Transcriptional trans-activating function of hepatitis B virus

Twu, Jr-Shin; Schloemer, Robert H.

doi:10.1128/jvi.61.11.3448-3453.1987

Cited by 264 publications

(90 citation statements)

References 46 publications

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“…The suppression in nude mouse tumor H 112-1 of viral core gene expression as a consequence of DNA methylation is reminiscent of events occurring in natural tumors. Viral core proteins are known inhibitors of transcriptional activation (Twu and Schloemer, 1987), and may therefore inhibit X gene expression (Twu et al, 1988). This may explain why HCCs are virtually absent in viremic HBV carriers who usually express large amounts of core/e protein.…”

Section: Discussionmentioning

confidence: 99%

Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA.

et al. 1990

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Persistent infection by hepatitis B virus (HBV) is epidemiologically correlated with the prevalence of hepatocellular carcinoma, but its role in tumor development is not yet understood. To study the putative oncogenic potential of HBV, a non‐malignant immortal mouse hepatocyte line FMH202 harboring metallothionein promoter‐driven simian virus 40 large tumor antigen was transfected with HBV DNA. All stably transfected clones which replicated HBV displayed malignant growth characteristics in soft agar and were tumorigenic upon inoculation in nude mice. The nude mice tumors were histologically classified as differentiated or anaplastic hepatocellular carcinomas. As with human liver carcinomas, rearrangements of in vitro integrated HBV sequences were observed in the nude mouse tumors, and in tumor‐derived cell lines. In one case, expression of viral core and surface antigens was blocked in the tumors, correlating with hypermethylation of the HBV genome. However, the expression of X gene was maintained in most tumors and tumor‐derived cell lines. X protein was detected in nuclei by immune fluorescence and by immune blot. These results provide the first demonstration that HBV displays oncogenic potential in an experimental system. This system could be useful to functionally identify HBV genes which convey a tumorigenic phenotype.

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Section: Discussionmentioning

confidence: 99%

Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA.

et al. 1990

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“…Almost all HBV-associated HCCs studied so far have chromosomally integrated HBV DNA (Buendia, 2000). The HBV genome encodes two transcriptional activators: the PreS2 activator LHBs (large hepatitis B virus surface protein; Hildt et al, 1996) and the HBx activator protein (Twu & Schloemer, 1987).…”

Section: Introductionmentioning

confidence: 99%

Reconstitution of gene expression from a regulatory‐protein‐deficient hepatitis B virus genome by cell‐permeable HBx protein

2003

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Various functions are ascribed to the HBx regulatory protein of the hepatitis B virus (HBV). Due to the low expression level ofHBx, it has been difficult to correlate spatial and temporal HBx expression levels with specific functions. Based on a novel cellpermeable peptide, known as the translocation motif (TLM), cellpermeable HBx fusion proteins were generated. The TLMHBx fusion protein is rapidly internalized from the medium into almost all cells, whereas no significant internalization was seen with wild-type HBx. The major fraction of internalized HBx protein moves from the cytoplasm to the nucleus. The cytosolic fraction, however, activates c-RAF1/extracellular-signal-related kinase 2 signalling and causes activation of activator protein 1 (AP1) and nuclear factor-κB. The TLM-HBx protein rescues HBV gene expression from an activator-deficient HBV genome. These results indicate that cell-permeable regulatory proteins provide a novel, efficient tool for a clearly defined, dose-dependent analysis of regulatory protein function, without affecting the integrity of the cell, and can be used for the safe reconstitution of virus production from a regulatory-protein-deficient virus genome.

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“…The X protein has recently been reported to be essential for establishment of infection . At a molecular level, HBx transactivates viral and host genes through a wide variety of cis elements present in RNA polymerase II promoters, including AP-1, AP-2, ATF, C/EBP, NF-KB sites, SRE (Twu and Schloemer, 1987;Seto et al, 1988; Twu and Robinson, 1989;Faktor and Shaul, 1990;Seto et al, 1990;Luber et al, 1991;Mahe et al, 1991;Lucito and Schneider, 1992;Lucito and Schneider, 1992;Avantaggiati et al, 1993) and one of the RNA polymerase III promoters (Aufiero and Schneider, 1990). Several endogenous genes important for cell proliferation and the inflammatory response are activated by HBx, such as c-fos, c-jun, ECAM and human IL8 (Mahe et al, 1991;Hu et al, 1992;Avantaggiati et al, 1993;Twu et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Human RPB5, a subunit shared by eukaryotic nuclear RNA polymerases, binds human hepatitis B virus X protein and may play a role in X transactivation.

et al. 1995

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The X gene of human hepatitis B virus encodes the polypeptide HBx which transactivates viral and host genes through a variety of cis‐acting enhancer elements present in RNA polymerases I, II and III promoters. To better understand the mechanism of X transactivation, we cloned cDNAs of proteins that bind HBx. Here we demonstrate that one of these cDNAs is a full‐length cDNA of human RPB5, a subunit shared by RNA polymerases. The HBx transactivation domain and the central region of human RPB5 were necessary for the specific binding of the two proteins as shown by: (i) in vitro assays using deletion mutants of fusion proteins; (ii) in vivo assays which detect associated proteins by co‐immunoprecipitation of the non‐fused proteins from transfected HepG2 cells. Over‐expressed HBx seemed to associate with assembled forms of endogenous human RPB5 in HBx‐transfected cells, since the endogenous RPB5 co‐immunoprecipitated with HBx. The HBx binding region of human RPB5 by itself stimulated chloramphenicol acetyltransferase activities from several different reporters having X‐responsive element(s). Our results support the idea that the interaction of HBx and human RPB5 can facilitate HBx transactivation and that human RPB5 has a domain which can communicate with transcriptional regulators.

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Transcriptional trans-activating function of hepatitis B virus

Cited by 264 publications

References 46 publications

Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA.

Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA.

Reconstitution of gene expression from a regulatory‐protein‐deficient hepatitis B virus genome by cell‐permeable HBx protein

Human RPB5, a subunit shared by eukaryotic nuclear RNA polymerases, binds human hepatitis B virus X protein and may play a role in X transactivation.

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