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Journal of Virology, October 2008, p. 10175-10187, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.00321-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Latent Membrane Protein 1 of Epstein-Barr Virus Activates the hTERT Promoter and Enhances Telomerase Activity in B Lymphocytes{triangledown}

Liliana Terrin,1 Jessica Dal Col,2 Enrica Rampazzo,1 Paola Zancai,2 Moreno Pedrotti,1 Grazia Ammirabile,1 Stefano Bergamin,2 Silvana Rizzo,2 Riccardo Dolcetti,2,{dagger}* and Anita De Rossi1,{dagger}

Unit of Viral Oncology, Department of Oncology and Surgical Sciences, IOV-IRCCS, Padova,1 Cancer Bioimmunotherapy Unit, Department of Medical Oncology, CRO-IRCCS, National Cancer Institute, Aviano, Italy2

Received 14 February 2008/ Accepted 25 July 2008

Transformation of primary B lymphocytes by Epstein-Barr virus requires the establishment of a strictly latent infection, the expression of several latent viral proteins, and sustained telomerase activity. Our previous findings indicated that induction of hTERT, the rate-limiting catalytic unit of the telomerase complex, was associated with the expression of the viral latent membrane protein 1 (LMP1). In the present study, we demonstrate that ectopic expression of LMP1 in BJAB and Ramos B cells resulted in an increase of hTERT transcripts, thus suggesting that LMP1 acts at the transcriptional level. This was confirmed by transient expression of a luciferase reporter plasmid containing the hTERT promoter cotransfected with an LMP1-expressing vector or transfected into B cells in which LMP1 expression was inducible. Consistently, silencing of LMP1 by small interfering RNA resulted in a reduction of hTERT transcripts. We also provide evidence indicating that LMP1-induced hTERT activation is independently mediated by NF-{kappa}B and by mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 pathways, whereas CD40, Akt, and mTOR signaling has no involvement. Moreover, our results do not support a role for c-Myc in mediating these effects on hTERT, since ectopic expression of LMP1 did not upregulate c-Myc and silencing of this oncogene or E box mutagenesis failed to inhibit LMP1-induced hTERT activation. These findings indicate that LMP1 simultaneously modulates multiple signal transduction pathways in B cells to transactivate the hTERT promoter and enhance telomerase activity, thus confirming the pleiotropic nature of this viral oncoprotein.

* Corresponding author. Mailing address: Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico-IRCCS, National Cancer Institute, Via Franco Gallini 2, 33081 Aviano (PN), Italy. Phone: 39 0434 659660. Fax: 39 0434 659659. E-mail: rdolcetti{at}cro.it

{triangledown} Published ahead of print on 6 August 2008.

{dagger} R.D. and A.D.R. share senior authorship.

Journal of Virology, October 2008, p. 10175-10187, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.00321-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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