Hepatitis B virus transcriptional activators: mechanisms and possible role in oncogenesis

Henkler, Frank; Koshy, Rajen

doi:10.1111/j.1365-2893.1996.tb00001.x

Cited by 94 publications

(86 citation statements)

References 110 publications

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“…The finding that HBV makes a genetic contribution to HCC by expression of the HBV-encoded X antigen (HBxAg) (Henkler and Koshy, 1996;Feitelson and Duan, 1997), suggests that the pathways whereby HBxAg contributes to hepatocarcinogenesis are relevant for the development of diagnostic/prognostic markers and/or antiviral and antitumor drugs.…”

Section: Introductionmentioning

confidence: 99%

“…HBxAg may do this by activating signal transduction pathways and by binding to transcription factors that influence host gene expression (Henkler and Koshy, 1996;Feitelson and Duan, 1997). Among these changes, HBxAg upregulates the expression of cellular proteins that promote cell growth and survival (Su et al, 1994;Terradillos et al, 1997), and suppresses expression or functionally inactivates negative growth regulatory proteins (Wang et al, 1994;Truant et al, 1995;Sun et al, 1998;Feitelson et al, 1999;Lian et al, 1999;Kondoh et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma

et al. 2005

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Hepatitis B virus (HBV)-encoded X antigen (HBxAg) contributes to the development of hepatocellular carcinoma (HCC). A frequent characteristic of HCC is reduced or absent expression of the cell adhesion protein, Ecadherin, although it is not known whether HBxAg plays a role. To address this, the levels of E-cadherin were determined in HBxAg-positive and -negative HepG2 cells in culture, and in tumor and surrounding nontumor liver from a panel of HBV carriers. The results showed an inverse relationship between HBxAg and E-cadherin expression both in tissue culture and in vivo. In HBxAgpositive cells, E-cadherin was suppressed at both the mRNA and protein levels. This was associated with hypermethylation of the E-cadherin promoter. Depressed E-cadherin correlated with HBxAg trans-activation function, as did the migration of HepG2 cells in vitro. Decreased expression of E-cadherin was also associated with the accumulation of b-catenin in the cytoplasm and/ or nuclei in tissues and cell lines, which is characteristic of activated b-catenin. Additional work showed that HBxAg-activated b-catenin. Together, these results suggest that the HBxAg is associated with decreased expression of E-cadherin, accumulation of b-catenin in the cytoplasm and nucleus, and increased cell migration, which may contribute importantly to hepatocarcinogenesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma

et al. 2005

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“…Although the multifunctional characteristics of viral protein HBx have been extensively studied, the pathogenic mechanism of HBx in human liver cancer remains largely unknown (2,3). In this study, we provide the first evidence that by inactivating GSK-3b via inhibiting the ERK pathways, HBx is able to inhibit cyclin D1 nucleus export and subsequent proteasomal degradation.…”

Section: Discussionmentioning

confidence: 79%

“…The HBV genome is a partially double-stranded, circular DNA containing four overlapping genes: S/preS, C/preC, P, and X. The X gene encodes a 17-kd HBV X protein (HBx), which is a multifunctional transactivator of both viral and cellular genes (2). It is widely accepted that HBx plays crucial roles in the pathogenesis of HBV-induced HCC, as X gene-transgenic mouse developed liver cancer promptly (3,4).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B Virus X Protein Stabilizes Cyclin D1 and Increases Cyclin D1 Nuclear Accumulation through ERK-Mediated Inactivation of GSK-3β

Chen

Zhang

Zheng

et al. 2015

Cancer Prevention Research

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The Hepatitis B virus X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). It has been suggested that the transcriptional activation of cyclin D1 by HBx is implicated in the development of HCC. However, numerous studies have shown that overexpression of cyclin D1 alone is not sufficient to drive oncogenic transformation. Herein, we investigated whether HBx can stabilize cyclin D1 and induce cyclin D1 protein nuclear accumulation, and thereby accelerate hepatocarcinogenesis. The effects of HBx on cyclin D1 stabilization were assessed in cell-based transfection, Western blot, immunoprecipitation, immunocytofluorescence staining, and flow-cytometric assays. The results demonstrated that ectopic expression of HBx in HCC cells could extend the half-life of cyclin D1 protein from 40-60 minutes to 80-110 minutes. HBx stabilized cyclin D1 primarily in the S phase of the cell cycle, in a manner dependent on the inactivation of GSK-3b, which was mediated by ERK activation. HBx also prompted the nuclear accumulation of cyclin D1, and cotransfection of the constitutively active mutant of GSK-3b along with HBx could reverse the nuclear accumulation and subsequent cell proliferation induced by HBx. Further, a positive correlation between HBx and nuclear cyclin D1 level was established in HCC specimens detected by an immunohistochemical assay. Taken together, our results indicated that HBx could stabilize and increase cyclin D1 nuclear accumulation through ERK-mediated inactivation of GSK-3b. This HBx-induced cyclin D1 upregulation might play an important role in HCC development and progression. Cancer Prev Res; 8(5); 455-63. Ó2015 AACR.

