Adenoviruses with tcf binding sites in multiple early promoters show enhanaced selectivity for tumour cells with constitutive activation of the Wnt signalling pathway.

Richard Derek Iggo, C. Fuerer

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

Mutation of the adenomatous polyposis coli and g-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.

Original languageEnglish
Pages (from-to)270-281
Number of pages12
JournalGene Therapy
Volume9
DOIs
Publication statusPublished - Feb 2002

Keywords

  • APC
  • beta-catenin
  • Tcf
  • E1A
  • colon cancer
  • oncolytic adenovirus
  • REPLICATION COMPETENT ADENOVIRUS
  • COLON-CARCINOMA CELLS
  • E1A PROTEINS INTERACT
  • BETA-CATENIN
  • TRANSCRIPTION FACTOR
  • C-MYC
  • MONOCLONAL-ANTIBODIES
  • GENE-THERAPY
  • CANCER
  • COACTIVATOR

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