scholarly journals The Hepatitis B Virus X Protein Modulates Hepatocyte Proliferation Pathways To Stimulate Viral Replication

2010 ◽  
Vol 84 (6) ◽  
pp. 2675-2686 ◽  
Author(s):  
Tricia L. Gearhart ◽  
Michael J. Bouchard
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatocyte Proliferation ◽  
X Protein ◽  
Experimental Conditions ◽  
Hbv Replication ◽  
B Virus ◽  
The Impact

ABSTRACT Worldwide, there are over 350 million people who are chronically infected with the human hepatitis B virus (HBV); chronic HBV infections are associated with the development of hepatocellular carcinoma (HCC). The results of various studies suggest that the HBV X protein (HBx) has a role in the development of HBV-associated HCC. HBx can regulate numerous cellular signal transduction pathways, including those that modulate cell proliferation. Many previous studies that analyzed the impact of HBx on cell proliferation pathways were conducted using established or immortalized cell lines, and when HBx was expressed in the absence of HBV replication, and the precise effect of HBx on these pathways has often differed depending on experimental conditions. We have studied the effect of HBx on cell proliferation in cultured primary rat hepatocytes, a biologically relevant system. We demonstrate that HBx, both by itself and in the context of HBV replication, affected the levels and activities of various cell cycle-regulatory proteins to induce normally quiescent hepatocytes to enter the G1 phase of the cell cycle but not to proceed to S phase. We linked HBx regulation of cell proliferation to cytosolic calcium signaling and HBx stimulation of HBV replication. Cumulatively, our studies suggest that HBx induces normally quiescent hepatocytes to enter the G1 phase of the cell cycle and that this calcium-dependent HBx activity is required for HBV replication. These studies identify an essential function of HBx during HBV replication and a mechanism that may connect HBV infections to the development of HCC.

The C-terminal region of the hepatitis B virus X protein is required for its stimulation of HBV replication in primary mouse hepatocytes

2012 ◽  
Vol 165 (2) ◽  
pp. 170-178 ◽  
Author(s):  
Na Luo ◽  
Yuan Cai ◽  
Jun Zhang ◽  
Weixue Tang ◽  
Betty L. Slagle ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Terminal Region ◽  
X Protein ◽  
Hbv Replication ◽  
Primary Mouse Hepatocytes ◽  
Primary Mouse ◽  
B Virus ◽  
Mouse Hepatocytes ◽  
Stimulation Of

Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis through interacting with a serine protease Hepsin

2004 ◽  
Vol 150 (4) ◽  
pp. 721-741 ◽  
Author(s):  
J.-L. Zhang ◽  
W.-G. Zhao ◽  
K.-L. Wu ◽  
K. Wang ◽  
X. Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Serine Protease ◽  
Cell Apoptosis ◽  
X Protein ◽  
Human Hepatitis ◽  
B Virus

scholarly journals Deletion and Functional Analysis of Hepatitis B Virus X Protein: Evidence for an Effect on Cell Cycle Regulators

2018 ◽  
Vol 49 (5) ◽  
pp. 1987-1998 ◽  
Author(s):  
Mashael R. Al-Anazi ◽  
Nyla Nazir ◽  
Dilek Colak ◽  
Mohammed N. Al-Ahdal ◽  
Ahmed A. Al-Qahtani
Keyword(s):  
Cell Cycle ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cyclin D1 ◽  
Full Length ◽  
Deletion Mutants ◽  
X Protein ◽  
P53 Expression ◽  
Huh7 Cells ◽  
B Virus

