This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wakisaka, N.
Right arrow Articles by Pagano, J. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wakisaka, N.
Right arrow Articles by Pagano, J. S.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2004, p. 5223-5234, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5223-5234.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Latent Membrane Protein 1 Induces Synthesis of Hypoxia-Inducible Factor 1{alpha}

Naohiro Wakisaka,1,2 Satoru Kondo,1,2 Tomokazu Yoshizaki,2 Shigeyuki Murono,2 Mitsuru Furukawa,2 and Joseph S. Pagano1*

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295,1 Department of Otolaryngology, School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan2

Received 16 October 2003/ Returned for modification 5 December 2003/ Accepted 25 March 2004

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1{alpha} and HIF-1ß that is the central regulator of responses to hypoxia. The specific binding of HIF-1 to the hypoxia-responsive element (HRE) induces the transcription of genes that respond to hypoxic conditions, including vascular endothelial growth factor (VEGF). Here we report that expression of HIF-1{alpha} is increased in diverse Epstein-Barr virus (EBV)-infected type II and III cell lines, which express EBV latent membrane protein 1 (LMP1), the principal EBV oncoprotein, as well as other latency proteins, but not in the parental EBV-negative cell lines. We show first that transfection of an LMP1 expression plasmid into Ad-AH cells, an EBV-negative nasopharyngeal epithelial cell line, induces synthesis of HIF-1{alpha} protein without increasing its stability or mRNA level. The mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059 markedly reduces induction of HIF-1{alpha} by LMP1. Catalase, an H2O2 scavenger, strongly suppresses LMP1-induced production of H2O2, which results in a decrease in the expression of HIF-1{alpha} induced by LMP1. Inhibition of the NF-{kappa}B, c-jun N-terminal kinase, p38 MAPK, and phosphatidylinositol 3-kinase pathways did not affect HIF-1{alpha} expression. Moreover, LMP1 induces HIF-1 DNA binding activity and upregulates HRE and VEGF promoter transcriptional activity. Finally, LMP1 increases the appearance of VEGF protein in extracellular fluids; induction of VEGF is suppressed by PD98059 or catalase. These results suggest that LMP1 increases HIF-1 activity through induction of HIF-1{alpha} protein expression, which is controlled by p42/p44 MAPK activity and H2O2. The ability of EBV, and specifically its major oncoprotein, LMP1, to induce HIF-1{alpha} along with other invasiveness and angiogenic factors reported previously discloses additional oncogenic properties of this tumor virus.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295. Phone: (919) 966-8644. Fax: (919) 966-9673. E-mail: Joseph_Pagano{at}med.unc.edu.

