This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kondo, S. Articles by Pagano, J. S. Search for Related Content PubMed PubMed Citation Articles by Kondo, S. Articles by Pagano, J. S.

EBV Latent Membrane Protein 1 Up-regulates Hypoxia-Inducible Factor 1 through Siah1-Mediated Down-regulation of Prolyl Hydroxylases 1 and 3 in Nasopharyngeal Epithelial Cells

¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ² Department of Microbiology, College of Natural Sciences, Pusan National University, Busan, South Korea; ³ Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan; and ⁴ Institut National de la Sante et de la Recherche Medicale U716, Cibles Moléculaires en Cancérologie, IFR Saint-Louis, Paris, France

Requests for reprints: Joseph S. Pagano, 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.

Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit . Recently, we have shown that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1 and subsequently expression of HIF1-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1 activation by LMP1 in nasopharyngeal epithelial cells: LMP1 up-regulates the level of Siah1 E3 ubiquitin ligase by enhancing its stability, which subsequently induces proteasomal degradation of prolyl HIF-hydroxylases 1 and 3 that normally mark HIF1 for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1 complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1 and is involved in a recently appreciated aspect of EBV-mediated tumorigenesis, namely, the angiogenesis process triggered by LMP1. (Cancer Res 2006; 66(20): 9870-7)

This article has been cited by other articles:

				L. Dalton-Griffin, S. J. Wilson, and P. Kellam X-Box Binding Protein 1 Contributes to Induction of the Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycle under Hypoxic Conditions J. Virol., July 15, 2009; 83(14): 7202 - 7209. [Abstract] [Full Text] [PDF]

				S. A. Gerber and J. S. Pober IFN-{alpha} Induces Transcription of Hypoxia-Inducible Factor-1{alpha} to Inhibit Proliferation of Human Endothelial Cells J. Immunol., July 15, 2008; 181(2): 1052 - 1062. [Abstract] [Full Text] [PDF]

				R. Abada, T. Dreyfuss-Grossman, Y. Herman-Bachinsky, H. Geva, S.-R. Masa, and R. Sarid SIAH-1 Interacts with the Kaposi's Sarcoma-Associated Herpesvirus-Encoded ORF45 Protein and Promotes Its Ubiquitylation and Proteasomal Degradation J. Virol., March 1, 2008; 82(5): 2230 - 2240. [Abstract] [Full Text] [PDF]

				T. Horikawa, J. Yang, S. Kondo, T. Yoshizaki, I. Joab, M. Furukawa, and J. S. Pagano Twist and Epithelial-Mesenchymal Transition Are Induced by the EBV Oncoprotein Latent Membrane Protein 1 and Are Associated with Metastatic Nasopharyngeal Carcinoma Cancer Res., March 1, 2007; 67(5): 1970 - 1978. [Abstract] [Full Text] [PDF]

				S. Kondo, T. Yoshizaki, N. Wakisaka, T. Horikawa, S. Murono, K. L. Jang, I. Joab, M. Furukawa, and J. S. Pagano 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., February 15, 2007; 81(4): 1554 - 1562. [Abstract] [Full Text] [PDF]