Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway.
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.
Fuerer
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Oncogene Group, Swiss Institute for Experimental Cancer Research (ISREC), Epalinges, Switzerland.
Iggo
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D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D051176:beta Catenin
D017500:Adenovirus E1A Proteins; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin