; D006498:Hepatectomy / Q000379:methods; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; C493972:Cdkn2c protein, mouse; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases