GAP31 from an ancient medicinal plant exhibits anti-viral activity through targeting to Epstein-Barr virus nuclear antigen 1
Copyright © 2019 Elsevier B.V. All rights reserved..
Since it was discovered as the first human tumor virus in 1964, Epstein-Barr Virus (EBV) is now implicated in several types of malignancies. Accordingly, certain aspects of EBV pathobiology have shown promise in anti-cancer research in developing virus-targeting methods for EBV-associated cancers. The unique role of EBV nuclear antigen 1 (EBNA1) in triggering episome-dependent functions has made it as the only latent gene to be expressed in most EBV+ neoplasms. Dimeric EBNA1 binds to the replication origin (oriP) to display its biological impact on EBV-driven cell transformation and maintenance. Hence, EBNA1/oriP has been made an ideal drug target site for anti-EBV protocol development. GAP31 protein was originally isolated from the seeds of an ancient medicinal plant Gelonium multiflorum. Although GAP31 has been shown to exhibit both anti-viral and anti-tumor activity, current understanding of the mechanistic picture underlying GAP31 functioning is not clear. Herein, we identify the EBNA1 DNA-binding domain as a core for GAP31 binding by performing affinity pulldown assays. Recombinant GAP31 (rGAP31) was shown to impair EBNA1-induced dimerization; consequently, it abrogated both EBNA1/oriP-mediated binding and transcription. Importantly, the therapeutic effects of GAP31 showed its capability to abrogate EBV-driven cell transformation and proliferation, and EBV-dependent tumorigenesis in xenograft animal models. Notably, the EBNA1 binding-mutant rGAP31R166A/R169A simply exhibits defective phenotypes in the above-mentioned studies. Our data suggest rGAP31 is a potential anti-viral drug which can be applied to the development of therapeutic strategies against EBV-related malignancies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:164 |
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| Enthalten in: |
Antiviral research - 164(2019) vom: 15. Apr., Seite 123-130 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shen, Chih-Lung [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 30.04.2020 Date Revised 30.04.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.antiviral.2019.02.015 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM294423222 |
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| 520 | |a Copyright © 2019 Elsevier B.V. All rights reserved. | ||
| 520 | |a Since it was discovered as the first human tumor virus in 1964, Epstein-Barr Virus (EBV) is now implicated in several types of malignancies. Accordingly, certain aspects of EBV pathobiology have shown promise in anti-cancer research in developing virus-targeting methods for EBV-associated cancers. The unique role of EBV nuclear antigen 1 (EBNA1) in triggering episome-dependent functions has made it as the only latent gene to be expressed in most EBV+ neoplasms. Dimeric EBNA1 binds to the replication origin (oriP) to display its biological impact on EBV-driven cell transformation and maintenance. Hence, EBNA1/oriP has been made an ideal drug target site for anti-EBV protocol development. GAP31 protein was originally isolated from the seeds of an ancient medicinal plant Gelonium multiflorum. Although GAP31 has been shown to exhibit both anti-viral and anti-tumor activity, current understanding of the mechanistic picture underlying GAP31 functioning is not clear. Herein, we identify the EBNA1 DNA-binding domain as a core for GAP31 binding by performing affinity pulldown assays. Recombinant GAP31 (rGAP31) was shown to impair EBNA1-induced dimerization; consequently, it abrogated both EBNA1/oriP-mediated binding and transcription. Importantly, the therapeutic effects of GAP31 showed its capability to abrogate EBV-driven cell transformation and proliferation, and EBV-dependent tumorigenesis in xenograft animal models. Notably, the EBNA1 binding-mutant rGAP31R166A/R169A simply exhibits defective phenotypes in the above-mentioned studies. Our data suggest rGAP31 is a potential anti-viral drug which can be applied to the development of therapeutic strategies against EBV-related malignancies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a EBV nuclear antigen 1 (EBNA1) | |
| 650 | 4 | |a Epstein-Barr virus (EBV) | |
| 650 | 4 | |a Gelonium Anti-HIV Protein 31 kDa (GAP31) | |
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| 650 | 7 | |a GAP31 protein, Gelonium multiflorum |2 NLM | |
| 650 | 7 | |a Plant Extracts |2 NLM | |
| 650 | 7 | |a Ribosome Inactivating Proteins, Type 1 |2 NLM | |
| 650 | 7 | |a EBV-encoded nuclear antigen 1 |2 NLM | |
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| 700 | 1 | |a Hsu, Hao-Jen |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jen-Hone |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Chih-Wen |e verfasserin |4 aut | |
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