pX, the HBV-encoded coactivator, interacts with components of the transcription machinery and stimulates transcription in a TAF-independent manner.

Haviv, Izhak; Vaizel, D; Shaul, Yosef

doi:10.1002/j.1460-2075.1996.tb00707.x

Cited by 99 publications

(111 citation statements)

References 61 publications

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“…Therefore an obvious question is how the HBx-RPB5-TFIIB trimeric interaction enables promoter selectivity in HBx transactivation. HBx alone does not transactivate the pGal4-CAT reporter but facilitates the activation of Gal4-VP16, suggesting that HBx acts during activated, but not basal transcription (33,63). 3 In this regard, HBx may directly or indirectly communicate with some transcriptional activators (19,20).…”

Section: Hbx Rpb5 and Tfiib May Form A Ternary Complex-mentioning

confidence: 99%

Hepatitis B Virus X Protein Is a Transcriptional Modulator That Communicates with Transcription Factor IIB and the RNA Polymerase II Subunit 5

Lin

Nomura

Cheong

et al. 1997

Journal of Biological Chemistry

158

174

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Hepatitis B virus X protein (HBx) transactivates viral and cellular genes through a wide variety of cis-elements. However, the mechanism is still obscure. Our finding that HBx directly interacts with RNA polymerase II subunit 5 (RPB5), a common subunit of RNA polymerases, implies that HBx directly modulates the function of RNA polymerase (Cheong, J. H., Yi, M., Lin, Y., and Murakami, S. (1995) EMBO J. 14, 142-150). In this context, we examined the possibility that HBx and RPB5 interact with other general transcription factors. HBx and RPB5 specifically bound to transcription factor IIB (TFIIB) in vitro, both of which were detected by either far-Western blotting or the glutathione S-transferaseresin pull-down assay. Delineation of the binding regions of these three proteins revealed that HBx, RPB5, and TFIIB each has two binding regions for the other two proteins. Co-immunoprecipitation using HepG2 cell lysates that express HBx demonstrated trimeric interaction in vivo. Some HBx substitution mutants, which had severely impaired transacting activity, exhibited reduced binding affinity with either TFIIB or RPB5 in a mutually exclusive manner, suggesting that HBx transactivation requires the interactions of both RPB5 and TFIIB. These results indicated that HBx is a novel virus modulator that facilitates transcriptional initiation by stabilizing the association between RNA polymerase and TFIIB through communication with RPB5 and TFIIB.

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Section: Hbx Rpb5 and Tfiib May Form A Ternary Complex-mentioning

confidence: 99%

Hepatitis B Virus X Protein Is a Transcriptional Modulator That Communicates with Transcription Factor IIB and the RNA Polymerase II Subunit 5

Lin

Nomura

Cheong

et al. 1997

Journal of Biological Chemistry

158

174

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“…Similarly, the cellular pathways targeted by the viral protein to achieve transcriptional transactivation are a matter of debate. Indeed, in several studies, X has been reported to directly act on the transcriptional machinery (Cheong et al, 1995;Haviv et al, 1996;Lin et al, 1998;Maguire et al, 1991). In others, X appears to act far more upstream, by modulating the signal transduction cascade in the cytoplasm (Benn et al, 1996;Chirillo et al, 1996;Henkler et al, 1998;Kekule et al, 1993;Klein and Schneider, 1997;Lee and Yun, 1998;Su and Schneider, 1996).…”

Section: Introductionmentioning

confidence: 99%

UVDDB p127-binding modulates activities and intracellular distribution of Hepatitis B virus X protein

2000

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Mammalian hepatitis B viruses encode a unique regulatory protein termed X, which is essential for infection and likely plays a role in the carcinogenic process associated with hepadnaviral infection. Among the numerous properties ascribed to X protein, two have been widely documented: promiscuous transcriptional transactivation and proapoptosis. However, full understanding of the mechanisms underlying these activities requires the identi®cation of the genuine X partners among the multiple X-binding host proteins. Here we show that (i) mutations in X protein, which markedly alter a nity for the host protein UVDDBp127, inactivate both transactivation and proapoptosis; (ii) ectopic fusion of a functional UVDDB-binding domain to a de®cient binding X mutant restored its activity; (iii) in contrast to the loss-of-binding mutants, a mutant with a strong gain-of-binding exerted trans-dominant negative e ects on wt X activity and localized in the nucleus and (iv) increase in intracellular UVDDB concentration enhanced both wt X-mediated transactivation and apoptosis. Taken together, our data provide strong evidence for a common upstream step in X mode of action, consisting of its productive interaction with UVDDB, via a structurally and functionally autonomous module. In addition, they underscore a nuclear location step of the viral protein that depends on its ability to bind UVDDB. Oncogene (2000) 19, 4417 ± 4426.

