Activated ras oncogene collaborates with HBx gene of hepatitis B virus to transform cells by suppressing HBx-mediated apoptosis

Kim, Young Chul; Song, Kyung Seob; Yoon, Gyesoon; Nam, Myeong Jin; Ryu, Wang Shick

doi:10.1038/sj.onc.1203840

Cited by 71 publications

(67 citation statements)

References 58 publications

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“…(61,62) Cellular senescence and crisis are the host defense mechanisms to suppress tumorigenesis. Knowledge of cellular senescence has accumulated during the last decade demonstrating the profound difference between mouse and human systems in several aspects, (63)(64)(65)(66) especially the critical contribution of telomere checkpoint control in cellular senescence of human cells. Overcoming processes of active oncogeneinduced senescence (OIS) is critical for cancer formation, not only in vitro but also in vivo.…”

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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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

View full text Add to dashboard Cite

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“…HBV is a DNA tumor virus, which encodes four open reading frames, S/preS, C/preC, P, and HBx (4). The oncogenicity of HBV is largely the result of HBx, the smallest gene encoding a 17-kDa protein (3,(5)(6)(7)(8). One major cellular function of HBx is its promiscuous transcriptional activation activity, a property that is believed to contribute to its oncogenicity (9).…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Interaction of the Hepatitis B Virus X Protein with the Crm1-dependent Nuclear Export Pathway

Forgues

Marrogi

Spillare

et al. 2001

Journal of Biological Chemistry

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The leucine-rich nuclear export signal (NES) is used to shuttle large cellular proteins from the nucleus to the cytoplasm. The nuclear export receptor Crm1 is essential in this process by recognizing the NES motif. Here, we show that the oncogenic hepatitis B virus (HBV) X protein (HBx) contains a functional NES motif. We found that the predominant cytoplasmic localization of HBx is sensitive to the drug leptomycin B (LMB), which specifically inactivates Crm1. Mutations at the two conserved leucine residues to alanine at the NES motif (L98A,L100A) resulted in a nuclear redistribution of HBx. A recombinant HBx protein binds to Crm1 in vitro. In addition, ectopic expression of HBx sequesters Crm1 in the cytoplasm. Furthermore, HBx activates NFB by inducing its nuclear translocation in a NES-dependent manner. Abnormal cytoplasmic sequestration of Crm1, accompanied by a nuclear localization of NFB, was also observed in hepatocytes from HBV-positive liver samples with chronic active hepatitis. We suggest that Crm1 may play a role in HBx-mediated liver carcinogenesis.

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“…These changes could occur in a variety of cellular genes leading to escape from normal cellular and environmental controls. So far, over 20 cellular genes down-or up-regulated or mutated in HCC such as ras (Ogata et al, 1991;Kim et al, 2001), c-myc, c-fos, and c-jun (Kawate et al, 1999;Yuen, et al, 2001), rho (Genda et al, 1999), TGFa (Chung et al, 2000), HGF and c-met (Ueki et al, 1997), c-erbB-2 (Collier et al, 1992), IGF-II (Takeda et al, 1996), u-PA (de Petro et al, 1998), MXR7 (Hsu et al, 1997), MDM2 (Endo et al, 2000), MAGE (Tahara et al, 1999), matrix metalloproteinase (Musso et al, 1997), Smads (Yakicier et al, 1999), p53 (Shimizu et al, 1999;Rashid et al, 1999), pRB Santoni-Rugiu et al, 1998), p16INK4 Liew et al, 1999), p21 WAF1/CIP1 , p27 Kip1 (Chen et al, 2000;Tannapfel et al, 2000), PTEN (Fujiwara et al, 2000;Yao et al, 1999), E-cadherin ), beta-catenin (de La Coste et al, 1998 and AXIN1 (Satoh et al, 2000) have been described in humans and mice. Many of them are involved in deregulation of intracellular signal transduction and cell cycle, leading eventually to an uncontrolled proliferation of cancerous cells.…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and characterization of a novel gene which is highly expressed in hepatocellular carcinoma

et al. 2002

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To gain new insight into the molecular mechanism underlying the pathogenesis of human primary hepatocellular carcinoma (HCC), we searched for HCC-specific molecules through screening genes that are differentially expressed between cancerous and noncancerous counterparts of liver and identified a novel HCC-associated gene, HCCA1 encoding a *80 kDa cytoplasmic protein that contains several proline-rich motifs likely for SH3-binding. HCCA1 transcript, albeit present in some adult tissues, is up-regulated selectively in HCC but not in other tumor cells. High expression of HCCA1 occurs as a late event frequently (89.2%) in HCCs and correlated significantly with the degree of tumor progression. When treated with antisense oligonucleotides to HCCA1, HCCA1 expression in HCC cells (HuH-7) was effectively suppressed and cell growth was down-regulated in a time-and dose-dependent manner. Furthermore, HuH-7 cells harboring the HCCA1 antisense expression clone displayed a remarkably reduced efficiency in colony formation. Together, these data strongly suggest that HCCA1 is a positive effector in cell proliferation and contributes to HCC carcinogenesis and progression. We believe that this protein will serve as a novel useful marker for HCC and is a potential target for pharmaceutical intervention of this malignant disease.

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Activated ras oncogene collaborates with HBx gene of hepatitis B virus to transform cells by suppressing HBx-mediated apoptosis

Cited by 71 publications

References 58 publications

Molecular functions and biological roles of hepatitis B virus x protein

Molecular functions and biological roles of hepatitis B virus x protein

Interaction of the Hepatitis B Virus X Protein with the Crm1-dependent Nuclear Export Pathway

Molecular cloning and characterization of a novel gene which is highly expressed in hepatocellular carcinoma

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