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“…The finding that HBxAg binds to a variety of transcription factors 16,17 supports the hypothesis that HBxAg trans-activation is relevant to HCC. 18 The binding and inactivation of the tumor suppressor p53 by HBxAg further implicates this virus product in the pathogenesis of HCC. [19][20][21] Given the multistep nature of carcinogenesis and the possibility that the action of HBxAg may contribute to multiple steps, additional HBxAg-binding proteins were sought.…”

mentioning

confidence: 99%

Identification of a protein isolated from senescent human cells that binds to hepatitis B virus X antigen

et al. 1998

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Hepatitis B virus-encoded X antigen contributes to the development of hepatocellular carcinoma. Given that X antigen functions by binding to other proteins, additional X-binding proteins were sought from an adult human liver cDNA library in a yeast two-hybrid system. The results yielded a clone encoding a 55-kd protein that is associated with replicative senescence (p55 sen ). Binding of p55 sen to X antigen was confirmed in vitro by immunoprecipitation and affinity chromatography. The expression of endogenous p55 sen inversely correlated with cell growth. Transient transfection of X antigen or p55 sen into HepG2 cells stimulated DNA synthesis by twofold to threefold, whereas cotransfection did not, suggesting that these molecules functionally interact. The detection of p55 sen in embryonic mouse liver, its absence in adult mouse and human livers, and its reappearance in livers from carriers with chronic liver disease, suggest that it may play important roles in the regulation of liver cell growth. The similarity between p55 sen and a notch ligand, which is involved in cell fate determinations during embryogenesis, implies that the binding of p55 sen by X antigen may also contribute to an alteration in cell fate, which is characteristic of carcinogenesis. (HEPATOLOGY 1998;27:228-239.)There are more than 300 million carriers of hepatitis B virus (HBV) worldwide who are at high risk for the development of chronic liver diseases, including hepatocellular carcinoma (HCC). 1,2 Although the relative risk for the development of HCC among carriers with liver disease is greater than 100, 3 the molecular mechanism(s) responsible for hepatocellular transformation have not been identified. The frequent finding of HBV DNA integrated into chromosomal DNA 4,5 resulted in an intensive search for cis-acting mechanisms operative in HCC, but the weight of the evidence does not support such mechanisms as being common in HBV-associated tumors. 4,6 The observation that HBV DNA fragments integrated randomly into many host chromosomes 4,6 and that the integrated viral DNA often overexpressed the HBV-encoded X antigen (HBxAg) 7,8 suggested that what the integrated viral sequences encoded was more important than the site of viral DNA integration. HBxAg made from these integrated fragments was subsequently shown to be active in transactivation assays 9-11 and transformed nontumorigenic cell lines, [12][13][14][15] suggesting that persistent high levels of HBxAg expression may shift the patterns of host gene expression relevant to the development of HCC. The finding that HBxAg binds to a variety of transcription factors 16,17 supports the hypothesis that HBxAg trans-activation is relevant to HCC. 18 The binding and inactivation of the tumor suppressor p53 by HBxAg further implicates this virus product in the pathogenesis of HCC. [19][20][21] Given the multistep nature of carcinogenesis and the possibility that the action of HBxAg may contribute to multiple steps, additional HBxAg-binding proteins were sought. MATERIALS AND METHODSYeast Two...

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Hepatitis B virus transcriptional activators: mechanisms and possible role in oncogenesis

Cited by 94 publications

References 110 publications

Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma

Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma

Hepatitis B Virus X Protein Stabilizes Cyclin D1 and Increases Cyclin D1 Nuclear Accumulation through ERK-Mediated Inactivation of GSK-3β

Identification of a protein isolated from senescent human cells that binds to hepatitis B virus X antigen

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