The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator

Kekulé, Alexander S.; Lauer, Ulrich M.; Meyer, Markus; Caselmann, Wolfgang H.; Hofschneider, Peter Hans; Koshy, Rajen

doi:10.1038/343457a0

Cited by 268 publications

(138 citation statements)

References 30 publications

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“…Previously, a transcription activation activity was ascribed to truncated forms of M protein (MHBs t ) (57). It might be speculated that the autoregulatory function of M protein uncovered in the present study is the same as that of MHBs t described previously.…”

Section: Protein Regulates Surface Gene Expression By Interacting Wsupporting

confidence: 67%

“…Upon close examination, however, these two are quite different. First, the transcription transactivator function of MHBs t was originally based on its ability to transactivate the SV40 promoter-reporter gene (57). Later, it was found that it may indirectly transactivate reporter genes containing transcription factor-binding sites, e.g.…”

Section: Protein Regulates Surface Gene Expression By Interacting Wmentioning

confidence: 99%

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Novel Autoregulatory Function of Hepatitis B Virus M Protein on Surface Gene Expression

Huang

Tsai

et al. 2005

Journal of Biological Chemistry

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The hepatitis B virus surface gene consists of a single open reading frame divided into three coding regions: pre-S1, pre-S2, and S. By alternate translation at each of the three initiation codons, L, M, and S proteins can be synthesized. Studies have shown that M protein is not essential for viral replication, virion morphogenesis, or in vitro infectivity. In this study, we show that native M protein can regulate surface gene expression at the transcriptional level. The regulatory effect of M protein is mediated through the CCAAT box within the S promoter. Deletion mapping analysis indicated that the transactivating effect of M protein is mediated through amino acids 1-57 of M protein (the MHBs au domain), although its maximal transactivation activity coincides with that of the pre-S2 domain. This conclusion is supported by the fact that disruption of the putative V8 protease site at the pre-S2/S domain junction not only rendered M protein incapable of transactivating the S promoter but also inactivated its nuclear translocation potential. Immunoprecipitation and immunoblot experiments demonstrated that pre-S2 interacts with the three subunits of the CCAAT box-binding factor/nuclear factor Y, the cognate binding protein of the CCAAT box. These results demonstrate and define a novel regulatory role of M protein, which, under natural conditions, may undergo a proteolytic process to generate an MHBs au species that will be translocated inside the nucleus, where it will interact with the CCAAT box-binding factor to regulate surface gene expression. Because the CCAAT box is located at a fixed position within numerous promoters, these observations might provide a plausible explanation for hepatitis B virus-associated hepatocarcinogenesis. Hepatitis B virus (HBV)1 infection causes a wide spectrum of liver diseases, including acute hepatitis, chronic active hepatitis, cirrhosis, and hepatocellular carcinoma (1-4). HBV belongs to the hepadnavirus family, and its particle coat consists of a lipid bilayer membrane and envelope proteins. It has a partial duplex DNA genome of ϳ3.2 kb and contains four overlapping open reading frames: DNA polymerase, core protein, surface antigen, and the X gene (5). The HBV surface (envelope) gene encodes three forms of viral surface proteins (6, 7). It is divided into three parts by two internal initiation codons: the pre-S1, pre-S2, and S regions. This combination of three regions forms the large surface antigen LHBsAg or L protein. In addition, the pre-S2 and S regions form the middle surface antigen MHBsAg or M protein. The small surface antigen SHBsAg or S protein, also called major S protein, constitutes the most abundant protein of HBV envelopes. The production of these three forms of surface protein (L, M, and S) is controlled by two tandem promoters. The upstream pre-S1 promoter controls the transcription of a 2.4-kb transcript that encodes L protein only. The downstream S promoter, ϳ240 bp away, specifies transcripts with heterogeneous 5Ј termini (5), with the largest transcript e...

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Section: Protein Regulates Surface Gene Expression By Interacting Wsupporting

confidence: 67%

Section: Protein Regulates Surface Gene Expression By Interacting Wmentioning

confidence: 99%

Novel Autoregulatory Function of Hepatitis B Virus M Protein on Surface Gene Expression

Huang

Tsai

et al. 2005

Journal of Biological Chemistry

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“…Such a mutant is capable of transactivating several promoters including those of oncogenic proteins. [32][33][34] The truncation point in the A529T mutant, however, was located just at the border of the defined ''transactivity-ON-region.'' 34 Clinically, none of the patients harboring this mutant developed hepatocellular carcinoma to date.…”

