Effect of hepatocyte proliferation and cellular DNA synthesis on hepatitis B virus replication

Özer, Ayşe; Khaoustov, Vladimir I.; Mearns, Mary; Lewis, Dorothy E.; Genta, Robert M.; Darlington, Gretchen J.; Yoffe, Boris

doi:10.1053/gast.1996.v110.pm8613059

Cited by 83 publications

(79 citation statements)

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“…Our cell cycle data indeed suggest that an early e ect of HBx expression, during infection by a non-lytic virus such as HBV, is to`activate' quiescent hepatocytes and maintain them in this state in G1 of the cell cycle as reported for the Tax protein of HTLV-1 (Chlichia et al, 1995). It has been shown that HBV replication depends on cell cycle and di erentiation status and is decreased in S phase (Ozer et al, 1996). Thus, maintenance of activated cells in late G1 might favor further rounds of HBV-DNA replication by inducing expression of liver speci®c transcription and replication factors, as increasing the pool of free dNTPs (Goulaoui et al, 1994).…”

Section: Discussionsupporting

confidence: 74%

Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

et al. 1999

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Chronic infection by HBV is the leading cause of hepatocellular carcinoma in man. Several lines of evidence suggest that the viral transactivator HBx plays a critical role in the molecular pathogenesis of HBVrelated HCC. To study the actual impact of HBx and the mechanism of its action, we have recently cloned and characterized a set of X-sequences from HCC in patients with chronic infection by HBV. In the present study, we have compared the e ects of HBx and its naturally arising mutants on cell growth and viability. We report that HBx inhibits clonal outgrowth of cells and induces apoptosis by a p53-independent pathway. Furthermore, HBx expression induced a late G1 cell cycle block prior to their counterselection by apoptosis. Importantly, mutations in the HBx-gene evolving in hepatocellular carcinoma abolished both HBx-induced growth arrest and apoptosis. Using a panel of engineered mutants we have mapped the growth suppressive e ect of HBx to domains shown to be required for its transactivating function. Based on these results, we propose that abrogation of the anti-proliferative and apoptotic e ects of HBx by naturally occurring mutations might render the hepatocytes susceptible to uncontrolled growth and contribute to multistep hepatocarcinogenesis associated with HBV-infection.

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Section: Discussionsupporting

confidence: 74%

Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

et al. 1999

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“…Consequently, HBx interaction with DDB1 and DDB2 might be involved in delay or inhibition of cell cycle progression beyond the G 1 /S phase border. This finding takes on particular significance, since HBV replicates very poorly in S phase cells but replicates well in nondividing cells (87). However, as the same interaction of HBx with DDB1 was reported by other groups to promote cell death, a role in promoting viral replication is in conflict with a role in cell death (11,14,69).…”

Section: Molecular Targets and Mechanism Of Hbx Actionmentioning

confidence: 64%

The Enigmatic X Gene of Hepatitis B Virus

Bouchard

Schneider

2004

J Virol

449

482

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2With an estimate of 350 million people chronically infected with the hepatitis B virus (HBV) worldwide, it is critically important to understand how persistent HBV infection is maintained and linked to chronic hepatitis, cirrhosis, and development of liver cancer (hepatocellular carcinoma [HCC]) (39). This review will focus on the HBV nonstructural X protein (HBx), a key regulatory protein of the virus that is at the intersection of HBV infection, replication, pathogenesis, and possibly carcinogenesis. The exact role of HBx in viral replication has yet to be established, and its link to the progression of HCC remains controversial. Moreover, it is still unclear whether development of HCC associated with chronic infection by HBV involves a viral protein, is solely the consequence of a continual inflammatory response to infection, or requires both. Understanding the role of HBx in HBV replication and its effect on hepatocyte biology may help resolve this issue. This review describes key studies and activities of HBx, often interpreted within the context of the viral life cycle. The reader is referred to several comprehensive reviews on the reported biological properties of HBx (3,78,137).

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“…The latter inactivates a number of key negative growth regulatory pathways, as indicated above, but as long as some are intact, the hepatocytes respond by growth arrest or apoptosis. The former condition supports HBV replication, which is favored in quiescent cells (Ozer et al, 1996), while the latter condition prevents untimely cell growth. The increased intracellular concentration of HBxAg may eect DNA repair pathways (Becker et al, 1998;Lee et al, 1995), resulting in the accumulation of mutations.…”

Section: Discussionmentioning

confidence: 98%

The translation initiation factor, hu-Sui1 may be a target of hepatitis B X antigen in hepatocarcinogenesis

et al. 1999

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The role of hepatitis B virus X antigen in the development of hepatocellular carcinoma was explored by stably transfecting HepG2 cells with an X antigen expression vector, and identifying the dierences in gene expression that distinguish X positive from X negative cells by subtractive PCR. One dierentially expressed gene, the human homolog of sui1 (hu-sui1), encodes a translation initiation factor whose expression was suppressed by X antigen in HepG2 cells. Hu-Sui1 was also expressed in nontumor liver but not in tumor cells from patients with hepatocellular carcinoma. Introduction of hu-sui1 into HepG2 cells inhibited cell growth in culture, in soft agar, and partially inhibited tumor formation in nude mice. Hence, the suppression of husui1 by X antigen may result in the abrogation of negative growth regulation and contribute to the development of hepatocellular carcinoma.

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Effect of hepatocyte proliferation and cellular DNA synthesis on hepatitis B virus replication

Cited by 83 publications

References 1 publication

Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

The Enigmatic X Gene of Hepatitis B Virus

The translation initiation factor, hu-Sui1 may be a target of hepatitis B X antigen in hepatocarcinogenesis

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