Activation of p53 tumor suppressor by hepatitis C virus core protein.
In addition to being a structural protein that packages the viral genomic RNA, hepatitis C virus (HCV) core protein possesses regulatory functions. In this report, we demonstrate that the HCV core protein could enhance the gene transactivation activity of the tumor suppressor p53, regardless of whether p53 was derived from an exogenous or an endogenous gene. The activation of p53 by the HCV core protein was supported by the observation that the HCV core protein could enhance the expression of p21(waf1/Cip1), a downstream effector gene of p53, in a p53-dependent manner. Further studies indicated that the HCV core protein could also suppress hepatocellular growth via p53. The HCV core protein and p53 could bind to each other in vitro, which was evidenced by the coimmunoprecipitation, the GST pull-down, and the Far-Western blot assays. The deletion-mapping analysis indicated that the carboxy-terminal sequence of p53 located between amino acids 366 and 380 was required for the core protein binding. These results raised the possibility that the HCV core protein might activate p53 through direct physical interaction. The persistent perturbation of p53 activity by the HCV core protein during chronic infection may have important consequences in HCV pathogenesis.
Lu
W
W
Department of Molecular Microbiology and Immunology, University of Southern California School of Medicine, Los Angeles, California 90033, USA.
Lo
S Y
SY
Chen
M
M
Wu
K j
Kj
Fung
Y K
YK
Ou
J H
JH
D006528:Carcinoma, Hepatocellular; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D016158:Genes, p53; D016174:Hepacivirus / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D015500:Chloramphenicol O-Acetyltransferase