Role of the Leucine Zipper of Marek's Disease Virus Oncoprotein Meq in Pathogenesis
Abstract
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.
Citation
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 https : / /hdl .handle .net /1969 .1 /ETD -TAMU -2009 -05 -614.