In vitro tumorigenicity of hepatitis B virus DNA and HBx protein

Seifer, Maria; Höhne, Martin; Schaefer, Stephan; Gerlich, Wolfram H.

doi:10.1016/0168-8278(91)90026-8

Cited by 82 publications

(53 citation statements)

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“…Several groups have demonstrated an oncogenic potential of HBV DNA in a wide range of experimental systems (for review: Schaefer (1999); Schaefer and Gerlich (1995)). Stable expression of a small viral protein, HBx, showed a weak ± but reproducible ± transforming eect of HBx in cell lines of liver origin (Oguey et al, 1996;Schaefer et al, 1998;Seifer et al, 1991a;Tarn et al, 1999), in murine ®broblasts (Seifer et al, 1991b;Shirakata et al, 1989) and in rat ®broblasts (Gottlob et al, 1998b) (for review: Schaefer (1999); Schaefer and Gerlich (1995)). …”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts

2000

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Epidemiology shows a clear correlation between chronic infection with the hepatitis B virus (HBV) and development of hepatocellular carcinoma (HCC). The potential role of the transactivating hepatitis B virus X protein (HBx) in transformation by HBV is controversial. Here we report that HBx suppresses transformation of primary rat embryo ®broblasts (REFs). Cooperating oncogenes like c-Ha-ras and c-myc transform REF very eciently but cotransfection with HBx suppressed transformation of REFs down to 5%. Similarly, transfection of HBx together with the cooperating oncogenes Ha-ras and SV40 LTAg or c-Ha-ras and mutant p53 reduced the number of foci to 13%. Comparable results were obtained with HBx in the context of the whole HBV. Suppression of focus formation in REF could be partly relieved by cotransfection of apoptosis inhibitors Bcl-2 or E1B. However, cotransfection of apoptosis inhibitors crmA and p35 did not in¯uence the proapoptotic functions of HBx. Thus, HBx may speci®cally activate the Bcl-2 sensitive pathway leading to apoptosis. Experiments with 13 HBx linker scanning mutants revealed that the domains necessary for HBx dependent transactivation overlap with the domains needed for the apoptotic/growth arrest functions of HBx.

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Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts

2000

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“…The transforming ability of HBx was examined with mouse hepatocyte-derived cell lines from the TGFα transgenic mouse or immortalized by SV40 Large T antigen. (58)(59)(60) In their reports the inefficient transformation of cells were observed, but some transformed clones expressing HBx were reported to form colonies in soft agar and tumors in nude mice. (59,60) But later the expression of HBx alone was reported to show apparent antitransforming ability in rat embryo fibroblasts due to the induction of cell apoptosis.…”

Section: −10mentioning

confidence: 99%

“…(58)(59)(60) In their reports the inefficient transformation of cells were observed, but some transformed clones expressing HBx were reported to form colonies in soft agar and tumors in nude mice. (59,60) But later the expression of HBx alone was reported to show apparent antitransforming ability in rat embryo fibroblasts due to the induction of cell apoptosis. (61,62) Cellular senescence and crisis are the host defense mechanisms to suppress tumorigenesis.…”

Section: −10mentioning

confidence: 99%

Molecular functions and biological roles of hepatitis B virus x protein

Tang¹,

Oishi²,

Kaneko³

et al. 2006

Cancer Science

266

244

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Chronic infection of hepatitis B virus (HBV) isH epatitis B virus (HBV) infection is a worldwide health problem and is one of the major causes of hepatocellular carcinoma (HCC) in the world. However, new incidences of HBV infection have been dramatically reduced by several prevention programs. The crucial role of HBV in hepatocarcinogenesis is beyond doubt, however, the mechanism by which HBV causes transformation of hepatocytes remains uncertain.(1-3) Hepatitis B virus X protein (HBx) has long been suspected to play a positive role in hepatocarcinogenesis because HCC incidence has been reported in animals infected with mammalian hepadnaviruses. Among these hepadnaviruses, open reading frame-X (X-ORF) is conserved in the genomes. However, hepatocarcinogenesis has not been found in avian infected with avian hepadnaviruses where X-ORF is absent. In addition to the putative contribution of HBx, other oncogenic mechanisms of the HBV-related hepatocarcinogenesis have also been proposed, such as the integration-dependent scenario of HBV DNA in host genomes, (4) and the inflammation-dependent scenario.(5) Since no higher incidence of HCC has been reported in HBV-expressing transgenic mice, (6) host immunological responses to HBV infection (but not HBV proliferation by itself ) might be primarily contributing to the HBV-related hepatocarcinogenesis. HBx, a small protein of 154 amino acids, is a multifunctional regulator that modulates a variety of host processes through directly or indirectly interacting with virus and host factors. (2,3) In this short review, we briefly summarize the life cycle of HBV, expression of HBx, and the molecular functions of HBx. We then focus on the recent progress on the biological roles of HBx in HBV replication and cellular transformation. Expression and functions of HBx. HBV is a prototype of Hepadnaviridae, hepatotropic small DNA viruses, of which hosts are among limited species of water birds, squirrels and primates. The HBV genome is a 3.2-kb circular, partially double-stranded DNA molecule with four overlapping ORFs, PC-C, PS-S, P, and X-ORFs (Fig. 1). (7) Once HBV infection of hepatocytes occurs, its genome is converted to covalently closed circular (CCC) DNA, which serves as the template for transcription by the host RNA polymerase II, generating the 3.5-, 2.4-, 2.1-, and 0.7-kb transcripts under control of four HBV promoters (Cp, PS1p, Sp, and Xp), respectively (Fig. 1). Two HBV enhancers (Enh I and Enh II) positively regulate transcription of the HBV promoters in combination with the transcription factors that bind these promoters.(7-9) HBV replicates by reverse transcription of the viral pregenomic 3.5-kb RNA (pgRNA) using the HBV polymerase that catalyzes RNA-dependent DNA synthesis and DNA-dependent DNA synthesis. (7,10) The reverse transcription of hepadnaviruses is unique among DNA viruses, and the primer of the reverse transcription is a tyrosine residue of an N-terminal domain of Pol that is distinct from reverse transcription of retroviruses. (10)

