The human hepatitis B virus transactivator X gene product regulates Sp1 mediated transcription of an insulin-like growth factor II promoter 4

Young Ik Lee, Sook Lee, Yoonik Lee, Yong Sik Bong, Sang Won Hyun, Young Do Yoo, Seong Jin Kim, Young Whoon Kim, Ha Ryung Poo

Research output: Contribution to journalArticle

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Abstract

Human hepatitis B virus (HBV) is one of the causative agents of hepatocellular carcinoma (HCC). The virus encodes a 17 kDa protein, X, which is known to be a causative agent in the formation of HCC. An insulin-like growth factor-II (IGF-II) is expressed during the formation of HCC. Among the four promoters of the IGF-II gene, promoters 2, 3 and 4 become activated during the formation of HCC. The high frequency of detection of hepatitis B virus X (HBV-X) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that the expressions of HBV-X and IGF-II are associated. Studies were carried out to test the relationship between the HBV-X gene product and the activation of IGF-II promoter 4. We demonstrated that the HBV-X protein increases the endogenous IGF-II expression from promoter 3 and 4 of IGF-II gene. Analysis of the fourth promoter of IGF-II gene showed that the HBV-X gene product positively regulates transcription. Two copies of a motif are responsible for conferring HBV-X regulation on the fourth promoter of IGF-II. These motifs have been identified as Sp1 binding sites. Sp1 binding to IGF-II P4 promoter was identified by gel mobility shift assay using purified Sp1. By using a GAL4-Sp1 fusion protein it was demonstrated that HBV-X positively regulates the Sp1 mediated transcriptional activity of IGF-II in vivo. A protein-affinity chromatography experiment showed that HBV-X protein does not bind directly to Sp1, but HBV-X does augment the DNA binding activity of the phosphorylated form of Sp1 in HepG2 cells. Sp1 was phosphorylated by HBV-X and its DNA-binding activity was up-regulated upon HBV-X transfections. Various HBV-X mutant expression vectors were used for the demonstration of specific interactions between Sp1 and HBV-X. These results indicate that HBV-X functions as a positive regulator of transcription, and that Sp1 is a direct target for the transcriptional regulation of IGF-II. Increasing the DNA binding ability of the phosphorylated form of Sp1 by HBV-X might be an important mechanism for regulating the IGF-II gene expression and possibly promoting cell division during hepatic carcinogenesis. Our experimental results suggest that expression of HBV-X might induce the expression of IGF-II and the IGF-II might play a role in hepatitis B virus pathogenesis during the formation of HCC.

Original languageEnglish
Pages (from-to)2367-2380
Number of pages14
JournalOncogene
Volume16
Issue number18
Publication statusPublished - 1998 May 7
Externally publishedYes

Fingerprint

Insulin-Like Growth Factor II
Trans-Activators
Hepatitis B virus
Genes
Hepatocellular Carcinoma
DNA
Proteins
Liver
Hep G2 Cells
Electrophoretic Mobility Shift Assay
Chronic Hepatitis
Liver Neoplasms
Affinity Chromatography
Cell Division
Transcriptional Activation

Keywords

  • Hepatitis B virus
  • Hepatocellular carcinoma
  • Insulin-like growth factor-II
  • Transactivation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

The human hepatitis B virus transactivator X gene product regulates Sp1 mediated transcription of an insulin-like growth factor II promoter 4. / Lee, Young Ik; Lee, Sook; Lee, Yoonik; Bong, Yong Sik; Hyun, Sang Won; Yoo, Young Do; Kim, Seong Jin; Kim, Young Whoon; Poo, Ha Ryung.

In: Oncogene, Vol. 16, No. 18, 07.05.1998, p. 2367-2380.

Research output: Contribution to journalArticle

Lee, YI, Lee, S, Lee, Y, Bong, YS, Hyun, SW, Yoo, YD, Kim, SJ, Kim, YW & Poo, HR 1998, 'The human hepatitis B virus transactivator X gene product regulates Sp1 mediated transcription of an insulin-like growth factor II promoter 4', Oncogene, vol. 16, no. 18, pp. 2367-2380.
Lee, Young Ik ; Lee, Sook ; Lee, Yoonik ; Bong, Yong Sik ; Hyun, Sang Won ; Yoo, Young Do ; Kim, Seong Jin ; Kim, Young Whoon ; Poo, Ha Ryung. / The human hepatitis B virus transactivator X gene product regulates Sp1 mediated transcription of an insulin-like growth factor II promoter 4. In: Oncogene. 1998 ; Vol. 16, No. 18. pp. 2367-2380.
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