Activation of p53 Tumor Suppressor by Hepatitis C Virus Core Protein

Abstract

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.

Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein

“…In this work, we presented evidence showing that HCV core protein and p53 associate both in vitro and in vivo, and colocalize at the perinuclear region and the subnuclear granular structures. Moreover, different from the findings by Lu et al (1999) and Otsuka et al (2000) that p53 transactivational activity is enhanced by HCV core protein, our results show that while low level of HCV core protein cooperates with p53 to transactivate the p53-responsive promoter activity, higher level of HCV core protein on the other hand downregulates the p53-mediated transactivation. Surprisingly, regardless of the activation or suppression of p53-dependent transcription, HCV core protein enhances the in vitro p53 DNA-binding affinity, presumably attributed by the induction of hyperacetylation of p53 at Lys 373 and Lys 382 residues.…”

“…In comparison to the findings by Lu et al (1999) and Otsuka et al (2000), our reporter analyses indicate that HCV core protein has dual effects on p53-mediated transactivation depending on viral protein concentration: inhibition at high level of expression and coactivation by low level of HCV core protein (Figure 4). We also showed that the acetylation and phosphorylation states of p53 are significantly altered in cells expressing HCV core protein (Figure 6).…”

“…Interestingly, this may also be the case for HCV. Previous studies indicate that of 10 viral proteins encoded by the HCV genome, HCV core protein, and nonstructural protein NS3 and NS5A physically interact with p53, albeit their effects on p53 transcriptional activity vary and are not conclusive yet (Ishido and Hotta, 1998;Ray et al, 1998;Lu et al, 1999;Otsuka et al, 2000;Arima et al, 2001;Kwun et al, 2001;Majumder et al, 2001). In the case of HCV core protein, the evidence of in vivo association and cellular localization is not available.…”

HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

“…Because p53 maintains the genetic integrity of cells by controlling progression through the cell cycle, the loss of p53 function, therefore, appears to be associated with increased genetic instability and the accumulation of mutations, which is likely to precede oncogenic transformation (Levine, 1993). Various tumor viruses encode proteins that interact with p53, including T antigen from SV40 (Lane and Crawford, 1979), E6 from human papillomavirus (Dyson et al, 1989), E1B 55-kDa from adenovirus (Sarnow et al, 1982), HBx from HBV (Wang et al, 1994(Wang et al, , 1995Ueda et al, 1995), and core protein from HCV (Otsuka et al, 2000;Ray et al, 1997;Lu et al, 1999). Most of the p53-interacting viral proteins were reported to suppress p53 function (Scheffner et al, 1992;Wang et al, 1994Wang et al, , 1995Dobner et al, 1996;Muralidhar et al, 1996;Uchida et al, 1996;Elmore et al, 1997;Mulloy et al, 1998;Pise-Masison et al, 1998;Prost et al, 1998;Ray et al, 1997;Sheppard et al, 1999).…”

Poroceratose superficial disseminada num doente com colangiocarcinoma: manifestação paraneoplásica?

“…7,8 Recent studies have highlighted the importance of this gene in the oncogenesis of hepatocellular carcinoma, cholangiocarcinoma and ovarian adenocarcinoma. [9][10][11] Overexpression of the p53 gene in keratinocytes above and adjacent to the cornoid lamella in porokeratosis lesions has also been demonstrated, resulting in early apoptosis and abnormal differentiation of these cells. This finding suggests its involvement in the pathogenesis of these lesions.…”