The oncogenic microRNA OncomiR-21 overexpressed during Marek's disease lymphomagenesis is transactivated by the viral oncoprotein Meq.
Gallid herpesvirus 2 (GaHV-2) is an oncogenic herpesvirus that causes T lymphoma in chicken. GaHV-2 encodes a basic leucine zipper (bZIP) protein of the AP-1 family, Meq. Upon formation of homo- or heterodimers with c-Jun, Meq may modulate the expression of viral and cellular genes involved in lymphomagenesis. GaHV-2 also encodes viral microRNAs (miRNAs) involved in latency and apoptosis escape. However, little is known about cellular miRNA deregulation during the development of GaHV-2-associated lymphoma. We determined the cellular miRNA expression profiles of chickens infected with a very virulent strain (RB-1B) or a vaccine strain (CVI988) or noninfected. Among the most deregulated cellular miRNAs, we focused our efforts on gga-miR-21, which is upregulated during GaHV-2 infection. We mapped the gga-miR-21 promoter to the 10th intron of the TMEM49 gene and found it to be driven by AP-1- and Ets-responsive elements. We show here that the viral oncoprotein Meq binds to this promoter, thereby transactivating gga-miR-21 expression. We confirmed that this miRNA targets chicken programmed death cell 4 (PDCD4) and promotes tumor cell growth and apoptosis escape. Finally, gga-miR-21 was overexpressed only during infection with a very virulent strain (RB-1B) and not during infection with a nononcogenic strain (CVI988), providing further evidence for its role in GaHV-2 lymphomagenesis. Our data therefore suggest an additional role for Meq in GaHV-2-mediated lymphomagenesis through the induction of miR-21 expression.
Transcription Lymphome Viro-Induit, UMR 7261 CNRS/University François Rabelais, Tours, France.
Grégoire
G
Stik
Ginette
G
Dambrine
Sébastien
S
Pfeffer
Denis
D
Rasschaert
D000818:Animals; D002645:Chickens; D020869:Gene Expression Profiling; D008381:Herpesvirus 2, Gallid / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D008223:Lymphoma / Q000473:pathology* / Q000821:virology; D008380:Marek Disease / Q000150:complications / Q000473:pathology*; D035683:MicroRNAs / Q000096:biosynthesis*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*
C100369:Eco-Q protein, Gallid herpesvirus 2; D035683:MicroRNAs; D009856:Oncogene Proteins, Viral; D037521:Virulence Factors