This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Wakisaka, N. Articles by Pagano, J. S. Search for Related Content PubMed PubMed Citation Articles by Wakisaka, N. Articles by Pagano, J. S.

Epstein-Barr Virus Latent Membrane Protein 1 Induces and Causes Release of Fibroblast Growth Factor-2¹

Lineberger Comprehensive Cancer Center [N. W., J. S. P.] and Departments of Medicine [J. S. P.] and Microbiology and Immunology [J. S. P.], University of North Carolina at Chapel Hill, North Carolina 27599-7295, and Department of Otolaryngology, School of Medicine, Kanazawa University, Ishikawa 920-8640, Japan [N. W., S. M., T. Y., M. F.]

We have shown that the EBV oncoprotein, latent membrane protein 1 (LMP1), induces a constellation of tumor-invasiveness factors. Fibroblast growth factor (FGF)-2 is angiogenic as well mitogenic. Although FGF-2 does not contain a hydrophobic signal sequence for secretion, FGF-2 is released extracellularly. However, the mechanism by which FGF-2 is released is unclear. Here we show first that LMP1 induces in epithelial cells the expression of FGF-2 mRNA and protein through both LMP1 COOH-terminal activation domains, CTAR 1 and CTAR 2, which can activate nuclear factor (NF)-B signaling and also the p38 mitogen-activated protein kinase pathway. Coexpression of IB (S32A/S36A), which cannot be phosphorylated and prevents NF-B activation, with LMP1 inhibited induction of FGF-2 by LMP1, which suggests that LMP1 induces FGF-2 via NF-B signaling. Moreover, unlike phorbol 12-myristate 13-acetate LMP1 also induced the release of the M_r 18,000 isoform of FGF-2 protein. Transfection of Ad-AH cells with LMP1 deletion mutants lacking either CTAR 1 or CTAR 2 also induced the release of the protein. Secretion was confirmed in 293 cells, which do not contain detectable endogenous FGF-2 protein, cotransfected with FGF-2 and LMP1. Finally, Na⁺/K⁺-ATPase participates in FGF-2 release, independently of the classical endoplasmic reticulum/Golgi pathway. In this study, the release of M_r 18,000 FGF-2 protein was partially suppressed by ouabain, which inhibits the activity of Na⁺/K⁺-ATPase 1 subunit, but not by Brefeldin A, which inhibits the endoplasmic reticulum/Golgi-dependent secretory pathway. In contrast, the release of M_r 18,000 FGF-2 protein was almost completely inhibited by IB (S32A/S36A). These results suggest that FGF-2 release is independently mediated by NF-B signaling, not simply a consequence of induction itself. Thus, NF-B signaling is involved in induction of expression and release of FGF-2 by LMP1.

This article has been cited by other articles:

				A. Tsuji, N. Wakisaka, S. Kondo, S. Murono, M. Furukawa, and T. Yoshizaki 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., September 1, 2008; 14(17): 5368 - 5375. [Abstract] [Full Text] [PDF]

				D. Xu, T. Coleman, J. Zhang, A. Fagot, C. Kotalik, L. Zhao, P. Trivedi, C. Jones, and L. Zhang Epstein-Barr Virus Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication in Primary Effusion Lymphomas J. Virol., June 1, 2007; 81(11): 6068 - 6078. [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]

				S. Kondo, S. Y. Seo, T. Yoshizaki, N. Wakisaka, M. Furukawa, I. Joab, K. L. Jang, and J. S. Pagano 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., October 15, 2006; 66(20): 9870 - 9877. [Abstract] [Full Text] [PDF]

				A. Li, H. Guo, X. Luo, J. Sheng, S. Yang, Y. Yin, J. Zhou, and J. Zhou Apomorphine-induced activation of dopamine receptors modulates FGF-2 expression in astrocytic cultures and promotes survival of dopaminergic neurons FASEB J, June 1, 2006; 20(8): 1263 - 1265. [Abstract] [Full Text] [PDF]

				H. Arbach, V. Viglasky, F. Lefeu, J.-M. Guinebretiere, V. Ramirez, N. Bride, N. Boualaga, T. Bauchet, J.-P. Peyrat, M.-C. Mathieu, et al. Epstein-Barr Virus (EBV) Genome and Expression in Breast Cancer Tissue: Effect of EBV Infection of Breast Cancer Cells on Resistance to Paclitaxel (Taxol) J. Virol., January 15, 2006; 80(2): 845 - 853. [Abstract] [Full Text] [PDF]

				K. Tanaka, J. Hasegawa, K. Asamitsu, and T. Okamoto Prevention of the Ultraviolet B-Mediated Skin Photoaging by a Nuclear Factor {kappa}B Inhibitor, Parthenolide J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 624 - 630. [Abstract] [Full Text] [PDF]

				L. Zhang, J. Zhang, Q. Lambert, C. J. Der, L. Del Valle, J. Miklossy, K. Khalili, Y. Zhou, and J. S. Pagano Interferon Regulatory Factor 7 Is Associated with Epstein-Barr Virus-Transformed Central Nervous System Lymphoma and Has Oncogenic Properties J. Virol., December 1, 2004; 78(23): 12987 - 12995. [Abstract] [Full Text] [PDF]

				N. Wakisaka, S. Kondo, T. Yoshizaki, S. Murono, M. Furukawa, and J. S. Pagano Epstein-Barr Virus Latent Membrane Protein 1 Induces Synthesis of Hypoxia-Inducible Factor 1{alpha} Mol. Cell. Biol., June 15, 2004; 24(12): 5223 - 5234. [Abstract] [Full Text] [PDF]

				L. Wang, N. Wakisaka, C. C Tomlinson, S. M DeWire, S. Krall, J. S Pagano, and B. Damania The Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV-8) K1 Protein Induces Expression of Angiogenic and Invasion Factors Cancer Res., April 15, 2004; 64(8): 2774 - 2781. [Abstract] [Full Text] [PDF]

				S. Ning, A. M. Hahn, L. E. Huye, and J. S. Pagano Interferon Regulatory Factor 7 Regulates Expression of Epstein-Barr Virus Latent Membrane Protein 1: a Regulatory Circuit J. Virol., September 1, 2003; 77(17): 9359 - 9368. [Abstract] [Full Text] [PDF]