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Ejegod, D.* ; Sørensen, K.D.* ; Moßbrugger, I. ; Quintanilla-Martinez, L. ; Schmidt, J. ; Pedersen, F.S.*

Control of pathogenicity and disease specificity of a T-lymphomagenic gammaretrovirus by E-box motifs but not by an overlapping glucocorticoid response element.

J. Virol. 83, 336-346 (2009)
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Although transcription factors of the basic-helix-loop-helix family have been shown to regulate enhancers of lymphomagenic gammaretroviruses through E-box motifs, overlap of an E-box motif (Egre) with the glucocorticoid response element (GRE) has obscured their function in vivo. We here report that Egre, but not the GRE affects disease induction by the murine T-lymphomagenic SL3-3 virus. Mutating all three copies of Egre prolonged the tumor latency period from 60 to 109 days. Further mutating an E-box motif (Ea/s) outside the enhancer prolonged the latency period to 180 days, suggesting that Ea/s works as a back-up site for Egre. While SL3-3 wt, GRE and Ea/s mutants induced exclusively T-cell lymphomas with wild type latencies, mainly of the CD4+CD8- phenotype, the Egre as well as the Egre plus Ea/s mutants induced B-cell lymphomas and myeloid leukemia in addition to T-cell lymphomas. T-cell lymphomas induced by the two Egre mutants had the same phenotype as those induced by SL3-3 wt, indicating incomplete disruption of T-cell lymphomagenesis in contrast to previous findings for a Runx site mutant of SL3-3. Mutating the Egre site or Egre plus Ea/s triggered several tumor phenotype-associated secondary enhancer changes encompassing neighboring sites, none of which led to regeneration of an E-box motif. Altogether, our results demonstrate a role for the E-box, but not the GRE in T-lymphomagenesis by SL3-3, unveil an inherent broader disease specificity of the virus, and strengthen the notion of selection for more potent enhancer variants of mutated viruses during tumor development.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter murine leukemia-virus; long terminal repeat; loop-helix proteins; mammary-tumor virus; mouse bone-marrow; binding-site; molecular-cloning; retrovirus SL3-3; in-vivo; transcriptional activators
ISSN (print) / ISBN 0022-538X
e-ISSN 1098-5514
Zeitschrift Journal of Virology
Quellenangaben Band: 83, Heft: 1, Seiten: 336-346 Artikelnummer: , Supplement: ,
Verlag American Society for Microbiology (ASM)
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pathology (PATH)
CF Comparative Medicine (AVM)