Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway
Open Access
- 1 February 2002
- journal article
- research article
- Published by Springer Nature in Gene Therapy
- Vol. 9 (4) , 270-281
- https://doi.org/10.1038/sj.gt.3301651
Abstract
Mutation of the adenomatous polyposis coli and β-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 β-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.Keywords
This publication has 46 references indexed in Scilit:
- High-Level, β-Catenin/TCF-Dependent Transgene Expression in Secondary Colorectal Cancer TissueMolecular Therapy, 2001
- Replicating Adenoviruses That Target Tumors with Constitutive Activation of the wnt Signaling PathwayJournal of Virology, 2001
- A Novel, Conditionally Replicative Adenovirus for the Treatment of Breast Cancer That Allows Controlled Replication of E1a-Deleted Adenoviral VectorsHuman Gene Therapy, 2000
- US gene therapy in crisisTrends in Genetics, 2000
- Conserved region 2 of adenovirus E1A has a function distinct from pRb binding required to prevent cell cycle arrest by p16INK4a or p27Kip1Oncogene, 2000
- A photosensitising adenovirus for photodynamic therapyGene Therapy, 1999
- Amino acids 1–29 of the adenovirus serotypes 12 and 2 E1A proteins interact with rap30 (TFIIF) and TBP in vitroVirus Research, 1998
- Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC −/− Colon CarcinomaScience, 1997
- Isolation and characterization of packaging cell lines that coexpress the adenovirus E1, DNA polymerase, and preterminal proteins: implications for gene therapyGene Therapy, 1997
- The adenovirus type 5 E1A enhancer contains two functionally distinct domains: One is specific for E1A and the other modulates all early units in cisCell, 1986