Activation of the human transforming growth factor alpha (TGF-alpha) gene by the hepatitis B viral X protein (HBx) through AP-2 sites.
The HBx protein is known as a transactivator and potential oncogene, and TGF-alpha as a potent mitogen in hepatocellular carcinoma. By assays of serial deletion of the promoter of TGF-alpha gene and the cotransfection of HBx and AP-2 expression vectors, we observed that the HBx significantly activated the promoter activity through AP-2 sites located in the proximal region of the TGF-alpha promoter (-136 to -30). This effect was also observed in the heterologous promoter assay system containing AP-2 sites. The mutation analyses of three AP-2 sites in the promoter revealed that all three AP-2 sites contributed to the activation of the TGF-a gene in the presence of HBx. Accordingly, the mRNA level of TGF-alpha was significantly elevated in the HBx-expressing cell, HepG2-HBx and the HBV-producing cell, HepG2-K8. These results suggest that the HBx protein could increase the mitogenic effect of TGF-alpha by the transactivation of the gene through AP-2 binding sites and consequently, these interactions may accelerate the process of hepatocarcinogenesis.
Kim
Jun Hwan
JH
School of Biological Sciences, Seoul National University, Korea.
Rho
Hyune Mo
HM
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D017384:Sequence Deletion; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein