Woodchuck hepatitis virus X protein is required for viral infection in vivo

Zoulim, Fabien; Saputelli, Jeffry; Seeger, Christoph

doi:10.1128/jvi.68.3.2026-2030.1994

Cited by 420 publications

(137 citation statements)

References 32 publications

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“…29 HBx is a 17-kd regulatory protein that is necessary for hepadnavirus replication in animal hosts. 30 There is evidence that HBx has an important role in the development of HCC in HBV-related chronic liver diseases. Other than transactivating a large and diverse number of viral and cellular promoters, 31 HBx can also upregulate RNA polymerase I-dependent promoters by stimulating ribosomal RNA transcription.…”

Section: Discussionmentioning

confidence: 99%

Nucleolar hypertrophy correlates with hepatocellular carcinoma development in cirrhosis due to HBV infection

et al. 2003

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Patients with cirrhosis are at significant risk for hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the relationship between the percentage of hepatocytes showing nucleolar hypertrophy and the development of HCC in cirrhosis of different causes. A total of 111 cirrhotic patients were studied, with a mean follow-up period of 83.3 months. Histologic sections from liver biopsy specimens were silver stained for selective visualization of the nucleolus; the nucleolar area was measured by image cytometry. Nucleoli with a size of 7 m 2 or greater were considered to be hypertrophic. The nucleolar index was obtained by calculating the percentage of hepatocytes disclosing a nucleolar area of 7 m 2 or greater. During the observation time, HCC was diagnosed in 39 of 111 patients. The incidence rate of HCC was greater in patients with nucleolar indexes of 2.5 or greater than in patients with nucleolar indexes of less than 2.5 (16.49%/y vs. 3.41%/y, respectively; P < .0001). The capacity of the nucleolar index to predict HCC development was separately tested in groups of patients divided by etiology, and it was found to be particularly relevant in hepatitis B virus (HBV)-related cirrhosis (P ‫؍‬ .0006). Among patients with hepatitis C virus (HCV) infection, high nucleolar-index values were associated with a greater risk for HCC development, but the difference in the incidence rate of HCC between groups with a nucleolar index of 2.5 or greater and less than 2.5 was not statistically significant (P ‫؍‬ .0944). In conclusion, our results have shown that high percentages of hepatocytes showing nucleolar hypertrophy significantly predict HCC development in patients with HBV infection, whereas their predictive value in HCV-related cirrhosis seems to be lower. (HEPATOLOGY 2003;37:72-78.) H epatocellular carcinoma (HCC) is one of the most prevalent tumors in humans. It is particularly common in certain regions of Asia and sub-Saharan Africa, but over the past decades its incidence has been increasing also in Western countries. 1 The prognosis of HCC is poor, and the application of various screening and treatment protocols during the past 25 years does not appear to have significantly improved the chances of survival of HCC patients. 2 Most HCCs occur in association with underlying chronic liver disease and, in more than 80% of cases, arise in cirrhotic liver. 3 The major risk factors affecting HCC development in cirrhotic patients are reported to be male sex, old age (over 60 years), alcohol abuse, and viral infection caused by hepatitis B virus (HBV) and hepatitis C virus (HCV). In addition to these well-established factors, hepatocyte proliferation rate 4-7 and the presence of large cell changes (LCC) 8,9 have been suggested as predictors of HCC occurrence in cirrhosis.Nucleolar hypertrophy or prominence, as frequently referred by pathologists, represents a morphologic feature that characterizes both proliferating and dysplastic hepatocytes. It is well known that after hematoxylin-eosin staining, nucleo...

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Section: Discussionmentioning

confidence: 99%

Nucleolar hypertrophy correlates with hepatocellular carcinoma development in cirrhosis due to HBV infection

et al. 2003

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“…In addition, the protein might have a mutagenic effect by interfering with DNA repair (Elmore et al, 1997;Becker et al, 1998). Despite a well-established function of the X protein WHx in the woodchuck hepatitis virus (WHV) life cycle (Zoulim et al, 1994), there are conflicting reports about the relevance of HBx for the life cycle of HBV (Bouchard et al, 2001a;Reifenberg et al, 2002;Stoeckl et al, 2003).…”

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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“…Despite its small size, the HBV genome contains at least three distinct promoters, all of which seem to be regulated by the viral enhancer (reviewed in Shaul, 1991) and its regulatory protein, pX. The open reading frame of pX is conserved among all mammalian hepadnaviridae, and it was shown to be essential for WHV infectivity (Chen et al, 1993;Zoulim et al, 1994). pX activates transcription of a vast number of genes through many different DNA elements (Faktor and Shaul, 1990;Cross et al, 1993), implying a more general effect on the transcription machinery.…”

Section: Introductionmentioning

confidence: 99%

pX, the HBV-encoded coactivator, interacts with components of the transcription machinery and stimulates transcription in a TAF-independent manner.

1996

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The X protein of hepatitis B virus (HBV) coactivates activators bearing potent (mostly acidic) activation domains. Here, we investigated the molecular mechanisms of this coactivation. We show that pX interacts with general transcription factors TFIIB and TFIIH, as well as with the potent activation domain of VP16. TFIIB interacts with both pX and VP16 simultaneously. In addition, the RNA polymerase II enzyme itself binds to pX. By reducing the activity of cellular coactivators, through squelching, we intensify the dependence of the activator on pX‐mediated coactivation. Squelching is essentially diminished in the presence of pX, both in vivo and in vitro. The target of pX in this activity is the template‐bound activator, and not the squelcher. Furthermore, by following transcription in a TAF‐deprived reaction, we demonstrate absolute dependence of the activator on the activity of pX. We propose that pX coactivates transcription by substituting cellular coactivators in activator‐preinitiation complex interactions.

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Woodchuck hepatitis virus X protein is required for viral infection in vivo

Cited by 420 publications

References 32 publications

Nucleolar hypertrophy correlates with hepatocellular carcinoma development in cirrhosis due to HBV infection

Nucleolar hypertrophy correlates with hepatocellular carcinoma development in cirrhosis due to HBV infection

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

pX, the HBV-encoded coactivator, interacts with components of the transcription machinery and stimulates transcription in a TAF-independent manner.

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