HBV integrants of hepatocellular carcinoma cell lines contain an active enhancer

Shamay, Meir; Agami, Reuven; Shaul, Yosef

doi:10.1038/sj.onc.1204879

Cited by 36 publications

(38 citation statements)

References 48 publications

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“…Several in vitro studies have shown the effects of HBxAg on cellular repair, proto-oncogenes, tumour suppressor gene, anti-apoptotic pathway and the induction of HCC in transgenic mice. These evidence support the probable direct effect of a HBV component, HBxAg, in the development of HCC [17][18][19][20][21][22][23][24].…”

Section: Molecular Studiessupporting

confidence: 69%

Chronic Hepatitis B infection and liver cancer

Wong¹,

Goh²

2006

Biomed. Imaging Interv. J.

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Hepatitis B virus (HBV) is one of the most well recognised human carcinogens. Since its discovery about 40 years ago, HBV has been studied extensively. This article summarises the evidence derived from various studies including epidemiological, animal model, histopathology studies and molecular genetics studies leading to the establishment of HBV as the main aetiological agent for hepatocellular carcinoma (HCC). The reduction in the incidence of childhood HCC due to mass hepatitis B vaccination in Taiwan is a dramatic demonstration of the critical aetiological role of hepatitis B in HCC. Thus it is essential for interventionalists to understand the epidemiological and pathogenesis of HCC to ensure optimal patient care.

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Section: Molecular Studiessupporting

confidence: 69%

Chronic Hepatitis B infection and liver cancer

Wong¹,

Goh²

2006

Biomed. Imaging Interv. J.

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“…HBV DNA in these cells was chromosomally integrated and episomal HBV particles were produced [25]. PLC/PRF/5 cells were originally derived from a human hepatoma biopsy and contained multiple HBV integrants that retained the innate enhancer of HBV [26,27]. For the increase of HBx protein by adriamycin, ChangX-34 cells were treated with 1 lg/ml of adriamycin for 1 day and PLC/PRF/5 and HepG2.2.15 cells were treated for 2-3 days.…”

Section: Methodsmentioning

confidence: 99%

“…We then further extended the effect of adriamycin in other HBV-related hepatoma cells, PLC/ PRF/5 and HepG2.2.15 cells. HBV DNA with the innate HBV enhancer was chromosomally integrated in these cells [25][26][27]. To determine the level of HBx protein in these cells, we employed immunofluorescence staining method and flow cytometric analysis using the anti-HBx antibody.…”

Section: Prolonged Treatment Of Adriamycin Increases the Cellular Levmentioning

confidence: 99%

“…To determine the level of HBx protein in these cells, we employed immunofluorescence staining method and flow cytometric analysis using the anti-HBx antibody. It is known that HBx protein in these cells was hardly detected by western blot analysis due to its low expression level [25][26][27] as well as poor immunogenicity of HBx protein. We had shown that the anti-HBx antibody available in our laboratory recognized HBx better in cells fixed in methanol/acetate [14] but not the denatured form of HBx on the SDS-PAGE (data not shown).…”

Section: Prolonged Treatment Of Adriamycin Increases the Cellular Levmentioning

confidence: 99%

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Reactive oxygen species modulates the intracellular level of HBx viral oncoprotein

Wang

Yun

Kim

et al. 2003

Biochemical and Biophysical Research Communications

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“…In addition, cellular factors involved in cell cycle control and apoptosis, including the tumor suppressor protein p53 (39), its homologue p73 (11), the proto-oncoprotein c-Abl (10), and RFX-1 (26,45), specifically bind and regulate EnhI activity. Recently, in vivo footprinting analysis has demonstrated that the EnhI region is occupied by the aforementioned cell cycle control proteins (43). EnhII is situated immediately upstream to the pg/pc promoter and has been implicated in regulating its transcription as well as the transcription of the preS2/S promoters (30,56).…”

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confidence: 99%

Enhancer I Predominance in Hepatitis B Virus Gene Expression

Doitsh

Shaul

2004

Molecular and Cellular Biology

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Previous studies of human hepatitis B virus (HBV) transcription revealed the requirement of two enhancer elements. Enhancer I (EnhI) is located upstream of the X promoter and is targeted by multiple activators, including basic leucine zipper proteins, and enhancer II (EnhII) is located upstream to the PreCore promoter and is targeted mainly by nuclear receptors (NRs). The mode of interplay between these enhancers and their unique contributions in regulating HBV transcription remained obscure. By using time course analysis we revealed that the HBV transcripts are categorized into early and late groups. Chang (CCL-13) cells are impaired in expression of the late transcripts. This could be corrected by overexpressing EnhII activators, such as hepatocyte nuclear factor 4␣, the retinoid X receptor ␣, and the peroxisome proliferator-activated receptor ␣, suggesting that in Chang cells EnhI but not EnhII is active. Replacing the 5-end EnhI sequence with a synthetic Gal4 response (UAS) DNA fragment ceased the production of the early transcripts. Under this condition NR overexpression poorly activated EnhII. However, activation of the UAS by Gal4-p53 restored both the expression of the early transcripts and the EnhII response to NRs. Thus, a functional EnhI is required for activation of EnhII. We found a major difference between Gal4-p53 and Gal4-VP16 behavior. Gal4-p53 activated the early transcripts, while Gal4-VP16 inhibited the early transcripts but activated the late transcripts. These findings indicate that the composition of the EnhI binding proteins may play a role in early to late switching. Our data provides strong evidence for the role of EnhI in regulating global and temporal HBV gene expression.Hepatitis B virus (HBV) is the prototype of the hepadnaviridae, a family of small hepatotropic enveloped viruses. The HBV genome consists of a partially double-stranded 3.2-kb DNA with four major open reading frames (ORFs). These ORFs encode the reverse transcriptase (Pol protein), Core proteins (preCore and Core), three surface antigen proteins (preS1, preS2, and S), and the X protein (pX). Upon infection the viral genome targets the host nucleus, where it detaches from the viral polymerase and is repaired, acquiring a covalently closed circular DNA (cccDNA) configuration. cccDNA serves as a template for mRNA synthesis by the host polymerase II. At least five promoters control the synthesis of the six major viral transcripts. Two distinct transcripts are initiated at the X-gene promoter (12,20,28), both encoding the X protein (12). One is a short 0.7-kb transcript named short-X RNA (sxRNA), and the other is a 3.9-kb transcript named long-X RNA (lxRNA). The preCore and Core promoters are about 30 bp apart and initiate the synthesis of the pregenomic and preCore RNA species, designated pg/pcRNA. The pgRNA has a dual function: it is used as a template for viral replication and is translated into the Core protein. This transcript is assumed to translate the Pol protein. Other major HBV transcripts initiate either at the ...

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HBV integrants of hepatocellular carcinoma cell lines contain an active enhancer

Cited by 36 publications

References 48 publications

Chronic Hepatitis B infection and liver cancer

Chronic Hepatitis B infection and liver cancer

Reactive oxygen species modulates the intracellular level of HBx viral oncoprotein

Enhancer I Predominance in Hepatitis B Virus Gene Expression

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