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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.

SUBMITTER: Forte E

PROVIDER: S-EPMC2648290 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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

Forte Eleonora E Luftig Micah A MA

Journal of virology 20090114 6

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 esta ...[more]

PMID: 19144715

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Project description:The Epstein-Barr virus (EBV) efficiently transforms primary B cells. Here, we show that this process starts immediately after cellular exposure to infectious viral particles. Virus binding to B cells led to the activation of intracytoplasmic tyrosine kinases and STAT3. Tegument proteins within the virion in turn activated the p38-MK2 pathway upon cell entry, independently of the viral DNA. Engagement of STAT3 and p38/MK2, two pro-inflammatory pathways, was essential for expression of the key EBV transforming gene EBNA2 but also facilitated IL-6 and TNFα release. However, these pathways simultaneously activated ZFP36L1, a stress response protein that targets transcripts with an AU-rich 3'UTR, to reduce IL-6 and TNFα transcription in infected cells. Expression of viral latent proteins after infection amplified the viral effects on p38 and MK2, but also on ZFP36L1, altogether resulting in a transitory and limited increase in IL-6 and TNFα transcription and release. Thus, EBV virions are not merely vehicles that allow injection of the viral DNA into the nucleus but manipulate cellular pathways to initiate transformation while limiting cytokine release. IMPORTANCE The Epstein-Barr virus efficiently infects and transforms B lymphocytes. During this process, infectious viral particles transport the viral genome to the nucleus of target cells. We show here that these complex viral structures serve additional crucial roles by activating transcription of the transforming genes encoded by the virus. We show that components of the infectious particle sequentially activate proinflammatory B lymphocyte signaling pathways that, in turn, activate viral gene expression but also cause cytokine release. However, virus infection activates expression of ZFP36L1, an RNA-binding stress protein that limits the length and the intensity of the cytokine response. Thus, the infectious particles can activate viral gene expression and initiate cellular transformation at the price of a limited immune response.

Dataset Information

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

Publications

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

Similar Datasets

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