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“…7,8,25,36 The likelihood that HBxAg mediates these alterations in cell behavior by binding to a variety of cellular proteins, including members of the transcriptional machinery, 16,18 one or more molecules involved in DNA repair, 21,37 a subunit of the proteasome, 38 and the tumor-suppressor protein p53, 19 point to some of the putative molecular pathways that may be relevant to the development of this tumor type. Given the complexity of growth control, and that carcinogenesis is a multistep process, it is likely that HBxAg may bind to and alter the function of other growth-regulatory proteins.…”

Section: Discussionmentioning

confidence: 99%

Identification of a protein isolated from senescent human cells that binds to hepatitis B virus X antigen

et al. 1998

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Hepatitis B virus-encoded X antigen contributes to the development of hepatocellular carcinoma. Given that X antigen functions by binding to other proteins, additional X-binding proteins were sought from an adult human liver cDNA library in a yeast two-hybrid system. The results yielded a clone encoding a 55-kd protein that is associated with replicative senescence (p55 sen ). Binding of p55 sen to X antigen was confirmed in vitro by immunoprecipitation and affinity chromatography. The expression of endogenous p55 sen inversely correlated with cell growth. Transient transfection of X antigen or p55 sen into HepG2 cells stimulated DNA synthesis by twofold to threefold, whereas cotransfection did not, suggesting that these molecules functionally interact. The detection of p55 sen in embryonic mouse liver, its absence in adult mouse and human livers, and its reappearance in livers from carriers with chronic liver disease, suggest that it may play important roles in the regulation of liver cell growth. The similarity between p55 sen and a notch ligand, which is involved in cell fate determinations during embryogenesis, implies that the binding of p55 sen by X antigen may also contribute to an alteration in cell fate, which is characteristic of carcinogenesis. (HEPATOLOGY 1998;27:228-239.)There are more than 300 million carriers of hepatitis B virus (HBV) worldwide who are at high risk for the development of chronic liver diseases, including hepatocellular carcinoma (HCC). 1,2 Although the relative risk for the development of HCC among carriers with liver disease is greater than 100, 3 the molecular mechanism(s) responsible for hepatocellular transformation have not been identified. The frequent finding of HBV DNA integrated into chromosomal DNA 4,5 resulted in an intensive search for cis-acting mechanisms operative in HCC, but the weight of the evidence does not support such mechanisms as being common in HBV-associated tumors. 4,6 The observation that HBV DNA fragments integrated randomly into many host chromosomes 4,6 and that the integrated viral DNA often overexpressed the HBV-encoded X antigen (HBxAg) 7,8 suggested that what the integrated viral sequences encoded was more important than the site of viral DNA integration. HBxAg made from these integrated fragments was subsequently shown to be active in transactivation assays 9-11 and transformed nontumorigenic cell lines, [12][13][14][15] suggesting that persistent high levels of HBxAg expression may shift the patterns of host gene expression relevant to the development of HCC. The finding that HBxAg binds to a variety of transcription factors 16,17 supports the hypothesis that HBxAg trans-activation is relevant to HCC. 18 The binding and inactivation of the tumor suppressor p53 by HBxAg further implicates this virus product in the pathogenesis of HCC. [19][20][21] Given the multistep nature of carcinogenesis and the possibility that the action of HBxAg may contribute to multiple steps, additional HBxAg-binding proteins were sought. MATERIALS AND METHODSYeast Two...

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pX, the HBV-encoded coactivator, interacts with components of the transcription machinery and stimulates transcription in a TAF-independent manner.

Cited by 99 publications

References 61 publications

Hepatitis B Virus X Protein Is a Transcriptional Modulator That Communicates with Transcription Factor IIB and the RNA Polymerase II Subunit 5

Hepatitis B Virus X Protein Is a Transcriptional Modulator That Communicates with Transcription Factor IIB and the RNA Polymerase II Subunit 5

UVDDB p127-binding modulates activities and intracellular distribution of Hepatitis B virus X protein

Identification of a protein isolated from senescent human cells that binds to hepatitis B virus X antigen

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