Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway.
Gene Ther
; 9(4): 270-81, 2002 Feb.
Article
en En
| MEDLINE
| ID: mdl-11896466
Mutation of the adenomatous polyposis coli and beta-catenin genes in colon cancer leads to constitutive activation of transcription from promoters containing binding sites for Tcf/LEF transcription factors. We have constructed adenoviruses with Tcf binding sites in the early promoters, in order to target viral replication to colon tumours. Tcf regulation of the E1A promoter confers a 100-fold selectivity for cells with activated wnt signalling in viral burst and cytopathic effect assays. p300 is a coactivator for beta-catenin, and E1A inhibits Tcf-dependent transcription through sequestration of p300, but mutation of the p300 binding site in E1A leads to a 10-fold reduction in cytopathic effect of all of the Tcf-regulated viruses. When Tcf sites are inserted in the E1A, E1B, E2 and E4 promoters the viruses show up to 100 000-fold selectivity for cells with activated wnt signalling.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Transducción de Señal
/
Transactivadores
/
Adenoviridae
/
Regiones Promotoras Genéticas
/
Neoplasias del Colon
Límite:
Humans
Idioma:
En
Revista:
Gene Ther
Asunto de la revista:
GENETICA MEDICA
/
TERAPEUTICA
Año:
2002
Tipo del documento:
Article
País de afiliación:
Suiza
Pais de publicación:
Reino Unido