Direct binding of hepatitis B virus X protein and retinoid X receptor contributes to phosphoenolpyruvate carboxykinase gene transactivation

Kong, Hee Jeong; Hong, Sun Hwa; Lee, Min Young; Kim, Han Do; Lee, Jae Woon; Cheong, Jae Hun

doi:10.1016/s0014-5793(00)02091-3

Cited by 27 publications

(13 citation statements)

References 22 publications

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“…The use of the second and third α helixes to interact with FXR was in contrast to the case of RXR, in which the first α helix was used for interaction (Fig. C, left panel), consistent with a previous report . To examine the functional relevance of the FXR‐interacting α helixes, we constructed two deletion mutants of HBx that lacked the second α helix (deletion of amino acids 73‐100 or Δ73‐100) or the third α helix (Δ100‐120).…”

Section: Resultssupporting

confidence: 76%

Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein–induced hepatocarcinogenesis

Niu

Slagle³

et al. 2017

Hepatology

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Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a HBV protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. The farnesoid X receptor (FXR) is a nuclear receptor known to have activities in anti-inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact HBV/HBx-induced hepatocarcinogenesis remains unclear. In this study, we showed that HBx can interact with FXR and function as a co-activator of FXR. Expression of HBx in vivo enhanced FXR responsive gene regulation. HBx also increased the transcriptional activity of FXR in luciferase reporter gene assay. The HBx-FXR interaction was confirmed by co-immunoprecipitation and GST-pull down assays, and the FXR AF-1 domain was mapped to bind to the third α helix in the C-terminal of HBx. We also found that the C-terminal truncated variants of HBx, which were found in clinical HCC, were not effective in transactivating FXR. Interestingly, recruitment of the full-length HBx, but not the C-terminal truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx-induced hepatocarcinogenesis. Conclusions We propose that transactivation of FXR by the full-length HBx may represent a protective mechanism to inhibit HCC, and this inhibition may have been compromised upon the appearance of the C-terminal truncated HBx, or when the expression and/or activity of FXR is decreased.

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Section: Resultssupporting

confidence: 76%

Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein–induced hepatocarcinogenesis

Niu

Slagle³

et al. 2017

Hepatology

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“…The ligand-dependent association of either HBx 17 or ASC-2 10 with RXR has been shown to stimulate activation of RXR-driven gene transcription ( Fig. 2A).…”

Section: Asc-2 Enhances Hbx-driven Transactivationmentioning

confidence: 99%

Hepatitis B virus X protein regulates transactivation activity and protein stability of the cancer-amplified transcription coactivator ASC-2

et al. 2003

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H epatitis B virus (HBV) mainly infects liver tissue and is associated with hepatitis and hepatocellular carcinoma. 1 Several findings suggest that HBV X protein (HBx) could be a causative factor in progression of these diseases. 2 HBx protein is known to regulate transcription of a variety of cellular and viral genes, although it does not bind to double-stranded DNA. The observation that genes stimulated by HBx lack any obvious consensus sequences suggests that HBx stimulates transcription by interacting with cellular proteins and/or components of signal transduction pathways. Consistent with this hypothesis, HBx has been shown to directly interact with transcriptional factors such as RPB5 of RNA polymerase, 3 TATA-binding protein, 4 and bZIP proteins 5 and leads to activation of signal transduction pathways including the Ras/Raf/mitogen-activated protein kinase, protein kinase C, Jak1-STAT, and nuclear factor B pathways. [6][7][8][9] Activating signal cointegrator 2 (ASC-2) is a recently identified transcriptional coactivator of nuclear receptors. 10 Similar, if not identical, molecules have been identified by others and variously termed TRBP, PRIP, and RAP250. 11-14 ASC-2, a typical ligand and AF2-dependent interactor of nuclear receptors, enhances receptor transactivation, either alone or in conjunction with SRC-1 and CBP/p300. Interestingly, ASC-2 is identical to AIB3, which was identified as a transcript that was overexpressed in human breast cancers. 15 ASC-2 can mediate transactivation of mitogenic transcription factors including SRF, AP-1, and nuclear factor B. 16 This observation suggests that overexpression of ASC-2 may promote tumorigenesis, consistent with the observation that ASC-2 copy number was amplified and overexpressed in cancer cell lines including BT-474, ZR-75-1, and MCF7.Interestingly, both HBx and ASC-2 proteins are capable of interacting with AP-1 and retinoid X receptor (RXR) transcription factors and function in a cooperative manner in specific transcriptional regulation. 16,17 These

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“…The identification of target proteins that directly interact with HBx is increasing, including Smad4 in TNFα signaling, 10 NF-AT in TNFα signaling, 55 retinoid X receptor in phosphoenolpyruvate carboxykinase expression, 64 and HIV Tat-binding protein (Tbp1), 65 a functional homologue of yeast Sug1, which interacted with cytoplasmic HBx and may be involved in transcriptional coactivation.…”

Section: Several Genes Recently Documented To Be Modulated By Hbxmentioning

confidence: 99%

Hepatitis B virus X protein: a multifunctional viral regulator

Murakami

2001

Journal of Gastroenterology

300

244

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Direct binding of hepatitis B virus X protein and retinoid X receptor contributes to phosphoenolpyruvate carboxykinase gene transactivation

Cited by 27 publications

References 22 publications

Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein–induced hepatocarcinogenesis

Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein–induced hepatocarcinogenesis

Hepatitis B virus X protein regulates transactivation activity and protein stability of the cancer-amplified transcription coactivator ASC-2

Hepatitis B virus X protein: a multifunctional viral regulator

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