title: MDM2-dependent inhibition of p53 is required for Epstein-Barr virus B-cell growth transformation and infected-cell survival.
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-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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Forte
authors.forename: Micah A
authors.initials: MA
authors.lastname: Luftig
mesh_terms: D017209:Apoptosis; D001402:B-Lymphocytes / Q000821:virology*; D002460:Cell Line; D002470:Cell Survival; D002472:Cell Transformation, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D014779:Virus Replication
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2