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MDM2-dependent inhibition of p53 is required for Epstein-Barr virus B-cell growth transformation and infected-cell survival.

Publication ,  Journal Article
Forte, E; Luftig, MA
Published in: J Virol
March 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-kappaB inhibition in killing LCLs. NF-kappaB 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.

Duke Scholars

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

March 2009

Volume

83

Issue

6

Start / End Page

2491 / 2499

Location

United States

Related Subject Headings

  • Virus Replication
  • Virology
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2
  • Piperazines
  • NF-kappa B
  • Imidazoles
  • Humans
  • Herpesvirus 4, Human
  • Enzyme Inhibitors
 

Citation

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Forte, E., & Luftig, M. A. (2009). MDM2-dependent inhibition of p53 is required for Epstein-Barr virus B-cell growth transformation and infected-cell survival. J Virol, 83(6), 2491–2499. https://doi.org/10.1128/JVI.01681-08
Forte, Eleonora, and Micah A. Luftig. “MDM2-dependent inhibition of p53 is required for Epstein-Barr virus B-cell growth transformation and infected-cell survival.J Virol 83, no. 6 (March 2009): 2491–99. https://doi.org/10.1128/JVI.01681-08.
Forte, Eleonora, and Micah A. Luftig. “MDM2-dependent inhibition of p53 is required for Epstein-Barr virus B-cell growth transformation and infected-cell survival.J Virol, vol. 83, no. 6, Mar. 2009, pp. 2491–99. Pubmed, doi:10.1128/JVI.01681-08.

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

March 2009

Volume

83

Issue

6

Start / End Page

2491 / 2499

Location

United States

Related Subject Headings

  • Virus Replication
  • Virology
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2
  • Piperazines
  • NF-kappa B
  • Imidazoles
  • Humans
  • Herpesvirus 4, Human
  • Enzyme Inhibitors