Detection of proteins encoded by the pre‐S region of hepatitis B virus in the sera of HBsAg carriers: relation to viral replication

Ibarra, Miren Zuriñe; Mora, Ignacio; Bartolomé, Javier; Porres, Juan Carlos; Carréño, Vicente

doi:10.1111/j.1600-0676.1989.tb00392.x

Cited by 6 publications

(3 citation statements)

References 10 publications

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“…In this status, the large form of HBsAg (LHBS) becomes largely expressed (5). Compared with small-form HBsAg, the large form includes an additional pre-S region, which is the upstream promoter region for the small form (5).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B Virus Pre-S2 Mutant Surface Antigen Induces Degradation of Cyclin-Dependent Kinase Inhibitor p27Kip1 through c-Jun Activation Domain-Binding Protein 1

Hsieh¹,

Wang

et al. 2007

Molecular Cancer Research

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The hepatitis B virus (HBV) large surface antigen (LHBS) mutant with deletion at the pre-S 2 region accumulates in endoplasmic reticulum (ER) and is associated with HBV-induced hepatocellular carcinogenesis. In this study, we found that the pre-S 2 LHBS mutant directly interacts with the Jun activation domain -binding protein 1 (JAB1). Association of pre-S 2 LHBS with JAB1 dissociated JAB1 from the JAB1/IRE1 complex in ER. The free (active) JAB1 then translocated into cell nuclei and rendered the Cdk inhibitor p27Kip1 to cytosolic proteasome for degradation. The pre-S 2 LHBS mutant induced hyperphosphorylation of tumor suppressor retinoblastoma (RB) via cyclin-dependent kinase 2 (Cdk2), a downstream molecule regulated by p27Kip1 . This effect is independent of the ER stress signaling pathway. The transgenic mice carrying the pre-S 2 mutant LHBS gene also exhibited Cdk2 activation, p27Kip1 degradation, as well as RB hyperphosphorylation. The mouse hepatocytes exhibited morphologic abnormalities such as chromatin condensation, multinucleation, and dysplasia of hepatocytes. In summary, the pre-S 2 LHBS mutant causes p27Kip1 degradation through direct interaction with JAB1. The pre-S 2 mutant LHBS is suggested to be a potential oncoprotein for HBV-related hepatocellular carcinoma.

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Section: Introductionmentioning

confidence: 99%

Hepatitis B Virus Pre-S2 Mutant Surface Antigen Induces Degradation of Cyclin-Dependent Kinase Inhibitor p27Kip1 through c-Jun Activation Domain-Binding Protein 1

Hsieh¹,

Wang

et al. 2007

Molecular Cancer Research

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“…LHBS and MHBS also facilitate secretion of the major HBS out of the host cell. In the chronic phase of HBV infection, the viral genome often integrates into the host chromosome and the viral replication is downregulated (2,3). In this phase, LHBS is expressed predominantly among various viral surface proteins (3).…”

Section: Hronic Hepatitis B Virus (Hbv) Infection Is the Most Impormentioning

confidence: 99%

“…In the chronic phase of HBV infection, the viral genome often integrates into the host chromosome and the viral replication is downregulated (2,3). In this phase, LHBS is expressed predominantly among various viral surface proteins (3). There also emerges the pre-S 2 mutant LHBS (⌬2 LHBS) that is truncated of approximately 17 amino acids (aa) in the N terminus of the pre-S 2 region of the protein and often also contains a point mutation in the start codon of the region, which leads to a dramatic decrease in the synthesis of MHBS (4,5) and potentially affects DNA polymerase activity due to overlap of the surface and polymerase genes in the viral genome.…”

Section: Hronic Hepatitis B Virus (Hbv) Infection Is the Most Impormentioning

confidence: 99%

Zinc-Dependent Interaction between JAB1 and Pre-S ₂ Mutant Large Surface Antigen of Hepatitis B Virus and Its Implications for Viral Hepatocarcinogenesis

