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Titolo:
INCREASED LYMPHOMAGENICITY AND RESTORED DISEASE SPECIFICITY OF AML1 SITE (CORE) MUTANT SL3-3 MURINE LEUKEMIA-VIRUS BY A 2ND-SITE ENHANCER VARIANT EVOLVED IN-VIVO
Autore:
ETHELBERG S; LOVMAND J; SCHMIDT J; LUZ A; PEDERSEN FS;
Indirizzi:
AARHUS UNIV,DEPT BIOL MOL & STRUCT,BLDG 130,CF MOLLERS ALLE DK-8000 AARHUS C DENMARK AARHUS UNIV,DEPT BIOL MOL & STRUCT DK-8000 AARHUS C DENMARK AARHUS UNIV,DEPT MED MICROBIOL & IMMUNOL DK-8000 AARHUS C DENMARK GSF FORSCHUNGSZENTRUM UMWELT & GESUNDHEIT,INST MOL VIROL D-85764 NEUHERBERG GERMANY GSF FORSCHUNGSZENTRUM UMWELT & GESUNDHEIT,INST PATHOL D-85764 NEUHERBERG GERMANY
Titolo Testata:
Journal of virology
fascicolo: 10, volume: 71, anno: 1997,
pagine: 7273 - 7280
SICI:
0022-538X(1997)71:10<7273:ILARDS>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACUTE MYELOID-LEUKEMIA; LONG TERMINAL REPEAT; I TRANSCRIPTIONAL ACTIVATORS; MOUSE RETROVIRUS SL3-3; MOLECULAR-CLONING; BINDING-FACTOR; C-MYB; ONCOGENIC RETROVIRUS; SINGLE-GENE; SEQUENCES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
54
Recensione:
Indirizzi per estratti:
Citazione:
S. Ethelberg et al., "INCREASED LYMPHOMAGENICITY AND RESTORED DISEASE SPECIFICITY OF AML1 SITE (CORE) MUTANT SL3-3 MURINE LEUKEMIA-VIRUS BY A 2ND-SITE ENHANCER VARIANT EVOLVED IN-VIVO", Journal of virology, 71(10), 1997, pp. 7273-7280

Abstract

SL3-3 is a highly T-lymphomagenic murine retrovirus. The major genetic determinant of disease is the transcriptional enhancer, which consists of a repeated region with densely packed binding sites for several transcription factors, including AML1 (also known as core binding factor and polyoma enhancer-binding protein 2) and nuclear factor 1 (NF1),Previously, we examined the enhancer structure of proviruses from murine tumors induced by SL3-3 with mutated AML1 (core) sites and found afew cases of second-site alterations. These consisted of deletions involving the NF1 sites and alterations in overall number of repeat elements, and they conferred increased enhancer strength in transient transcription assays. We have now tested the pathogenicity of a virus harboring one such second-site variant enhancer in inbred NMR1 mice, It induced lymphomas with a 100% incidence and a significantly shorter latency than the AML1 mutant it evolved from, The enhancer structure thus represents the selection for a more tumorigenic virus variant during the pathogenic process, Sequencing of provirus from the induced tumors showed the new enhancer variant to be genetically stable. Also, Southern blotting showed that the tumors induced by the variant were T-cell lymphomas, as were the wild-type-induced lymphomas, In contrast, tumors induced by the original core/AML1 site I-II mutant appeared to be ofnon-TT-cell origin and several proviral genomes with altered enhancerregions could be found in the tumors. Moreover, reporter constructs with the new tumor-derived variant could not be transactivated by AML1 in cotransfection experiments as could the wild type. These results emphasize the importance of both core/AML1 site I and site II for the pathogenic potential of SL3-3 and at the same time show that second-sitealterations can form a viral variant with a substantial pathogenic potential although both AML1 sites I and II are nonfunctional.

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Documento generato il 20/01/21 alle ore 11:49:43