Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth

被引:58
作者
Ilyin, GP [1 ]
Glaise, D [1 ]
Gilot, D [1 ]
Baffet, G [1 ]
Guguen-Guillouzo, C [1 ]
机构
[1] Hop Pontchaillou, INSERM, U522, F-35033 Rennes, France
来源
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2003年 / 285卷 / 01期
关键词
liver; hepatocyte growth control; signal transduction;
D O I
10.1152/ajpgi.00309.2002
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Unlike a large number of cell types that undergo terminal differentiation associated with permanent withdrawal from the cell cycle, mature quiescent hepatocytes retain high proliferative potential. We report here a specific behavior of members of the Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors during development of the rat liver and proliferation of normal hepatocytes. Expression of p21, p27, and p57 transcripts and proteins was downregulated during the differentiation process to low or undetectable levels in adult liver. In contrast to p27, p21 protein increased in a mitogen-dependent manner in isolated hepatocytes and its expression pattern correlated with that of cyclin D1. In proliferating hepatocytes, p21 was predominantly associated with cyclin D1, these proteins were colocalized in the nucleus and p21-associated retinoblastoma protein ( pRb) kinase activity increased in parallel with that of cyclin D1. Overexpression of p21 in mitogen-stimulated hepatocytes reduced DNA synthesis. In contrast, inhibition of p21 expression by antisense or small interfering RNAs oligonucleotides accelerated S phase entry. Finally, expression of p21 and cyclin D1, but not p27 proteins was regulated by MAPK kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase-ferric-reducing ability power/mammalian target of rapamycin signal transduction pathways. In conclusion, these results demonstrate a specific and differential regulation of p21 and p27 during hepatocyte differentiation and proliferation that may contribute to the control of quiescent differentiated hepatic cell proliferating activity.
引用
收藏
页码:G115 / G127
页数:13
相关论文
共 67 条
[1]  
AGRAWAL D, 1995, CELL GROWTH DIFFER, V6, P1199
[2]   Regulation of G1 cyclin-dependent kinases in the liver:: role of nuclear localization and p27 sequestration [J].
Albrecht, JH ;
Rieland, BM ;
Nelsen, CJ ;
Ahonen, CL .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 1999, 277 (06) :G1207-G1216
[3]  
Albrecht JH, 1999, CELL GROWTH DIFFER, V10, P397
[4]   Involvement of p21 and p27 in the regulation of CDK activity and cell cycle progression in the regenerating liver [J].
Albrecht, JH ;
Poon, RYC ;
Ahonen, CL ;
Rieland, BM ;
Deng, CX ;
Crary, GS .
ONCOGENE, 1998, 16 (16) :2141-2150
[5]   Regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1/Sdi1) gene expression in hepatic regeneration [J].
Albrecht, JH ;
Meyer, AH ;
Hu, MY .
HEPATOLOGY, 1997, 25 (03) :557-563
[6]  
Awad MM, 2000, CELL GROWTH DIFFER, V11, P325
[7]   The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts [J].
Cheng, MG ;
Olivier, P ;
Diehl, JA ;
Fero, M ;
Roussel, MF ;
Roberts, JM ;
Sherr, CJ .
EMBO JOURNAL, 1999, 18 (06) :1571-1583
[8]   Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1) [J].
Cheng, MG ;
Sexl, V ;
Sherr, CJ ;
Roussel, MF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (03) :1091-1096
[9]   Requirement of p27(Kip1) for restriction point control of the fibroblast cell cycle [J].
Coats, S ;
Flanagan, WM ;
Nourse, J ;
Roberts, JM .
SCIENCE, 1996, 272 (5263) :877-880
[10]   PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival [J].
Coutant, A ;
Rescan, C ;
Gilot, D ;
Loyer, P ;
Guguen-Guillouzo, C ;
Baffet, G .
HEPATOLOGY, 2002, 36 (05) :1079-1088