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J. Biol. Chem., Vol. 278, Issue 11, 9353-9360, March 14, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/11/9353    most recent M205944200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, W.-J. Articles by Chang, C. Search for Related Content PubMed PubMed Citation Articles by Lin, W.-J. Articles by Chang, C. Social Bookmarking                      What's this?

Suppression of Hepatitis B Virus Core Promoter by the Nuclear Orphan Receptor TR4^*

Wen-Jye Lin^§, Jie Li^§¶, Yi-Fen Lee, Shauh-Der Yeh, Saleh Altuwaijri, Jing-Hsiung Ou^¶, and Chawnshang Chang

From the  George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14642 and the ^¶ Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California 90033

The TR4 orphan receptor is a member of the nuclear receptor superfamily that modulates gene expression via binding to the AGGTCA direct repeat hormone response element. Here we report a functional study of TR4 interaction with the core promoter of the hepatitis B virus (HBV). The electrophoretic mobility shift assay shows that TR4 can bind to the direct repeat 1 sequence element (AGGTTAAAGGTCT, nucleotide coordinates 1757-1769, TR4RE-HBV) on the HBV core promoter. TR4 also can enhance the activity of a synthetic luciferase reporter linked with four copies of TR4RE-HBV in either liver HepG2 or non-liver H1299 cells in a dose-dependent manner. Surprisingly, TR4 represses the activity of a luciferase reporter containing the entire HBV genome sequences. Moreover, mutation of this TR4RE-HBV site in the HBV core promoter diminishes the TR4 suppression effect. This TR4-induced suppression of HBV core promoter activity is further confirmed by primer extension analysis of the HBV core RNAs, showing that TR4 represses both pre-core and core mRNAs. Further dissection of this repressive mechanism indicates that TR4 may suppress the HBV core promoter activity via repressing HNF4-mediated transactivation by protein-protein interactions without inhibition of HNF4 DNA binding. Furthermore, our results indicate that the N- and C-terminal regions of TR4 protein are required for TR4-HNF4 interaction. It is possible that TR4-HNF4 interaction may block the HNF4 function that results in the suppression of HBV gene expression. Together, these results demonstrate that TR4 can serve as a negative modulator in the transcriptional regulation of HBV core gene expression.

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