Altered DNA Mutation Spectrum in Aflatoxin B1-Treated Transgenic Mice That Express the Hepatitis B Virus X Protein

ABSTRACT Humans chronically infected with hepatitis B virus (HBV) are at further risk of liver cancer upon exposure to dietary aflatoxin B1 (AFB1), a carcinogenic product of the mold Aspergillus flavus. For the present study, we utilized double-transgenic mice (ATX mice) that express the HBV X protein (HBx) and possess a bacteriophage lambda transgene to evaluate the in vivo effect of HBx expression on AFB1-induced DNA mutations. The expression of HBx correlated with a 24% increase in mutation frequency overall and an approximately twofold increase in the incidence of G/C-to-T/A transversion mutations following AFB1 exposure. These results are consistent with a model in which expression of HBx during chronic HBV infection may contribute to the development of hepatocellular carcinoma following exposure to environmental carcinogens.

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

Journal of Virology ◽

10.1128/jvi.74.11.5266-5272.2000 ◽

2000 ◽

Vol 74 (11) ◽

pp. 5266-5272 ◽

Cited By ~ 34

Author(s):

Charles R. Madden ◽

Milton J. Finegold ◽

Betty L. Slagle

Keyword(s):

Dna Repair ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Transgenic Mice ◽

Spontaneous Mutations ◽

Environmental Carcinogens ◽

X Protein ◽

B Virus ◽

The Impact

ABSTRACT 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 α-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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In vivo expression of the hepatitis B virus X protein in transgenic mice

Journal of Hepatology ◽

10.1016/0168-8278(89)90541-2 ◽

1989 ◽

Vol 9 ◽

pp. S183

Author(s):

M. Levrero ◽

C. Balsano ◽

G. Natoli ◽

M.L. Avantaggiati ◽

E. De Marzio ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Transgenic Mice ◽

X Protein ◽

B Virus ◽

In Vivo Expression

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Transgenic mice expressing hepatitis B virus X protein are more susceptible to carcinogen induced hepatocarcinogenesis

Experimental and Molecular Pathology ◽

10.1016/j.yexmp.2003.09.001 ◽

2004 ◽

Vol 76 (1) ◽

pp. 44-50 ◽

Cited By ~ 29

Author(s):

Huanzhang Zhu ◽

Yun Wang ◽

Jianquan Chen ◽

Guoxiang Cheng ◽

Jinglun Xue

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Transgenic Mice ◽

X Protein ◽

B Virus

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Antiviral effect of hepatitis B virus S/C gene loci antisense locked nucleic acid on transgenic mice in vivo

Genetics and Molecular Research ◽

10.4238/2015.august.21.16 ◽

2015 ◽

Vol 14 (3) ◽

pp. 10087-10095 ◽

Cited By ~ 6

Author(s):

Y.B. Deng ◽

H.J. Qin ◽

Y.H. Luo ◽

Z.R. Liang ◽

J.J. Zou

Keyword(s):

Hepatitis B Virus ◽

Nucleic Acid ◽

Hepatitis B ◽

Transgenic Mice ◽

Antiviral Effect ◽

Locked Nucleic Acid ◽

B Virus

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Diagnosis of biliary duct cysts in transgenic mice expressing the hepatitis B virus X-protein

Journal of Hepatology ◽

10.1016/j.jhep.2003.10.030 ◽

2004 ◽

Vol 40 (2) ◽

pp. 356-357 ◽

Cited By ~ 1

Author(s):

Olaf Dirsch ◽

Florian Rödicker ◽

Christoph U Herborn ◽

Gero Hilken ◽

Brigitte M Pützer

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Transgenic Mice ◽

Biliary Duct ◽

X Protein ◽

B Virus

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Inhibition of Cellular Proteasome Activities Mediates HBX-Independent Hepatitis B Virus Replication In Vivo

Journal of Virology ◽

10.1128/jvi.00579-10 ◽

2010 ◽

Vol 84 (18) ◽

pp. 9326-9331 ◽

Cited By ~ 13

Author(s):

Zhensheng Zhang ◽

Eun Sun ◽

Jing-hsiung James Ou ◽

T. Jake Liang

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Transgenic Mice ◽

Productive Infection ◽

Minor Effect ◽

Hbv Replication ◽

B Virus ◽

Culture Models ◽

A Minor

ABSTRACT The X protein (HBX) of the hepatitis B virus (HBV) is essential for HBV productive infection in vivo. Our previous study (Z. Hu, Z. Zhang, E. Doo, O. Coux, A. L. Goldberg, and T. J. Liang, J. Virol. 73:7231-7240, 1999) shows that interaction of HBX with the proteasome complex may underlie the pleiotropic functions of HBX. Previously, we demonstrated that HBX affects hepadnaviral replication through a proteasome-dependent pathway in cell culture models. In the present study, we studied the effect of the proteasome inhibitor MLN-273 in two HBV mouse models. We demonstrated that administration of MLN-273 to transgenic mice containing the replication-competent HBV genome with the defective HBX gene substantially enhanced HBV replication, while the compound had a minor effect on wild-type HBV transgenic mice. Similar results were obtained by using C57BL/6 mice infected with recombinant adenoviruses expressing the replicating HBV genome. Our data suggest that HBV replication is subjected to regulation by cellular proteasome and HBX functions through the inhibition of proteasome activities to enhance HBV replication in vivo.

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