Role of the adenomatous polyposis coli gene product in human cardiac development and disease.
Expressed sequence tag (EST) and digital Northern analyses of human fetal, adult, and hypertrophic heart cDNA libraries revealed ESTs with high homology to adenomatosis polyposis coli (APC) and its associated protein, beta-catenin, as well as their differential expression. Thus, we hypothesize that the APC/beta-catenin pathway may play a role in cardiac development and disease. Reverse transcriptase-polymerase chain reaction analysis exhibited a higher APC expression in adult compared with fetal and hypertrophic heart but no significant difference in beta-catenin mRNA level. However, beta-catenin protein level was higher in fetal and hypertrophic heart compared with adult heart, suggesting the post-translational regulation of beta-catenin by APC in the cardiovascular system. In vitro antisense inhibition of APC resulted a higher beta-catenin protein expression leading to an incomplete myotube formation, suggesting APC/beta-catenin pathway involvement in myotube development. Western blot analysis further reveals three novel isoforms, APC-F, APC-A, and APC-D, ubiquitously expressed in fetal, adult, and hypertrophic heart, respectively. Isoform switching during development and disease pathogenesis suggests functionally distinct roles for each isoform. These data (i) demonstrate the usefulness of genome-based expression analysis for rapid discovery of differentially expressed genes, (ii) implicate the APC/beta-catenin pathway in the cardiovascular development, and (iii) demonstrate APC isoform switching during cardiac development and disease.
Rezvani
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Institute of Medical Sciences, Center for Cardiovascular Research and the Cardiac Gene Unit, The Toronto Hospital, University of Toronto, Toronto, Ontario M5G 1L5, Canada.
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D025601:Adenomatous Polyposis Coli Protein; D000328:Adult; D015152:Blotting, Northern; D015153:Blotting, Western; D006332:Cardiomegaly / Q000209:etiology*; D002454:Cell Differentiation; D002455:Cell Division; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D020224:Expressed Sequence Tags; D006321:Heart / Q000254:growth & development*; D006801:Humans; D009363:Neoplasm Proteins / Q000502:physiology*; D009716:Numerical Analysis, Computer-Assisted; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011499:Protein Processing, Post-Translational; D015534:Trans-Activators; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D015534:Trans-Activators; D051176:beta Catenin