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A Mammalian Two-Hybrid System for Adenomatous Polyposis Coli-Mutated Colon Cancer Therapeutics¹

Cancer Research Institute, University of California, San Francisco, School of Medicine, San Francisco, California 94143-0128 [K. W., O. T., F. M.], and Daiichi Pharmaceutical Co. Ltd., New Product Research Laboratories III, Tokyo 134-8630, Japan [K. W.]

Colon cancer cells frequently lose expression of the tumor suppressor adenomatous polyposis coli (APC). As result, ß-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/ß-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/ß-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/ß-catenin and intact ß-catenin levels and inhibited reporter gene expression. In colon cancer cells such as SW48 that have wild-type APC, GAL4/ß-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.

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