Studies on human colon cancer gene APC by targeted expression in Drosophila

Mutations in human Adenomatous Polyposis Coli (APC) gene are associated wit h both familial and sporadic colorectal tumors. APC is known to down regula te beta -catenin levels, a transducer of Wnt signaling. The aim of this stu dy is to provide transgenic Drosophila expressing either full-length or tru ncated forms of human APC (hAPC) protein and methods for using them in func tional,genomics and drug screening. Consistent with its biochemical propert ies, targeted expression of either full-length hAPC or its beta -catenin bi nding domain alone negatively regulated the function of the beta -catenin h omologue, Armadillo (Arm) and thereby, inhibited Wnt/Wg signaling during fl y development. hAPC inhibited Arm function even in the absence of GSK-3 bet a activity, although the latter was required to mediate the degradation of Arm. Consistent with this, hAPC suppressed the phenotypes induced by the ov er-expression of degradation-resistant forms of Arm. Subsequently, using hA PC-induced eye phenotypes as the assay in a suppressor-enhancer screen, we have identified two new loci in Drosophila, which modulate Wnt/Wg signaling . In addition, an anti-colon cancer drug, indomethacin, specifically enhanc ed hAPC-induced phenotypes.