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 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

Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the cMYC protooncogene at the transcriptional level

1991 ◽  
Vol 176 (3) ◽  
pp. 985-992 ◽  
Author(s):  
Clara Balsano ◽  
Maria Laura Avantaggiati ◽  
Gioacchino Natoli ◽  
Elisabetta De Marzio ◽  
Hans Will ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Full Length ◽  
Transcriptional Level ◽  
X Protein ◽  
B Virus

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.

scholarly journals Dual effects of hepatitis B virus X protein on the regulation of cell-cycle control depending on the status of cellular p53

2002 ◽  
Vol 83 (11) ◽  
pp. 2765-2772 ◽  
Author(s):  
Ji Young Ahn ◽  
Eun Young Jung ◽  
Hyun Jin Kwun ◽  
Chang-Woo Lee ◽  
Young-Chul Sung ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dependent Manner ◽  
Checkpoint Control ◽  
X Protein ◽  
Low Level ◽  
Hepatic Diseases ◽  
B Virus ◽  
The Status

Despite the extensive studies on the roles of hepatitis B virus (HBV) X protein (HBx) in the development of hepatocellular carcinomas (HCCs), the mechanisms by which HBx contributes to HCC remain controversial. In this study, the effect of HBx on the G1–S checkpoint control depending on the status of p53 was compared. Transcription of p21waf1/cip1 was activated by HBx in the presence of functional p53 in a dose-dependent manner. However, it was repressed by HBx when p53 was absent or present at a low level. Furthermore, the growth rate of the HBx-expressing NIH3T3 cell lines compared with that of the parental cells was decreased when p53 was upregulated by a DNA-damaging agent, cisplatin, whereas it increased approximately twofold when p53 was present at a very low level. Thus, the opposite effects of HBx on the regulation of the cell cycle depending on the status of p53 might be important to understand the progression of hepatic diseases in HBV-positive patients.

scholarly journals Mutations in the C-terminus of the X protein of hepatitis B virus regulate Wnt-5a expression in hepatoma Huh7 cells: cDNA microarray and proteomic analyses

2008 ◽  
Vol 29 (6) ◽  
pp. 1207-1214 ◽  
Author(s):  
Xiaohong Liu ◽  
Li Wang ◽  
Shuhui Zhang ◽  
Jing Lin ◽  
Shunmin Zhang ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cdna Microarray ◽  
X Protein ◽  
C Terminus ◽  
Huh7 Cells ◽  
B Virus ◽  
Proteomic Analyses

Hepatitis B virus X protein mutants exhibit distinct biological activities in hepatoma Huh7 cells

2008 ◽  
Vol 373 (4) ◽  
pp. 643-647 ◽  
Author(s):  
Xiaohong Liu ◽  
Shuhui Zhang ◽  
Jing Lin ◽  
Shunmin Zhang ◽  
Mark A. Feitelson ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Biological Activities ◽  
X Protein ◽  
Protein Mutants ◽  
Huh7 Cells ◽  
B Virus

scholarly journals Different Regions of Hepatitis B Virus X Protein Are Required for Enhancement of bZip-Mediated Transactivation versus Transrepression

2000 ◽  
Vol 74 (1) ◽  
pp. 83-90 ◽  
Author(s):  
Sangeeta Barnabas ◽  
Ourania M. Andrisani
Keyword(s):  
Amino Acid ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Deletion Mutants ◽  
Amino Acid Residues ◽  
X Protein ◽  
Amino Acid Region ◽  
B Virus

ABSTRACT The hepatitis B virus X protein (pX) interacts directly with the bZip transactivator CREB and the bZip repressors ICERIIγ and ATF3, increasing their DNA-binding affinity in vitro and their transcriptional efficacy in vivo. However, the mechanism of bZip-pX interaction and of the pX-mediated increase in the bZip transcriptional efficacy remains to be understood. In this study with deletion mutants of pX, we delineated a 67-amino-acid region spanning residues 49 to 115 required for direct CREB, ATF3, and ICER IIγ interaction in vitro and in vivo and increased bZip/CRE binding in vitro. Transient transfections of the pX deletion mutants in AML12 hepatocytes demonstrate that pX49–115 is as effective as the full-length pX in enhancing the ATF3- and ICERIIγ-mediated transrepression. However, this pX region is inactive in increasing the transactivation efficacy of CREB; additional amino acid residues present in pX49–140are required to mediate the increased transactivation efficacy of CREB in vivo. This requirement for different regions of pX in affecting CREB transactivation suggests that amino acid residues 115 to 140 integrate additional events in effecting pX-mediated transactivation, such as concomitant interactions with select components of the basal transcriptional apparatus.

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