In vivo activity of the hepatitis B virus core promoter: tissue specificity and temporal regulation

Billet, Olivier; Grimber, G.; Levrero, Massimo; Seye, K A; Briand, Pascale; Joulin, Virginie

doi:10.1128/jvi.69.9.5912-5916.1995

Cited by 48 publications

(17 citation statements)

References 30 publications

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“…The finding that HBx does not alter liver MF in vivo is consistent with previous studies of HBx transgenic mice (5,14,21,39,43). The contribution of HBx expression to oncogenesis in two transgenic mouse lines that do develop HCC is open to interpretation (27,64).…”

Section: Discussionsupporting

confidence: 89%

“…Several lines of evidence indicate that HBx may also contribute to the development of HCC. Although the majority of HBx transgenic mouse lines do not demonstrate an increased incidence of liver cancer under normal conditions (5,14,21,34,39,43), such mice are more susceptible to the tumorigenic effects of hepatocarcinogens (14,50) or the oncogene c-myc (54). Based on these observations, HBx is believed to be an important cofactor in HBV-associated liver cancer.…”

mentioning

confidence: 99%

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Expression of Hepatitis B Virus X Protein Does Not Alter the Accumulation of Spontaneous Mutations in Transgenic Mice

Madden¹,

Finegold

Slagle³

2000

J. Virol.

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Chronic infection with hepatitis B virus (HBV) is one of the major etiological factors in the development of human hepatocellular carcinoma. Transgenic mice that express the HBV X protein (HBx) have previously been shown to be more sensitive to the effects of hepatocarcinogens, although the mechanism for this cofactor role remains unknown. The ability of HBx to inhibit DNA repair in transiently transfected cell lines suggests one possible pathway. In the present study, primary hepatocytes isolated from transgenic mice that possess the HBV X gene under the control of the human ␣-1-antitrypsin regulatory region (ATX mice) were found to be deficient in their ability to conduct unscheduled DNA synthesis in response to UV-induced DNA damage. In order to measure the impact of HBx expression on DNA repair in vivo, double-transgenic mice that express HBx and possess a bacteriophage lambda transgene were sacrificed at 30, 90, and 240 days of age. Mutation frequency was determined for high-molecular-weight liver DNA of ATX and control mice by functional analysis of the lambda transgene. Expression of HBx did not significantly increase the accumulation of spontaneous mutations. These results are consistent with previous studies of HBx transgenic mice in which no effect of HBx on liver histology was apparent. This new animal model provides a powerful system in which to investigate the in vivo cooperation between HBx expression and environmental carcinogens.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Expression of Hepatitis B Virus X Protein Does Not Alter the Accumulation of Spontaneous Mutations in Transgenic Mice

Madden¹,

Finegold

Slagle³

2000

J. Virol.

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“…Only by replacement of CP with the metallothionein IIA promoter can HBV replicate in HeLa cells [44]. This strict liver cell specificity of HBV and the differential regulation of CP results from the interactions of its cis-acting elements with transacting factors present in various tissues and cell types and during different stages of liver cell differentiation [25,45]. The co-operative interaction of various liverenriched and ubiquitous factors is necessary for liver-specific expression from the CP.…”

Section: Liver Specificity Of the Core Promotermentioning

confidence: 99%

The core promoter of hepatitis B virus

Kramvis

Kew

1999

Journal of Viral Hepatitis

130

114

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The core promoter (CP) of hepatitis B virus (HBV) plays a central role in HBV replication and morphogenesis, directing the transcription of both species of 3.5 kb mRNA: pregenomic (pg) RNA and precore (pre-C) mRNA. The CP overlaps the 3' end of the X open-reading frame (ORF) and the 5' end of the pre-C/C ORF. The major functional elements of the CP are the upper regulatory region (URR) and the basic core promoter (BCP). The BCP is sufficient for accurate initiation of both pre-C mRNA and pgRNA transcription. It contains four AT-rich regions and the initiators for pre-C mRNA and pgRNA transcription. The upstream regulatory region consists of the negative regulatory element and the core upstream regulatory sequence. Co-operative interaction of various liver-enriched and ubiquitous transcription factors is necessary for liver-specific expression from the CP. These factors bind to the CP. Sequence conservation within the CP is crucial for maintaining active viral replication, and variation may contribute to the persistence of HBV within the host, leading to chronic infection and, ultimately, hepatocarcinogenesis. The most frequently described mutations within this region are an A to T transversion at position 1762 together with a G to A transition at position 1764. This double mutant is accompanied by a reduced level of hepatitis B e antigen (HBeAg) expression. Deletions, insertions and duplications occur within the CP.

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“…A high incidence of HCC was found in Tg mice, subsequent to microinjecting a 1.15 kb HBV subtype adr DNA fragment with nucleotide positions 707 to 1856 in the viral genome. In contrast, the HBx Tg mice generated in other laboratories developed no obvious hepatic pathology, although they expressed the X-gene in liver cells and the HBx protein could be detected in some cases [29][30][31][32]. Therefore, HBx was concerened with an oncogenic role.…”

Section: Generation Of Hbx Tg Mice Inducing Liver Cancermentioning

confidence: 90%

Relevance of reactive oxygen species in liver disease observed in transgenic mice expressing the hepatitis B virus X protein

2020

Lab Anim Res

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The hepatitis B virus (HBV) infects approximately 240 million people worldwide, causing chronic liver disease (CLD) and liver cancer. Although numerous studies have been performed to date, unfortunately there is no conclusive drug or treatment for HBV induced liver disease. The hepatitis B virus X (HBx) is considered a key player in inducing CLD and hepatocellular carcinoma (HCC). We generated transgenic (Tg) mice expressing HBx protein, inducing HCC at the age of 11-18 months. The incidence of histological phenotype, including liver tumor, differed depending on the genetic background of HBx Tg mice. Fatty change and tumor generation were observed much earlier in livers of HBx Tg hybrid (C57BL/6 and CBA) (HBx-Tg hybrid) mice than in HBx Tg C57BL/6 (HBx-Tg B6) mice. Inflammation was also enhanced in the HBx-Tg B6 mice as compared to HBx-Tg hybrid mice. HBx may be involved in inducing and promoting hepatic steatosis, glycemia, hepatic fibrosis, and liver cancer. Reactive oxygen species (ROS) generation was remarkably increased in livers of HBx Tg young mice compared to young wild type control mice. Previous studies on HBx Tg mice indicate that the HBx-induced ROS plays a role in inducing and promoting CLD and HCC.

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In vivo activity of the hepatitis B virus core promoter: tissue specificity and temporal regulation

Cited by 48 publications

References 30 publications

Expression of Hepatitis B Virus X Protein Does Not Alter the Accumulation of Spontaneous Mutations in Transgenic Mice

Expression of Hepatitis B Virus X Protein Does Not Alter the Accumulation of Spontaneous Mutations in Transgenic Mice

The core promoter of hepatitis B virus

Relevance of reactive oxygen species in liver disease observed in transgenic mice expressing the hepatitis B virus X protein

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