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Journal of Virology, May 2007, p. 4848-4857, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.02530-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Involvement of the Oncoprotein c-Myc in Viral Telomerase RNA Gene Regulation during Marek's Disease Virus-Induced Lymphomagenesis

Marina Shkreli,^1,2, Ginette Dambrine,¹ Denis Soubieux,¹ Emmanuel Kut,¹ and Denis Rasschaert^1,2*

Equipe Télomérase et Lymphome Viro-induit, Centre INRA de Tours, Unité IASP 213, 37380 Nouzilly, France,¹ Université François-Rabelais Sciences et Techniques, Parc de Grandmont, 37200 Tours, France²

Received 16 November 2006/ Accepted 13 February 2007

Marek's disease virus (MDV) is an alphaherpesvirus that induces a highly malignant T-lymphoma in chickens. The viral genome encodes two identical copies of a viral telomerase RNA subunit (vTR) that exhibits 88% sequence identity to its chicken ortholog chTR. The minimal telomerase ribonucleoprotein complex consists of a protein subunit with reverse transcriptase activity (TERT) and an RNA subunit (TR). The active complex compensates for the progressive telomere shortening that occurs during mitosis and is involved in the cell immortalization process. We show here that the upregulation of telomerase activity is associated with an increase in vTR gene expression in chickens infected with the highly oncogenic MDV strain RB-1B. A comparative functional analysis of the viral and chicken TR promoters, based on luciferase reporter assays, revealed that the vTR promoter was up to threefold more efficient than the chTR promoter in avian cells. We demonstrated, by directed mutagenesis of the vTR promoter region, that the stronger transcriptional activity of the vTR promoter resulted largely from an E-box located two nucleotides downstream from the transcriptional start site of the vTR gene. Furthermore, transactivation assays and chromatin immunoprecipitation assays demonstrated the involvement of the c-Myc oncoprotein in the transcriptional regulation of vTR. Finally, an Ets binding site was specifically implicated in the transcriptional regulation of vTR in the MDV-transformed lymphoblastoid cell line MSB-1.

Published ahead of print on 21 February 2007.

Present address: Department of Medicine, Division of Hematology, and Cancer Biology Program, Stanford School of Medicine, Stanford, CA 94305.