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Journal of Virology, April 2001, p. 3537-3546, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3537-3546.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Direct and Indirect Regulation of Cytokine and Cell Cycle Proteins by EBNA-2 during Epstein-Barr Virus Infection

Lindsay C. Spender,1 Georgina H. Cornish,1 Benjamin Rowland,1,dagger Bettina Kempkes,2 and Paul J. Farrell1,3,*

Ludwig Institute for Cancer Research1 and Virology and Cell Biology Section,3 Imperial College School of Medicine, London W2 1PG, United Kingdom, and Institute for Clinical Molecular Biology, GSF, Munich 81377, Germany2

Received 1 November 2000/Accepted 19 January 2001

We have studied the pathways of regulation of cytokine and cell cycle control proteins during infection of human B lymphocytes by Epstein-Barr virus (EBV). Among 30 cytokine RNAs analyzed by the RNase protection assay, tumor necrosis factor alpha (TNF-alpha ), granulocyte colony-stimulating factor, lymphotoxin (LT), and LTbeta were found to be regulated within 20 h of EBV infection of primary B cells. Similar results were obtained using the estrogen-regulated EBNA-2 cell line EREB2.5, in which RNAs for LT and TNF-alpha were induced within 6 h of activation of EBNA-2. Expression of Notch also caused an induction of TNF-alpha RNA. The induction of TNF-alpha RNA by EBNA-2 was indirect, and constitutive expression of either LMP-1 or c-myc proteins did not substitute for EBNA-2 in induction of TNF-alpha RNA. Cyclin D2 is also an indirect target of EBNA-2-mediated transactivation. EBNA-2 was found to activate the cyclin D2 promoter in a transient-transfection assay. A mutant of EBNA-2 that does not bind RBP-Jkappa retained some activity in this assay, and activation did not depend on the presence of B-cell-specific factors. Deletion analysis of the cyclin D2 promoter revealed that removal of sequences containing E-box c-myc consensus DNA binding sequences did not reduce EBNA-2-mediated activation of the cyclin D2 promoter in the transient-transfection assay. The results indicate that cytokines are an early target of EBNA-2 and that EBNA-2 can regulate cyclin D2 transcription in EBV-infected cells by mechanisms additional to the c-myc pathway.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Imperial College School of Medicine, Norfolk Place, London W2 1PG, United Kingdom. Phone: 44-20-7563-7703. Fax: 44-20-7724-8586. E-mail: p.farrell{at}ic.ac.uk.

dagger Present address: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

Journal of Virology, April 2001, p. 3537-3546, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3537-3546.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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