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Journal of Virology, December 2004, p. 12987-12995, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.12987-12995.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Interferon Regulatory Factor 7 Is Associated with Epstein-Barr Virus-Transformed Central Nervous System Lymphoma and Has Oncogenic Properties

Luwen Zhang,1* Jun Zhang,1 Que Lambert,2,3 Channing J. Der,2,3 Luis Del Valle,4 Judith Miklossy,4 Kamel Khalili,4 You Zhou,5 and Joseph S. Pagano2,6,7*

Nebraska Center for Virology, School of Biological Sciences,1 Department of Veterinary and Biomedical Science, University of Nebraska, Lincoln, Nebraska,5 Lineberger Comprehensive Cancer Center,2 Department of Medicine,6 Department of Microbiology and Immunology,7 Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina,3 Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, Pennsylvania4

Received 15 April 2004/ Accepted 23 July 2004

Interferon regulatory factor 7 (IRF-7) is implicated in the regulation of Epstein-Barr virus (EBV) latency. EBV transforms primary B cells, and the major EBV oncoprotein, latent membrane protein 1 (LMP-1), is required for the process. LMP-1 both induces the expression of IRF-7 and activates the IRF-7 protein by phosphorylation and nuclear translocation. Here we report that the expression of IRF-7 is increased in EBV-immortalized B lymphocytes compared with that in primary B cells. IRF-7 was phosphorylated and predominantly localized in the nucleus in the immortalized cells. The expression of IRF-7 was detected in 19 of 27 specimens of primary lymphomas of the human central nervous system by immunohistochemical analysis. The association between LMP-1 and IRF-7 was statistically highly significant for these specimens. An appreciable amount of the IRF-7 expressed in lymphoma cells was localized in the nucleus. Furthermore, IRF-7 promoted the anchorage-independent growth of NIH 3T3 cells. LMP-1 and IRF-7 showed additive effects on the growth transformation of NIH 3T3 cells. IRF-7-expressing NIH 3T3 cells formed tumors in athymic mice. Thus, IRF-7 has oncogenic properties and, along with LMP-1, may mediate or potentiate the EBV transformation process in the pathogenesis of EBV-associated lymphomas.

* Corresponding author. Mailing address for Luwen Zhang: E141 Beadle Center, NE Center for Virology, School of Biological Sciences, University of Nebraska, 1901 Vine St., Lincoln, NE 68588. Phone: (402) 472-5905. Fax: (402) 472-8722. E-mail: lzhang2{at}unlnotes.unl.edu. Mailing address for Joseph S. Pagano: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599. Phone: (919) 966-5907. Fax: (919) 966-9673. E-mail: joseph_pagano{at}med.unc.edu.

Journal of Virology, December 2004, p. 12987-12995, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.12987-12995.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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