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“…Several studies using transgenic mice and cell culture models yielded contrasting conclusions. Some studies suggest that the development of HCC is closely linked to HBx expression (7)(8)(9)(10), although HBx alone may be insufficient for HCC development (11,12). Other results suggest that HBx has the ability to suppress cell transformation through induction of apoptosis (13,14).…”

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Structural and biochemical analysis of Bcl-2 interaction with the hepatitis B virus protein HBx

Jiang

Liu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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HBx is a hepatitis B virus protein that is required for viral infectivity and replication. Anti-apoptotic Bcl-2 family members are thought to be among the important host targets of HBx. However, the structure and function of HBx are poorly understood and the molecular mechanism of HBx-induced carcinogenesis remains unknown. In this study, we report biochemical and structural characterization of HBx. The recombinant HBx protein contains metal ions, in particular iron and zinc. A BH3-like motif in HBx (residues 110-135) binds Bcl-2 with a dissociation constant of ∼193 μM, which is drastically lower than that for a canonical BH3 motif from Bim or Bad. Structural analysis reveals that, similar to other BH3 motifs, the BH3-like motif of HBx adopts an amphipathic α-helix and binds the conserved BH3-binding groove on Bcl-2. Unlike the helical Bim or Bad BH3 motif, the C-terminal portion of the bound HBx BH3-like motif has an extended conformation and makes considerably fewer interactions with Bcl-2. These observations suggest that HBx may modulate Bcl-2 function in a way that is different from that of the classical BH3-only proteins.Bcl-2 | hepatitis B virus | apoptosis | crystal structure T he human hepatitis B virus (HBV) is a prototypical hepadnavirus that specifically infects hepatocytes (1, 2). Over 240 million people worldwide are chronically infected by HBV according to the World Health Organization. Persistent HBV infection is one of the major risk factors for the development of hepatocellular carcinoma (HCC), accounting for over 50% of all HCC cases (3, 4). The genome of HBV encodes only four proteins, among which the product of the X gene (HBx) is least understood (1).HBx contains 154 residues and is closely associated with HCC development. The X gene is most frequently integrated and preferentially maintained in HBV-associated HCC, and HBx expression is frequently detected in HCC patients (5, 6). Several studies using transgenic mice and cell culture models yielded contrasting conclusions. Some studies suggest that the development of HCC is closely linked to HBx expression (7-10), although HBx alone may be insufficient for HCC development (11,12). Other results suggest that HBx has the ability to suppress cell transformation through induction of apoptosis (13,14). As such, the molecular mechanism of HBx-induced cellular transformation remains enigmatic.Numerous cellular activities are reported to be modulated by HBx through interactions with various host targets. For example, HBx-mediated transcriptional activation is achieved through its interaction with transcription factors (15, 16) or components involved in the basal transcriptional machinery (17-19). HBx can also modulate cellular proliferation and viability through interactions with p53 and Bcl-2 family members. Reflecting its enigmatic functions, HBx has been demonstrated to either induce apoptosis (20) or prevent apoptosis (21).HBx was recently found to contain a BH3-like motif in its C-terminal sequences (22). Experiments carried out in human hepato...

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In vitro tumorigenicity of hepatitis B virus DNA and HBx protein

Cited by 82 publications

References 18 publications

Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts

Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts

Molecular functions and biological roles of hepatitis B virus x protein

Structural and biochemical analysis of Bcl-2 interaction with the hepatitis B virus protein HBx

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