Characterization of the hepatitis B virus- and nucleocapsid gene transcriptional regulatory elements

Zhang, Pei; Raney, Anneke K.; McLachlan, Alan

doi:10.1016/0042-6822(92)90163-j

Cited by 45 publications

(32 citation statements)

References 56 publications

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“…In contrast, the TR4-CpFL supershift complex was observed in the presence of an anti-TR4 antibody using in vitro translated TR4 lysates (lanes 3 and 4). Moreover, when we replaced wild type TR4RE-HBV with various mutants, we found that TR4 could only bind specifically to the wild type TR4RE-HBV, but not to other mutated TR4RE-HBVs, except for the M3 mutant, which has marginal binding (lanes [5][6][7][8][9][10]. The M1 double mutant with nucleotides changed from A to T (1765) and G to A (1767) represents the HBV mutant frequently found in the patients with chronic hepatitis (33).…”

Section: Tr4 Protein Binds Specifically To the Tr4re-hbv Consensus Simentioning

confidence: 99%

“…The core promoter controls the expression of the 3.5-kb core mRNA (C mRNA) as the template for replication, and the expression of the pre-core mRNA (pre-C mRNA) for the translation of the HBeAg precursor (6). Recently, multiple binding sites for liverspecific or ubiquitous transcription factors and several hormone response elements (HRE) have been identified in the core promoter region, including Sp1 (7,8), TATA-binding protein (9), HNF3 (10), HNF4␣ (11), C/EBP (12), and other members of the nuclear receptor superfamily, such as the retinoid X receptor (RXR␣), peroxisome proliferator-activated receptor (PPAR␣), COUP-TF1, and ARP1 (13). For example, HNF4␣ and RXR␣/PPAR␣ can stimulate the expression of the 3.5-kb core RNA, COUP-TF1 suppresses the expression of both the pre-C RNA and C RNA, and TR2 preferentially represses the expression of the pre-C RNA (14).…”

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confidence: 99%

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

Lin

Lee

et al. 2003

Journal of Biological Chemistry

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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.Hepatitis B virus (HBV) 1 is a small virus with a 3.2-kb partially double-stranded DNA genome, containing four open reading frames: the surface antigen, the core antigen, the polymerase, and the X protein (1, 2). HBV is a major pathogen causing acute and chronic liver diseases, such as cirrhosis and hepatocellular carcinoma (3, 4). HBV transcripts are regulated by the transcriptional control of four different promoters and two enhancer elements (5). HBV is replicated from a RNA intermediate as a template for reverse transcription (1). The core promoter controls the expression of the 3.5-kb core mRNA (C mRNA) as the template for replication, and the expression of the pre-core mRNA (pre-C mRNA) for the translation of the HBeAg precursor (6). Recently, multiple binding sites for liverspecific or ubiquitous transcription factors and several hormone response elements (HRE) have been identified in the core promoter region, including Sp1 (7, 8), TATA-binding protein (9), HNF3 (10), HNF4␣ (11), C/EBP (12), and other members of the nuclear receptor superfamily, such as the retinoid X receptor (RXR␣), peroxisome proliferator-activated receptor (PPAR␣), COUP-TF1, and ARP1 (13). For example, HNF4␣ and RXR␣/PPAR␣ can stimulate the expression of the 3.5-kb core RNA, COUP-TF1 suppresses the expression of both the pre-C RNA and C RNA, and TR2 preferentially represses the expression of ...

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Section: Tr4 Protein Binds Specifically To the Tr4re-hbv Consensus Simentioning

confidence: 99%

mentioning

confidence: 99%

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

Lin

Lee

et al. 2003

Journal of Biological Chemistry

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“…McLachan, The Scripps Research Institute, La Jolla, California, USA) corresponding to the luciferase gene under the control of the capsid or HBx gene promoters, respectively, have been previously described (15). Cell culture and transfection.…”

Section: In Vivo Expression Of a New Hepatitis B Virus Protein Encodementioning

confidence: 99%

In vivo expression of a new hepatitis B virus protein encoded by a spliced RNA

Soussan¹,

Garreau²,

Zylberberg³

et al. 2000

J. Clin. Invest.

137

116

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“…Enhancer I is located upstream of the X gene and overlaps the X promoter (Shaul et al, 1985 ;Zhang et al, 1992). Enhancer II is located within the X ORF and is associated with the C promoter (Yee, 1989).…”

Section: Introductionmentioning

confidence: 99%

The hepatitis B virus MHBst167 protein is a pleiotropic transactivator mediating its effect via ubiquitous cellular transcription factors.

Caselmann

Renner²,

Schl√oter³

et al. 1997

Journal of General Virology

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C-terminally truncated surface proteins of hepatitis B virus (HBV) are frequently translated from genomically integrated viral sequences. They may be relevant for hepatocarcinogenesis by stimulating gene expression. First, we examined the transactivating potential of middle hepatitis B surface protein truncated at amino acid (aa) position 167 (MHBs t167 ) on the HBV regulatory element. In transient cotransfection assays using Chang liver or HepG2 cell lines and chloramphenicol acetyltransferase (CAT) reporter constructs only the HBV enhancer I, but no other HBV regulatory elements like the X promoter, the S1 or S2 promoter or the enhancer II/core promoter could be stimulated by MHBs t167 . Since there is no evidence for a direct

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Characterization of the hepatitis B virus- and nucleocapsid gene transcriptional regulatory elements

Cited by 45 publications

References 56 publications

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

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

In vivo expression of a new hepatitis B virus protein encoded by a spliced RNA

The hepatitis B virus MHBst167 protein is a pleiotropic transactivator mediating its effect via ubiquitous cellular transcription factors.

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