Hsu

Chuang

et al. 2013

J Virol

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f Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The pre-S 2 mutant large HBV surface protein (⌬2 LHBS), which contains an in-frame deletion of approximately 17 amino acids in LHBS, is highly associated with risks and prognoses of HBV-induced HCC. It was previously reported that ⌬2 LHBS interacts with the Jun activation domain-binding protein 1 (JAB1), a zinc metalloprotease. This promotes the degradation of the cell cycle regulator p27Kip1 and is believed to be the major mechanism for ⌬2 LHBS-induced HCC. In this study, it was found that the interaction between JAB1 and ⌬2 LHBS is facilitated by divalent metal Zn 2؉ ions. C hronic hepatitis B virus (HBV) infection is the most important cause of hepatocellular carcinoma (HCC) worldwide.HBV causes necroinflammatory liver disease of variable duration and severity. A major portion of the viral hepatitis progresses into liver cirrhosis and dysplasia and ultimately into HCC. HBV surface antigen (HBsAg), the major component comprising the viral envelope, is the main serum and tissue marker for the viral infection status (1). HBsAg causes sustained hepatic inflammation and injury in the chronic phase of HBV infection and is therefore highly associated with HCC incidence.The HBS gene contains three in-frame gene segments: pre-S 1 , pre-S 2 , and major (or small) S. Using different start codons but sharing the same C terminus, the viral surface proteins include large, middle, and major protein products. The major HBsAg composes the majority of the viral envelope, whereas the middle and large HBS (MHBS and LHBS), usually much less expressed, are minor envelope proteins. LHBS and MHBS also facilitate secretion of the major HBS out of the host cell. In the chronic phase of HBV infection, the viral genome often integrates into the host chromosome and the viral replication is downregulated (2, 3). In this phase, LHBS is expressed predominantly among various viral surface proteins (3). There also emerges the pre-S 2 mutant LHBS (⌬2 LHBS) that is truncated of approximately 17 amino acids (aa) in the N terminus of the pre-S 2 region of the protein and often also contains a point mutation in the start codon of the region, which leads to a dramatic decrease in the synthesis of MHBS (4, 5) and potentially affects DNA polymerase activity due to overlap of the surface and polymerase genes in the viral genome. We previously (5-7) found that ⌬2 LHBS contributed to the histological morphology of the type II ground glass hepatocyte (GGH) preneoplastic lesions, which was characterized by the marginal HBS staining pattern and proliferation in clusters as hepatic nodules. We recently (8) also found that the type II GGH harboring ⌬2 LHBS was a biomarker for tumor recurrence and worse survival of HCC patients after hepatectomy surgery. Therefore, ⌬2 LHBS is highly associated with risks and prognoses of HBV-induced HCC (9, 10).We previously (6) reported that ⌬2 LHBS accumulates in endoplasmic reticulum (ER), which induces strong ER stre...

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Immunogenicity of a recombinant pre-S2-containing hepatitis B vaccine versus plasma-derived vaccine administered as a booster

Bucher

Francioli

Geudelin

et al. 1994

Eur. J. Clin. Microbiol. Infect. Dis.

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GenHevac B Pasteur is a recombinant hepatitis B vaccine derived from a mammalian cell line and containing HBs as well as pre-S2 antigens. Its immunogenicity was compared to that of the plasma-derived vaccine Hevac B Pasteur in a population primovaccinated 5.5 years earlier with four injections of the same plasma vaccine. The booster injection with either GenHevac or Hevac was administered to 295 subjects with residual anti-HBs titres below 500 IU/l (group 1: 0-9; group 2: 10-99; group 3: 100-499 IU/l). After four weeks, GenHevac had induced higher anti-HBs responses than Hevac in all groups, particularly among the low responders of group 1. Response to the vaccine occurred earlier with GenHevac. Mean anti-pre-S2 production was moderate in all groups for both vaccines (GenHevac: 60 IU/l; Hevac: 31 IU/l) and was not found in the 32 subjects who produced less than 100 IU/l anti-HBs. The results of the present study indicate that GenHevac is at least as immunogenic as Hevac.

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Detection of proteins encoded by the pre‐S region of hepatitis B virus in the sera of HBsAg carriers: relation to viral replication

Cited by 6 publications

References 10 publications

Hepatitis B Virus Pre-S2 Mutant Surface Antigen Induces Degradation of Cyclin-Dependent Kinase Inhibitor p27Kip1 through c-Jun Activation Domain-Binding Protein 1

Hepatitis B Virus Pre-S2 Mutant Surface Antigen Induces Degradation of Cyclin-Dependent Kinase Inhibitor p27Kip1 through c-Jun Activation Domain-Binding Protein 1

Zinc-Dependent Interaction between JAB1 and Pre-S ₂ Mutant Large Surface Antigen of Hepatitis B Virus and Its Implications for Viral Hepatocarcinogenesis

Immunogenicity of a recombinant pre-S2-containing hepatitis B vaccine versus plasma-derived vaccine administered as a booster

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Detection of proteins encoded by the pre‐S region of hepatitis B virus in the sera of HBsAg carriers: relation to viral replication

Cited by 6 publications

References 10 publications

Hepatitis B Virus Pre-S2 Mutant Surface Antigen Induces Degradation of Cyclin-Dependent Kinase Inhibitor p27Kip1 through c-Jun Activation Domain-Binding Protein 1

Hepatitis B Virus Pre-S2 Mutant Surface Antigen Induces Degradation of Cyclin-Dependent Kinase Inhibitor p27Kip1 through c-Jun Activation Domain-Binding Protein 1

Zinc-Dependent Interaction between JAB1 and Pre-S 2 Mutant Large Surface Antigen of Hepatitis B Virus and Its Implications for Viral Hepatocarcinogenesis

Immunogenicity of a recombinant pre-S2-containing hepatitis B vaccine versus plasma-derived vaccine administered as a booster

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Zinc-Dependent Interaction between JAB1 and Pre-S ₂ Mutant Large Surface Antigen of Hepatitis B Virus and Its Implications for Viral Hepatocarcinogenesis