Molecular and Cellular Biology, June 2004, p. 5223-5234, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5223-5234.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • O'Neil, J. D., Owen, T. J., Wood, V. H. J., Date, K. L., Valentine, R., Chukwuma, M. B., Arrand, J. R., Dawson, C. W., Young, L. S. (2008). Epstein-Barr virus-encoded EBNA1 modulates the AP-1 transcription factor pathway in nasopharyngeal carcinoma cells and enhances angiogenesis in vitro. J. Gen. Virol. 89: 2833-2842 [Abstract] [Full Text]  
  • Tsuji, A., Wakisaka, N., Kondo, S., Murono, S., Furukawa, M., Yoshizaki, T. (2008). Induction of Receptor for Advanced Glycation End Products by EBV Latent Membrane Protein 1 and Its Correlation with Angiogenesis and Cervical Lymph Node Metastasis in Nasopharyngeal Carcinoma. Clin. Cancer Res. 14: 5368-5375 [Abstract] [Full Text]  
  • Gerber, S. A., Pober, J. S. (2008). IFN-{alpha} Induces Transcription of Hypoxia-Inducible Factor-1{alpha} to Inhibit Proliferation of Human Endothelial Cells. J. Immunol. 181: 1052-1062 [Abstract] [Full Text]  
  • Bayele, H. K., Peyssonnaux, C., Giatromanolaki, A., Arrais-Silva, W. W., Mohamed, H. S., Collins, H., Giorgio, S., Koukourakis, M., Johnson, R. S., Blackwell, J. M., Nizet, V., Srai, S. K. S. (2007). HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite. Blood 110: 3039-3048 [Abstract] [Full Text]  
  • Charalambous, C. T., Hannigan, A., Tsimbouri, P., McPhee, G. M., Wilson, J. B. (2007). Latent membrane protein 1-induced EGFR signalling is negatively regulated by TGF{alpha} prior to neoplasia. Carcinogenesis 28: 1839-1848 [Abstract] [Full Text]  
  • Horikawa, T., Yang, J., Kondo, S., Yoshizaki, T., Joab, I., Furukawa, M., Pagano, J. S. (2007). Twist and Epithelial-Mesenchymal Transition Are Induced by the EBV Oncoprotein Latent Membrane Protein 1 and Are Associated with Metastatic Nasopharyngeal Carcinoma. Cancer Res. 67: 1970-1978 [Abstract] [Full Text]  
  • Kondo, S., Yoshizaki, T., Wakisaka, N., Horikawa, T., Murono, S., Jang, K. L., Joab, I., Furukawa, M., Pagano, J. S. (2007). MUC1 Induced by Epstein-Barr Virus Latent Membrane Protein 1 Causes Dissociation of the Cell-Matrix Interaction and Cellular Invasiveness via STAT Signaling. J. Virol. 81: 1554-1562 [Abstract] [Full Text]  
  • Hwang, I. I. L., Watson, I. R., Der, S. D., Ohh, M. (2006). Loss of VHL Confers Hypoxia-Inducible Factor (HIF)-Dependent Resistance to Vesicular Stomatitis Virus: Role of HIF in Antiviral Response. J. Virol. 80: 10712-10723 [Abstract] [Full Text]  
  • Kondo, S., Seo, S. Y., Yoshizaki, T., Wakisaka, N., Furukawa, M., Joab, I., Jang, K. L., Pagano, J. S. (2006). EBV Latent Membrane Protein 1 Up-regulates Hypoxia-Inducible Factor 1{alpha} through Siah1-Mediated Down-regulation of Prolyl Hydroxylases 1 and 3 in Nasopharyngeal Epithelial Cells.. Cancer Res. 66: 9870-9877 [Abstract] [Full Text]  
  • Cai, Q., Lan, K., Verma, S. C., Si, H., Lin, D., Robertson, E. S. (2006). Kaposi's Sarcoma-Associated Herpesvirus Latent Protein LANA Interacts with HIF-1{alpha} To Upregulate RTA Expression during Hypoxia: Latency Control under Low Oxygen Conditions.. J. Virol. 80: 7965-7975 [Abstract] [Full Text]  
  • Zhao, L.-J., Zhang, X.-L., Zhao, P., Cao, J., Cao, M.-M., Zhu, S.-Y., Liu, H.-Q., Qi, Z.-T. (2006). Up-regulation of ERK and p38 MAPK signaling pathways by hepatitis C virus E2 envelope protein in human T lymphoma cell line. J. Leukoc. Biol. 80: 424-432 [Abstract] [Full Text]  
  • Wenger, R. H., Stiehl, D. P., Camenisch, G. (2005). Integration of Oxygen Signaling at the Consensus HRE. Sci Signal 2005: re12-re12 [Abstract] [Full Text]  
  • Ning, S., Huye, L. E., Pagano, J. S. (2005). Interferon Regulatory Factor 5 Represses Expression of the Epstein-Barr Virus Oncoprotein LMP1: Braking of the IRF7/LMP1 Regulatory Circuit. J. Virol. 79: 11671-11676 [Abstract] [Full Text]  
  • Zhang, L., Zhang, J., Lambert, Q., Der, C. J., Del Valle, L., Miklossy, J., Khalili, K., Zhou, Y., Pagano, J. S. (2004). Interferon Regulatory Factor 7 Is Associated with Epstein-Barr Virus-Transformed Central Nervous System Lymphoma and Has Oncogenic Properties. J. Virol. 78: 12987-12995 [Abstract] [Full Text]  
  • Carbone, M., Klein, G., Gruber, J., Wong, M. (2004). Modern Criteria to Establish Human Cancer Etiology. Cancer Res. 64: 5518-5524 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»