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confidence: 99%

Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy

et al. 2000

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Tyrosine-methionine-aspartate-aspartate (YMDD)-motif mutants may emerge and elicit immune clearance during prolonged lamivudine treatment. The aim of this study was to investigate the virological events following development of the original mutants. Twenty-three patients who developed YMDD-motif mutants during the Asian lamivudine trial were included. Serial serum samples from these patients were subjected to sequence analysis to identify new mutants. Site-directed mutagenesis experiments were performed to investigate whether the new mutations were responsible for lamivudine resistance. Of the 23 patients included, 13 harbored either one or a mixture of the two common YMDD-motif mutants (methionine 552-to-isoleucine [M552I] and leucine 528-to-methionine/methionine 552-to-valine [L528M/M552V]) throughout the course, whereas in the remaining 10 patients, distinct mutants became dominant over the original mutants to cause continuing chronic hepatitis. Of them, 3 developed an alanine 529-to-threonine (A529T) mutant, 6 developed a leucine 528-to-methionine/methionine 552-to-isoleucine (L528M/ M552I) mutant, and 1 developed these two mutants sequentially. Site-directed mutagenesis experiments confirmed that the aforementioned mutations were responsible for the resistance to lamivudine in vitro. The nucleotide substitution in the A529T mutant concomitantly generated a stop codon at the surface gene, leading to impaired secretion of HBsAg. Strikingly, the replication of this mutant was lamivudine dependent. These results suggested that distinct lamivudine-resistant mutants could emerge and replace the original YMDD-motif mutants as the cause of continuing chronic hepatitis during prolonged lamivudine therapy. (HEPATOLOGY 2000;31:1318-1326.)Lamivudine, (-)-␤-L-2Ј,3Ј-dideoxy-3Ј-thiacytidine, is a nucleoside analogue with a potent inhibitory effect on RNA-dependent DNA polymerase of hepatitis B virus (HBV) and human immunodeficiency virus. 1-4 Its antiviral effects against HBV have been established both in vitro and in vivo. [5][6][7] Although suppression of viral replication, as determined by negativity of serum HBV DNA, can be achieved in most patients, clearance of hepatitis B virus e antigen (HBeAg) was only seen in a minority of patients. 5 Such discrepancy was believed to be attributed to the persistence of HBV covalently closed circular DNA in the nuclei of hepatocytes, which resulted in rapid relapse of HBV replication after withdrawal of lamivudine. 8,9 Prolonged use of lamivudine was therefore proposed and is now under clinical evaluation. 10 The emergence of lamivudine-resistant mutants, however, casts a new challenge for such strategy. [11][12][13][14][15][16][17][18][19][20][21] The resistant viruses were initially noticed in patients under immunosuppressive therapy but were later found in immunocompetent patients. Although such mutants were initially considered replication defective, 22 we have recently shown that acute exacerbations occurred frequently and hepatic decompensation may develop in patients with ...

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“…To compare the mRNA expression in various organs of these mice, we performed both RT-PCR analysis and ribonuclease protection assay (RPA) [6]. Antisense RNA probe labeled with 33 P-CTP was generated as a transcript RNA [7,9].…”

mentioning

confidence: 99%

Sequence analysis and Expression of Nramp-1 Gene in Bcgr and Bcgs Mice.

Nakanaga

Maeda

Myojin

et al. 1999

The Journal of Veterinary Medical Science

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ABSTRACT. Nucleic acid sequence of complemental DNA open reading frame for Nramp-1 gene was compared among DBA/2 (Bcg r ), C57BL/6 (Bcg s ) and C57BL/6-Bcg r mice which was previously developed as M. avium-resistant mouse strain (Xu, et al. Veterinary Microbiology 50:73-79 (1996)). Total RNA was isolated from various organs of DBA/2, C57BL/6 and C57BL/6-Bcg r . Nramp-1 cDNA was constructed from their mRNAs by gene amplification (PCR) technique and their open reading frame sequences were compared. The results clearly showed that our C57BL/6-Bcg r was almost identical with the DNA sequence of the DBA/2 mice. In contrast, C57BL/6-Bcg s mice differed only on the substitution of adenine for guanine of the nucleic acid at position 596. This corresponded to the site of amino acid substitution (glycine to asparate) at position 169 in predicted NRAMP which had been reported. The expression of Nramp-1 mRNA was more prominent in spleens and livers and there appeared to be no significant difference among the strains of mice.-KEY WORDS: mRNA expression, mycobacterial infection, Nramp-1.

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The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator

Cited by 268 publications

References 30 publications

Novel Autoregulatory Function of Hepatitis B Virus M Protein on Surface Gene Expression

Novel Autoregulatory Function of Hepatitis B Virus M Protein on Surface Gene Expression

Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy

Sequence analysis and Expression of Nramp-1 Gene in Bcgr and Bcgs Mice.

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