X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter

Su, Jiun-Ming; Lai, Xiang-Me; Lan, Keng‐Hsin; Li, Chung–Pin; Chao, Yee; Yen, Sang‐Hue; Chang, Full‐Young; Lee, Shou‐Dong; Lee, Wei-Ping

doi:10.1002/hep.21675

Cited by 35 publications

(33 citation statements)

References 60 publications

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“…HBx exhibits many activities in vitro. In a cell culture system, HBx is able to activate the transcription of host genes, such as c-Myc, as well as viral genes [5,6] . HBx is also involved in different cytoplasmic signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiles of human liver cells mediated by hepatitis B virus X protein

Zhang

Shan

et al. 2009

Acta Pharmacol Sin

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Aim:To demonstrate the gene expression profiles mediated by hepatitis B virus X protein (HBx), we characterized the molecular features of pathogenesis associated with HBx in a human liver cell model. Methods: We examined gene expression profiles in L-O2-X cells, an engineered L-O2 cell line that constitutively expresses HBx, relative to L-O2 cells using an Agilent 22 K human 70-mer oligonucleotide microarray representing more than 21,329 unique, well-characterized Homo sapiens genes. Western blot analysis and RNA interference (RNAi) targeting HBx mRNA validated the overexpression of proliferating cell nuclear antigen (PCNA) and Bcl-2 in L-O2-X cells. Meanwhile, the BrdU incorporation assay was used to test cell proliferation mediated by upregulated cyclooxygenase-2 (COX-2). Results:The microarray showed that the expression levels of 152 genes were remarkably altered; 82 of the genes were upregulated and 70 genes were downregulated in L-O2-X cells. The altered genes were associated with signal transduction pathways, cell cycle, metastasis, transcriptional regulation, immune response, metabolism, and other processes. PCNA and Bcl-2 were upregulated in L-O2-X cells. Furthermore, we found that COX-2 upregulation in L-O2-X cells enhanced proliferation using the BrdU incorporation assay, whereas indomethacin (an inhibitor of COX-2) abolished the promotion. Conclusion: Our findings provide new evidence that HBx is able to regulate many genes that may be involved in the carcinogenesis. These regulated genes mediated by HBx may serve as molecular targets for the prevention and treatment of hepatocellular carcinoma.

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Section: Introductionmentioning

confidence: 99%

Gene expression profiles of human liver cells mediated by hepatitis B virus X protein

Zhang

Shan

et al. 2009

Acta Pharmacol Sin

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“…MAZ has been implicated in the activation of a number of genes, including RAG-2, Adenovirus major late, (9,14,25,37,49,50,66,70,71,72). In addition, MAZ has been shown to repress its own gene, as well as c-myc, eNOS, Sp4, telomerase, and eosinophil-derived neurotoxin (28,34,57,60,62,69). Despite its abundant expression in skeletal and cardiac muscle (58,59), the functional role of MAZ in these tissues has not been explored, and to date, no MAZ knockout mouse has been described.…”

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confidence: 99%

Quantitative Proteomic Identification of MAZ as a Transcriptional Regulator of Muscle-Specific Genes in Skeletal and Cardiac Myocytes

