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Cancer Res. 2001 Feb 1;61(3):854-8.

A mammalian two-hybrid system for adenomatous polyposis coli-mutated colon cancer therapeutics.

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  • 1Cancer Research Institute, University of California, San Francisco, School of Medicine, 94143-0128, USA.

Abstract

Colon cancer cells frequently lose expression of the tumor suppressor adenomatous polyposis coli (APC). As result, beta-catenin accumulates and activates transcription of Tcf-responsive genes. Here we describe a novel mammalian two-hybrid system that selectively kills APC-mutated cells. This system consists of GAL4/beta-catenin, VP16/Tcf4, and a gene that is transcribed when GAL4 and VP16 associate. In APC-mutated human colon cancer cells, such as SW480, GAL4/beta-catenin accumulates, and in the presence of VP16/Tcf4, induces high levels of expression of the reporter gene. Expression of wild-type APC reduced GAL4/beta-catenin and intact beta-catenin levels and inhibited reporter gene expression. In colon cancer cells such as SW48 that have wild-type APC, GAL4/beta-catenin was degraded, and expression levels of the output gene were low. Replacement of the reporter gene with a suicide gene resulted in selective killing of SW480 cells. This system may be applicable for broader use of gene therapy by targeting diseases that involve protein degradation.

PMID:
11221869
[PubMed - indexed for MEDLINE]
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