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Journal of Virology, March 2009, p. 2491-2499, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01681-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

MDM2-Dependent Inhibition of p53 Is Required for Epstein-Barr Virus B-Cell Growth Transformation and Infected-Cell Survival{triangledown} ,§

Eleonora Forte and Micah A. Luftig*

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710

Received 6 August 2008/ Accepted 2 January 2009

Epstein-Barr virus (EBV) growth transformation of primary B lymphocytes into indefinitely proliferating lymphoblastoid cell lines (LCLs) depends on the concerted activities of a subset of viral proteins expressed during latency. EBV drives quiescent B cells into S phase, and consequently, a host response is activated that includes expression of p53 and its target genes. Since LCLs retain wild-type p53, it was of interest to determine what contribution the p53 pathway may have in controlling established LCL growth and EBV-mediated transformation of primary B cells. We found that liberation of p53 through chemical antagonism of one of its major ubiquitin ligases, MDM2, using the small-molecule Nutlin-3 led to apoptosis of established LCLs and suppressed EBV-mediated transformation of primary B cells. The activation of latent p53 induced target genes associated with apoptosis. Furthermore, MDM2 antagonism synergized with NF-{kappa}B inhibition in killing LCLs. NF-{kappa}B was important to increase steady-state MDM2 protein levels rather than in affecting p53-dependent transcription, suggesting a unique mechanism by which LCLs survive in the presence of a primed p53 pathway. Nutlin sensitivity of EBV-infected cells provides a novel system for studying the pathways that dictate LCL survival and regulate EBV transformation. Finally, MDM2 antagonists may be considered for therapeutic intervention in EBV-associated malignancies expressing wild-type p53.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710. Phone: (919) 668-3091. Fax: (919) 684-2790. E-mail: micah.luftig{at}duke.edu

{triangledown} Published ahead of print on 14 January 2009.

§ Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, March 2009, p. 2491-2499, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01681-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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