title: Studies on human colon cancer gene APC by targeted expression in Drosophila.
abstract: Mutations in human Adenomatous Polyposis Coli (APC) gene are associated with both familial and sporadic colorectal tumors. APC is known to down regulate beta-catenin levels, a transducer of Wnt signaling. The aim of this study is to provide transgenic Drosophila expressing either full-length or truncated forms of human APC (hAPC) protein and methods for using them in functional genomics and drug screening. Consistent with its biochemical properties, targeted expression of either full-length hAPC or its beta-catenin binding domain alone negatively regulated the function of the beta-catenin homologue, Armadillo (Arm) and thereby, inhibited Wnt/Wg signaling during fly development. hAPC inhibited Arm function even in the absence of GSK-3beta activity, although the latter was required to mediate the degradation of Arm. Consistent with this, hAPC suppressed the phenotypes induced by the over-expression of degradation-resistant forms of Arm. Subsequently, using hAPC-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 enhanced hAPC-induced phenotypes.
authors.affiliation: Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, India 500 007.
authors.forename: P
authors.initials: P
authors.lastname: Bhandari
authors.forename: L S
authors.initials: LS
authors.lastname: Shashidhara
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology; D051186:Armadillo Domain Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000502:physiology; D004330:Drosophila / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins; D004354:Drug Screening Assays, Antitumor; D005123:Eye / Q000033:anatomy & histology / Q000196:embryology / Q000648:ultrastructure; D018390:Gene Targeting; D017491:Genes, APC; D017344:Genes, Insect; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D019476:Insect Proteins / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology; D015534:Trans-Activators; D014157:Transcription Factors; D014162:Transfection; D051155:Wnt1 Protein; D051176:beta Catenin
chemical_list: C495305:ARM protein, Drosophila; D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; D051186:Armadillo Domain Proteins; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051155:Wnt1 Protein; D051176:beta Catenin; C074622:wg protein, Drosophila; D017346:Protein Serine-Threonine Kinases; C080335:Sgg protein, Drosophila; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D007213:Indomethacin