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PLoS One. 2011;6(12):e28714. doi: 10.1371/journal.pone.0028714. Epub 2011 Dec 9.

Adenoviral vector driven by a minimal Rad51 promoter is selective for p53-deficient tumor cells.

Author information

1
Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States of America.

Abstract

BACKGROUND:

The full length Rad51 promoter is highly active in cancer cells but not in normal cells. We therefore set out to assess whether we could confer this tumor-selectivity to an adenovirus vector.

METHODOLOGY/PRINCIPAL FINDINGS:

Expression of an adenovirally-vectored luciferase reporter gene from the Rad51 promoter was up to 50 fold higher in cancer cells than in normal cells. Further evaluations of a panel of truncated promoter mutants identified a 447 bp minimal core promoter element that retained the full tumor selectivity and transcriptional activity of the original promoter, in the context of an adenovirus vector. This core Rad51 promoter was highly active in cancer cells that lack functional p53, but less active in normal cells and in cancer cell lines with intact p53 function. Exogenous expression of p53 in a p53 null cell line strongly suppressed activity of the Rad51 core promoter, underscoring the selectivity of this promoter for p53-deficient cells. Follow-up experiments showed that the p53-dependent suppression of the Rad51 core promoter was mediated via an indirect, p300 coactivator dependent mechanism. Finally, transduction of target cells with an adenovirus vector encoding the thymidine kinase gene under transcriptional control of the Rad51 core promoter resulted in efficient killing of p53 defective cancer cells, but not of normal cells, upon addition of ganciclovir.

CONCLUSIONS/SIGNIFICANCE:

Overall, these experiments demonstrated that a small core domain of the Rad51 promoter can be used to target selective transgene expression from adenoviral vectors to tumor cells lacking functional p53.

PMID:
22174876
PMCID:
PMC3235156
DOI:
10.1371/journal.pone.0028714
[Indexed for MEDLINE]
Free PMC Article

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