P53 controls hepatitis C virus non-structural protein 5A-mediated downregulation of GADD45? expression via the NF-?B and PI3K-Akt pathways.

ABSTRACT: Growth arrest and DNA-damage-inducible gene 45-? (GADD45?) protein has been shown to be a tumour suppressor and is implicated in cell-cycle arrest and suppression of cell growth. The hepatitis C virus (HCV) non-structural 5A (NS5A) protein plays an important role in cell survival and is linked to the development of hepatocellular carcinoma (HCC). However, the role of HCV NS5A in the development of HCC remains to be clarified. This study sought to determine whether GADD45? mediates HCV NS5A-induced cellular survival and to elucidate the molecular mechanism of GADD45? expression regulated by HCV NS5A. It was found that HCV NS5A downregulated GADD45? expression at the transcriptional level by decreasing promoter activity, mRNA transcription and protein levels. Knockdown of p53 resulted in a similar decrease in GADD45? expression to that caused by HCV NS5A, whilst overexpression of p53 reversed the HCV NS5A-mediated downregulation of GADD45?. HCV NS5A repressed p53 expression, which was followed by a subsequent decrease in GADD45? expression. Further evidence was provided showing that HCV NS5A led to increases of phosphorylated nuclear factor-?B and Akt levels. Inhibition of these pathways using pharmacological inhibitors or specific small interfering RNAs rescued HCV NS5A-mediated downregulation of p53 and GADD45?. It was also found that HCV NS5A protein and depletion of GADD45? increased cell growth, whereas ectopic expression of GADD45? eliminated HCV NS5A-induced cell proliferation. These results indicated that HCV NS5A downregulates GADD45? expression and subsequently triggers cellular proliferation. These findings provide new insights suggesting that HCV NS5A could contribute to the occurrence of HCV-related HCC.

SUBMITTER: Cheng D 

PROVIDER: S-EPMC3709614 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature