MDM2-dependent inhibition of p53 is required for epstein-barr virus B-cell growth transformation and infected-cell survival

Eleonora Forte, Micah A. Luftig

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

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-κB inhibition in killing LCLs. NF-κB 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.

Original languageEnglish (US)
Pages (from-to)2491-2499
Number of pages9
JournalJournal of virology
Volume83
Issue number6
DOIs
StatePublished - Mar 2009

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Fingerprint Dive into the research topics of 'MDM2-dependent inhibition of p53 is required for epstein-barr virus B-cell growth transformation and infected-cell survival'. Together they form a unique fingerprint.

Cite this