Hepatitis C virus core protein represses the p21 promoter through inhibition of a TGF-beta pathway.
The increased proliferation rate of hepatocytes is one of the major risk factors for the development of hepatocellular carcinoma. In this study, we investigated the mechanism by which hepatitis C virus (HCV) core protein represses transcription of the universal cyclin-dependent kinase inhibitor p21 gene in murine fibroblast NIH 3T3 cells. From the transient reporter assays of p21 promoter, we found that the TGF-beta-responsive element (TbetaRE) located between -83 and -74 of the p21 promoter is responsible for the effect. The TGF-beta-induced p21 promoter activity was specifically decreased by HCV core protein and in the presence of the inhibitory Smad7 the repression effect was almost completely abolished. Furthermore, HCV core protein stimulated the growth rate of NIH 3T3 cells and could overcome growth arrest by TGF-beta but not by butyrate, suggesting that HCV core protein stimulates cell cycle progression by repressing p21 transcription through a TGF-beta pathway.
Lee
Mi Nam
MN
Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1.
Jung
Eun Young
EY
Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1.
Kwun
Hyun Jin
HJ
Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1.
Jun
Hong Ki
HK
Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1.
Yu
Dae-Yeul
DY
Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea2.
Choi
Yung Hyun
YH
Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Pusan 614-052, Korea3.
Jang
Kyung Lib
KL
Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea1.
D016475:3T3 Cells; D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus