title: N-terminal truncation mutations of adenomatous polyposis coli are associated with primary cilia defects.
abstract: Adenomatous polyposis coli (APC) gene is a tumor suppressor gene and its truncated mutations cause a few cilia-related diseases such as Gardner's syndrome. However, little is known about the mechanism that links APC mutations and cilia disorder. APC mutations lead to the expression of N-terminal fragments, which have dominant effects in tumors owing to loss of the C-terminal region or a gain of function. The present study investigated the impact of tumor-associated N-terminal APC fragments on primary cilia assembly and the possible molecular mechanism involved. We discovered that expression of tumor-associated N-terminal APC fragments (APC-N, APC-N1, APC-N2, and APC-N3, which contain amino acids 1-1018, 1-448, 449-781, and 782-1018 respectively), resulted in primary cilia defects. We found that a β-catenin/PI3K/AKT/GSK-3β feedback signal cascade is responsible for causing N-terminal APC fragment-induced cilia defects. In this cascade, dysfunctions of both β-catenin and GSK-3β were involved in the up-regulation of HDAC6 and subsequent decreased acetylated tubulin levels, which thereby led to cilia defects. These data suggest a mechanism for linking N-terminal APC fragments and cilia loss, thus accelerating our understanding of human cilia-related diseases such as Gardner's syndrome and their cause due to APC mutations.
authors.affiliation: Institute of Biotechnology, >Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Taiyuan 030006, China; MOE Key Lab of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Song
authors.affiliation: Institute of Biotechnology, >Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Taiyuan 030006, China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Institute of Biotechnology, >Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Taiyuan 030006, China.
authors.forename: Wensi
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Newton
authors.affiliation: Institute of Biotechnology, >Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Taiyuan 030006, China; College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: lzy@sxu.edu.cn.
authors.forename: Zhuoyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Biotechnology, >Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Taiyuan 030006, China.
authors.forename: Wenling
authors.initials: W
authors.lastname: Li
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002923:Cilia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D010446:Peptide Fragments; D051176:beta Catenin; D049452:Green Fluorescent Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases
keywords: Adenomatous polyposis coli; Ciliogenesis; Gardner's syndrome; Primary cilia; Tumor-associated N-terminal APC fragments