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Journal of Virology, July 2000, p. 5810-5818, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Transforming Growth Factor Beta 1 Stimulates Expression of the Epstein-Barr Virus BZLF1 Immediate-Early Gene Product ZEBRA by an Indirect Mechanism Which Requires the MAPK Kinase Pathway

Hassan Fahmi,1,2 Chantal Cochet,1 Zakariae Hmama,2 Paule Opolon,3 and Irene Joab1,*

Laboratory of Immunology, Faculty of Science, Université Sidi Mohamed Ben Abdellah, Fès, Morocco,2 and Laboratoire de Pharmacologie Expérimentale et Clinique, INSERM EPI 99-32, Institut de Génétique Moléculaire, 75010 Paris,1 and CNRS UMR 1582, Institut Gustave Roussy, 94800 Villejuif,3 France

Received 9 December 1999/Accepted 4 April 2000

Disruption of Epstein-Barr virus (EBV) latency is mediated by ZEBRA, the protein product of the immediate-early EBV gene, BZLF1. In vitro, phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), induces reactivation of EBV. However, the physiological stimuli responsible for the disruption of viral latency are not well characterized. Transforming growth factor beta 1 (TGF-beta 1) has also been shown to trigger the reactivation of EBV in Burkitt lymphoma cell lines; however, the effect of TGF-beta 1 on ZEBRA expression has not been reported. To further understand this phenomenon, we have investigated the effect of TGF-beta 1 on ZEBRA expression. Our results indicate that the treatment of different EBV-positive Burkitt's lymphoma cell lines with TGF-beta 1 induces a time-dependent activation of BZLF1 transcription with a corresponding increase in the production of the protein ZEBRA. TGF-beta 1 has been shown to exert its effects through a wide range of intracellular routes; in the present study, we have explored these pathways. Transient expression of Smad proteins on their own had no effect on ZEBRA expression. A specific inhibitor of p38 mitogen-activated protein kinase (MAPK), SB203580, did not affect TGF-beta 1-induced ZEBRA expression, whereas treatment with the MAPK/ERK kinase inhibitors, PD98059 and U0126, dramatically decreased this induction. This suggests that TGF-beta 1 effect on BZLF1 expression requires the MAPK pathway. However, in Raji and B95-8 cells additional routes can be used, as (i) the inhibition of ZEBRA induction by PD98059 or U0126 was incomplete, whereas these inhibitors completely abolished PMA-induced ZEBRA expression, (ii) TGF-beta 1 induction of ZEBRA expression occurs in PKC-depleted cells, (iii) in Raji and in B95-8 cells, the effect of TGF-beta 1 and PMA are additive. Transient transfection of the EBV-negative B-cell line DG75 with a BZLF1 promoter-fusion construct (Zp-CAT) showed that under conditions where the BZLF1 promoter is activated by PMA treatment, TGF-beta 1 had no significant effect on the expression of the chloramphenicol acetyltransferase gene. Furthermore, TGF-beta 1 induction of BZLF1 transcripts is dependent on de novo protein synthesis, which suggests that TGF-beta 1 induces BZLF1 expression by an indirect mechanism.

* Corresponding author. Mailing address: Laboratoire de Pharmacologie Expérimentale et Clinique, INSERM EPI 99-32, Institut de Génétique Moléculaire, 27 rue Juliette Dodu, 75010 Paris, France. Phone: 33 (1) 42 49 92 68. Fax: 33 (1) 42 49 48 38. E-mail: i.joab{at}chu-stlouis.fr.

Journal of Virology, July 2000, p. 5810-5818, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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