Himeda

Ranish

Hauschka

2008

Molecular and Cellular Biology

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We identified a conserved sequence within the Muscle creatine kinase (MCK) promoter that is critical for high-level activity in skeletal and cardiac myocytes (MCK Promoter Element X [MPEX]). After selectively enriching for MPEX-binding factor(s) (MPEX-BFs), ICAT-based quantitative proteomics was used to identify MPEX-BF candidates, one of which was MAZ (Myc-associated zinc finger protein). MAZ transactivates the MCK promoter and binds the MPEX site in vitro, and chromatin immunoprecipitation analysis demonstrates enrichment of MAZ at the endogenous MCK promoter and other muscle gene promoters (Skeletal ␣-actin, Desmin, and ␣-Myosin heavy chain) in skeletal and cardiac myocytes. Consistent with its role in muscle gene transcription, MAZ transcripts and DNA-binding activity are upregulated during skeletal myocyte differentiation. Furthermore, MAZ was shown to bind numerous sequences (e.g., CTCCTCCC and CTCCACCC) that diverge from the GA box binding motif. Alternate motifs were identified in many muscle promoters, including Myogenin and MEF2C, and one motif was shown to be critical for Six4 promoter activity in both skeletal and cardiac myocytes. Interestingly, MAZ occupies and is able to transactivate the Six4 promoter in skeletal but not cardiac myocytes. Taken together, these findings are consistent with a previously unrecognized role for MAZ in muscle gene regulation.The mouse Muscle creatine kinase (MCK) gene serves as a useful model for understanding muscle-specific gene transcription since its expression is restricted to terminally differentiated striated muscle, where it is one of the most abundantly expressed genes. Transcription of MCK is regulated by an upstream enhancer (Ϫ1256 to Ϫ1050), a proximal promoter (Ϫ358 to ϩ7), and an intron 1 modulatory region (ϩ740 to ϩ1731). The upstream enhancer confers muscle-specific expression to reporter constructs in cell culture, transgenic mice, and virus-mediated gene transfer (1,13,24,30,31,56,61) and contains at least seven control elements, which were identified by footprinting, deletion/mutation analysis, and gel mobility shift assays (1,8,16,39,41). The sequences and relative positions of elements in the MCK enhancer (CArG/SRE, AP2, MEF3, A/T-rich, left and right E-boxes, and MEF2) are highly conserved between mammalian species, and many of the associated transcription factors have been identified (11,19,20,27,39,68).In contrast to the upstream enhancer, very little is known about the highly conserved (Ϫ358 to ϩ7) region comprising the MCK proximal promoter. Studies with cultured cells and transgenic mice have demonstrated that the MCK promoter alone is capable of driving muscle-specific expression (30,56) and that it is ϳ40-fold more active in skeletal than in cardiac myocytes (C. L. Himeda and S. D. Hauschka, unpublished data). However, the MCK promoter also synergizes with the upstream enhancer to drive much higher expression of reporter constructs in both types of striated muscle (13,56). The MCK promoter is known to contain a highly conserved E-box and CA...

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“…When proapoptotic domain was deleted, truncated HBx had more telomerase induction activity than wild-type. Just as Su et al [26] pointed out, HBx isoforms decreased telomerase in the early stage of HCC, and HBx proteins increased telomerase activity in the development of carcinoma.…”

Section: Discussionmentioning

confidence: 94%

“…However, the effects of HBx on telomerase activity have been controversial. Su et al [26] found that some but not all HBx isoforms from chronic infection of HBV reduce telomere length by acting as a transcriptional corepressor of MAZ on the human telomerase promoter. Zhang et al [27] reported that the natural mutant of the HBx protein truncated 27 amino acids at the COOH terminal and wild-type HBx protein could stimulate the promoter transcriptional activities of hTERT in LO2 cells.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein upregulates transcriptional activation of human telomerase reverse transcriptase

et al. 2010

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It is well known that telomerase activation and virus infection are strongly associated with human hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) plays an important role in HCC pathogenesis. However, the mechanisms of HBx on telomerase activity are not well understood. To determine the potential roles of HBx in telomerase activity, both transfection and antisense assay were designed to examine the effects of HBx on telomerase in this report. Results showed that HBX gene increased telomerase activity and human telomerase reverse transcriptase (hTERT) expression in HBx-transfected cells and HBx-positive HCC samples. Co-transfection and luciferase reporter assay showed that HBx could stimulate hTERT promoter in a dose-dependent manner in different cells. Truncated and mutant reporter assays revealed that Sp1 binding sites mapped at -132 to +5 nt in hTERT promote were important for HBx-mediated upregulation of hTERT. Western blot did not show any change of Sp1 expression in HBx-transfected cells, but EMSA showed evidence of that HBx increased binding of Sp1 to its target DNA. These results provide new insights into the role of HBx in liver carcinogenesis.

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X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter

Cited by 35 publications

References 60 publications

Gene expression profiles of human liver cells mediated by hepatitis B virus X protein

Gene expression profiles of human liver cells mediated by hepatitis B virus X protein

Quantitative Proteomic Identification of MAZ as a Transcriptional Regulator of Muscle-Specific Genes in Skeletal and Cardiac Myocytes

Hepatitis B virus X protein upregulates transcriptional activation of human telomerase reverse transcriptase

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