The Meq oncoprotein of Marek's disease virus interacts with p53 and inhibits its transcriptional and apoptotic activities

Abstract

BackgroundMarek's disease virus (MDV) is an oncogenic herpesvirus, which causes malignant lymphoma in chickens. The Meq protein of MDV, which is expressed abundantly in MDV-infected cells and in Marek's disease (MD) tumor cells, functions as a transcriptional activator and has been proposed to play an important role in oncogenic transformation. Preliminary studies demonstrated that Meq is able to bind p53 in vitro, as demonstrated using a protein-binding assay. This observation prompted us to examine whether the interaction between Meq and p53 occurs in cells, and to investigate the biological significance of this interaction.ResultsWe confirmed first that Meq interacted directly with p53 using a yeast two-hybrid assay and an immunoprecipitation assay, and we investigated the biological significance of this interaction subsequently. Exogenous expression of Meq resulted in the inhibition of p53-mediated transcriptional activity and apoptosis, as analyzed using a p53 luciferase reporter assay and a TUNEL assay. The inhibitory effect of Meq on transcriptional activity mediated by p53 was dependent on the physical interaction between these two proteins, because a Meq deletion mutant that lacked the p53-binding region lost the ability to inhibit p53-mediated transcriptional activity and apoptosis. The Meq variants L-Meq and S-Meq, but not VS-Meq and ∆Meq, which were expressed in MD tumor cells and MDV-infected cells, exerted an inhibitory effect on p53 transcriptional activity. In addition, ∆Meq was found to act as a negative regulator of Meq.ConclusionsThe Meq oncoprotein interacts directly with p53 and inhibits p53-mediated transcriptional activity and apoptosis. These findings provide valuable insight into the molecular basis for the function of Meq in MDV oncogenesis.

Transcriptional Analysis of Host Responses to Marek's Disease Virus Infection in Chicken Thymus

“…Current evidence indicates that MDV has evolved multiple mechanisms to thwart this cellular response to protect cells against apoptosis [26,27]. One of the latest discoveries is that the Meq oncoprotein of MDV inhibited p53-dependent transcription and apoptosis by interacting directly with p53 [26]. In our study, we further found that several genes of p53-dependent apoptosis pathway including CHEK2, CYCS, APAF1, and PERP were downregulated in infected thymuses at 21 and 28 dpi.…”

“…Apoptosis has been shown to be a common host cell response to viral infection [25], which is advantageous for the host as it eliminates virus-infected cells. Current evidence indicates that MDV has evolved multiple mechanisms to thwart this cellular response to protect cells against apoptosis [26,27]. One of the latest discoveries is that the Meq oncoprotein of MDV inhibited p53-dependent transcription and apoptosis by interacting directly with p53 [26].…”

Analysis of protein expression profiles in the thymus of chickens infected with Marek’s disease virus

“…Within this map, we found that MIF, HSP90AA1, NPM1, STMN1(OP18) and VIM can interact with the tumour suppressor protein TP53. It has been reported that the Meq oncoprotein directly interacts with p53 and inhibits p53-mediated transcriptional activity and apoptosis [14]. This scenario could provide an interesting link between MEQ and these proteins and enhance our understanding of MDV pathogenesis.…”

Microsatellite Instability in Chicken Lymphoma Induced by Gallid Herpesvirus 2

“…The transcriptional regulator MEQ is considered to be the major viral oncoprotein of GaHV-2. The MEQ interacts directly with p53 and inhibits p53-mediated transcriptional activity [25]. Both the MMR system and the p53 pathway are critical in the maintenance of genomic integrity [26], [27].…”