Transcriptional Repression of p53 Promoter by Hepatitis C Virus Core Protein

Abstract

Our previous results have suggested that the putative core protein of hepatitis C virus (HCV) transcriptionally regulates cellular and viral genes, inhibits cisplatin and c-myc-mediated apoptotic cell death under certain conditions, and transforms primary rat embryo fibroblast cells with a cooperative oncogene. Because HCV appears to cause hepatocellular carcinoma, we evaluated the regulatory role of the HCV core protein on p53, a well known tumor suppressor gene, by an in vitro transfection assay. HCV core protein repressed transcriptional activity of the p53 promoter when tested separately in COS7 and HeLa cells. Deletion mutational analysis of the HCV core gene indicated that the regulatory domain involved in the repression of p53 transcriptional activity is located around amino acid residues 80 -122 encompassing a putative DNA binding motif and two major phosphorylation sites. Results from this study suggest that the putative core protein may have an important biological role in the promotion of cell growth by repressing p53 transcription, and this appears to be consistent with certain earlier observations about HCV core moving into the nucleus.

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

“…The core protein has also been shown to act in ways that might confer a survival advantage on HCV. It can modulate cellular and viral promoter activities, [31][32][33][34] bind to host RNA helicase to interfere with host RNA translation, and interact with host. 35 Recent data has suggested that HCV core may mediate an immunosupressive effect in vivo.…”

Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth.

“…Induction of p21 also occurs via p53-independent pathways (Liu et al, 1996 ;Michieli et al, 1994). Since HCV appears to play a role in the development of hepatocellular carcinoma, the effect of HCV NS5A protein on the human p53 promoter was examined by an in vitro transient transfection of NIH3T3 cells as described previously (Ray et al, 1997). The result suggested that NS5A does not have a detectable regulatory role in transcription from the p53 promoter (data not shown).…”

Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes

“…Several lines of evidence indicate that increased oxidative stress is an important pathogenetic mechanism in CHC (3)(4)(5)(6)(7)(8)(9). HCV core and nonstructural proteins have been shown to cause transcriptional modulation as either trans-activators or trans-suppressors of cellular signaling pathways through interference with intracellular oxidation/reduction reactions (10)(11)(12). The HCV core protein alters mitochondrial function and results directly in an increase in the cellular abundance of reactive oxygen species (ROS) with consequent increases in cellular lipid peroxidation (13)(14)(15)(16).…”