title: p53 controls hepatitis C virus non-structural protein 5A-mediated downregulation of GADD45α expression via the NF-κB and PI3K-Akt pathways.
abstract: Growth arrest and DNA-damage-inducible gene 45-α (GADD45α) 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 GADD45α mediates HCV NS5A-induced cellular survival and to elucidate the molecular mechanism of GADD45α expression regulated by HCV NS5A. It was found that HCV NS5A downregulated GADD45α expression at the transcriptional level by decreasing promoter activity, mRNA transcription and protein levels. Knockdown of p53 resulted in a similar decrease in GADD45α expression to that caused by HCV NS5A, whilst overexpression of p53 reversed the HCV NS5A-mediated downregulation of GADD45α. HCV NS5A repressed p53 expression, which was followed by a subsequent decrease in GADD45α expression. Further evidence was provided showing that HCV NS5A led to increases of phosphorylated nuclear factor-κB and Akt levels. Inhibition of these pathways using pharmacological inhibitors or specific small interfering RNAs rescued HCV NS5A-mediated downregulation of p53 and GADD45α. It was also found that HCV NS5A protein and depletion of GADD45α increased cell growth, whereas ectopic expression of GADD45α eliminated HCV NS5A-induced cell proliferation. These results indicated that HCV NS5A downregulates GADD45α expression and subsequently triggers cellular proliferation. These findings provide new insights suggesting that HCV NS5A could contribute to the occurrence of HCV-related HCC.
authors.affiliation: Liver Diseases Center, Department of Infectious Diseases, Second Xiangya Hospital, Xiangya Medical School, Central South University, Changsha 410011, PR China.
authors.forename: Du
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100176, PR China.
authors.forename: Leiliang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Liver Diseases Center, Department of Infectious Diseases, Second Xiangya Hospital, Xiangya Medical School, Central South University, Changsha 410011, PR China.
authors.forename: Yongfang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Liver Diseases Center, Department of Infectious Diseases, Second Xiangya Hospital, Xiangya Medical School, Central South University, Changsha 410011, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Liver Diseases Center, Department of Infectious Diseases, Second Xiangya Hospital, Xiangya Medical School, Central South University, Changsha 410011, PR China.
authors.forename: Xinqiang
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Liver Diseases Center, Department of Infectious Diseases, Second Xiangya Hospital, Xiangya Medical School, Central South University, Changsha 410011, PR China.
authors.forename: Guozhong
authors.initials: G
authors.lastname: Gong
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation; D016174:Hepacivirus / Q000472:pathogenicity*; D022781:Hepatocytes / Q000502:physiology / Q000821:virology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*; D000097642:GADD45 Proteins; D012324:RNA-Dependent RNA Polymerase
chemical_list: D018797:Cell Cycle Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase