Role of the Leucine Zipper of Marek's Disease Virus Oncoprotein Meq in Pathogenesis
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Marek's disease virus (MDV), the etiologic agent of Marek's disease, is a potent oncogenic herpesvirus. MDV is highly contagious and elicits a rapid onset of malignant T-cell lymphomas in chickens within several weeks after infection. The MDV genome encodes an oncoprotein, Meq, which shares resemblance with the Jun/Fos family of bZIP transcription factors. Similar to c-Jun, the leucine zipper region of Meq allows the formation of homo- and heterodimers. Meq homo- and heterodimers have different DNA binding affinities and transcriptional activity; therefore, they may differentially regulate transcription of viral and cellular genes. Previous in vitro data has suggested that Meq homodimers may be involved in regulating viral latency/reactivation, while Meq/c-Jun heterodimers are involved in transformation. Therefore, this research investigates the role of Meq homodimers and Meq-Jun heterodimers in the pathogenicity of MDV, by generating chimeric meq genes, which contain the leucine zipper region of the yeast transcription factor GCN4 (meqGCN) or leucine zipper region of c-Fos (meqFos). Thus producing Meq proteins that exclusively homodimerize (MeqGCN) or heterodimerize with Jun family members (MeqFos). Recombinant viruses (rMd5-MeqGCN and rMd5- MeqFos) containing the chimeric genes meqGCN or meqFos, respectively, in place of parental meq were generated with overlapping cosmid clones of Md5, a very virulent MDV strain. The chimeric genes were evaluated in vitro and retained DNA binding and transactivation/repressive functions, however, selected cells expressing MeqGCN and MeqFos had reduced colony formation in soft agar. Both the rMd5-MeqGCN and rMd5- MeqFos viruses replicated in vitro and in vivo, but rMd5-MeqGCN was unable to transform T-cells in infected chickens, while rMd5-MeqFos induced preneoplastic nerve lesions in 50% of infected birds. However, a third virus rMd5-MeqFos/GCN, which contains one copy of each meqGCN and meqFos, induced preneoplastic nerve lesions in 60% of infected chickens and neoplastic lesions in 20% of infected chickens. These data provide the first in vivo evidence that both Meq homodimers and heterodimers are necessary for MDV induced transformation.
Suchodolski, Paulette F. (2009). Role of the Leucine Zipper of Marek's Disease Virus Oncoprotein Meq in Pathogenesis. Doctoral dissertation, Texas A&M University. Available electronically from