Background/Aims: The hepatitis B virus X protein (HBx) is a viral trans-activator that plays a crucial role in pathogenesis of hepatocellular carcinoma (HCC) via an unknown mechanism. The role of HBx in modulating cell proliferation and programmed cell death is replete with controversies. Thus, the goal of this study was to elucidate the effect of HBx and its deletion mutants on cell cycle progression in human hepatoma cells. Methods: Huh7 cells transfected with either full-length or truncated HBx were tested for their mitogenic potential based on their effect on the expression of key cell cycle-related proteins (p27, cyclin D1, p21, and p53) and pro-apoptotic proteins such as cleaved poly (ADP-ribose) polymerase (PARP) and Bax. Western blotting and immunofluorescence techniques were applied to detect changes in the expression levels and intracellular localization, respectively, of the investigated proteins. Also, Quantitative real-time PCR (qRT-PCR) was used to detect changes in RNA levels. Results: An increased anchorage-independent growth of cells transfected with HBx-WT and its deletion mutants was observed. The cell cycle regulatory molecules were differentially modulated by full-length HBx (1-154) and its different N- and C-terminal truncated forms (HBx (31-154), HBx (61-154), HBx (1-94), and HBx (61-124)). An enhanced modulation of p27, p21, and cyclin D1 was associated with HBx (1-154), whereas p53 expression was significantly inhibited by HBx (61-124). Similarly, the expression of cleaved PARP and Bax was efficiently suppressed by HBx (1-94) and HBx (61-154). Conclusion: The HBx-WT and its mutants play a critical role in the pathogenesis and progression of HCC by modulating cell cycle regulatory proteins.

Hepatitis B Virus X Protein Induces Cell Proliferation in Malignant Hepatocytes

2015 ◽  
Vol 5 ◽  
pp. S57
Author(s):  
Manikankana Bandopadhyay ◽  
Neelakshi Sarkar ◽  
Dipanwita Das ◽  
Ananya Pal ◽  
Debraj Saha ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
X Protein ◽  
B Virus

Hepatitis B virus X protein induces apoptosis and cell cycle deregulation through interfering with DNA repair and checkpoint responses

2007 ◽  
Vol 0 (0) ◽  
pp. 070915183826001-??? ◽  
Author(s):  
Hong-Ying Chen ◽  
Nan-Hong Tang ◽  
Na Lin ◽  
Zhi-Xin Chen ◽  
Xiao-Zhong Wang
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
X Protein ◽  
B Virus ◽  
Cell Cycle Deregulation

scholarly journals Hepatitis B Virus X Protein Induces Perinuclear Mitochondrial Clustering in Microtubule- and Dynein-Dependent Manners

2006 ◽  
Vol 81 (4) ◽  
pp. 1714-1726 ◽  
Author(s):  
Sujeong Kim ◽  
Hye-Young Kim ◽  
Seungmin Lee ◽  
Sung Woo Kim ◽  
Seonghyang Sohn ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Nuclear Periphery ◽  
Mitogen Activated Protein Kinase ◽  
Transport Systems ◽  
Dependent Manner ◽  
Atpase Inhibitor ◽  
X Protein ◽  
Hbv Replication ◽  
B Virus

ABSTRACT The hepatitis B virus (HBV) X protein (HBx) is thought to play a key role in HBV replication and the development of liver cancer. It became apparent that HBx induces mitochondrial clustering at the nuclear periphery, but the molecular basis for mitochondrial clustering is not understood. Since mitochondria move along the cytoskeleton as a cargo of motor proteins, we hypothesized that mitochondrial clustering induced by HBx occurs by an altered intracellular motility. Here, we demonstrated that the treatment of HBx-expressing cells with a microtubule-disrupting drug (nocodazole) abrogated mitochondrial clustering, while the removal of nocodazole restored clustering within 30 to 60 min, indicating that mitochondrial transport is occurring in a microtubule-dependent manner. The addition of a cytochalasin D-disrupting actin filament, however, did not measurably affect mitochondrial clustering. Mitochondrial clustering was further studied by observations of HBV-related hepatoma cells and HBV-replicating cells. Importantly, the abrogation of the dynein activity in HBx-expressing cells by microinjection of a neutralizing anti-dynein intermediate-chain antibody, dynamitin overexpression, or the addition of a dynein ATPase inhibitor significantly suppressed the mitochondrial clustering. In addition, HBx induced the activation of the p38 mitogen-activated protein kinase (MAPK) and inhibition of the p38 kinase activity by SB203580-attenuated HBx-induced mitochondrial clustering. Taken together, HBx activation of the p38 MAPK contributed to the increase in the microtubule-dependent dynein activity. The data suggest that HBx plays a novel regulatory role in subcellular transport systems, perhaps facilitating the process of maturation and/or assembly of progeny particles during HBV replication. Furthermore, mitochondrion aggregation induced by HBx may represent a cellular process that underlies disease progression during chronic viral infection.

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

2000 ◽  
Vol 74 (11) ◽  
pp. 5266-5272 ◽  
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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