Luedde Tom, Rodriguez Maria E, Tacke Frank, Xiong Yue, Brenner David A, Trautwein Christian
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
Hepatology. 2003 Apr;37(4):833-41. doi: 10.1053/jhep.2003.50136.
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.
p18（INK4c）属于细胞周期蛋白依赖性激酶抑制蛋白家族，该家族靶向细胞周期蛋白依赖性激酶并抑制其催化活性。p18（INK4c）在体内细胞周期进程中的作用目前了解甚少。因此，我们研究了肝脏再生过程中静止和增殖肝细胞中p18的表达及其生理相关性。我们使用单突变（p18[INK4c]、p27[KIP1]、p21[CIP1/WAF1]）和双突变（p18/p21、p18/p27）小鼠进行分析。发现静止肝细胞中有p18表达，部分肝切除（PH）后有轻微上调。p18基因敲除动物在PH后细胞周期进程正常。然而，当使用p18/p21和p18/p27双突变小鼠时，与野生型（wt）和单基因敲除动物相比，细胞周期进程存在明显差异。在p18/p21基因敲除动物中，G1期缩短，这可通过PH后细胞周期蛋白D和增殖细胞核抗原（PCNA）表达提前以及细胞周期蛋白依赖性激酶（CDK）激活得以证明。相反，在p18/p27基因敲除动物中，G1期未改变，但PH后48小时增殖肝细胞（5-溴-2'-脱氧尿苷[BrdU]和PCNA阳性）数量增加。总之，我们的结果表明p18参与了PH后的细胞周期进程。此外，我们还提供了证据表明，通过不同细胞周期抑制剂的协同作用，PH后肝细胞中DNA合成的时间和强度受到严格调控。
