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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.
AuthorsLi Song, Yuxin Jia, Wensi Zhu, Ian P Newton, Zhuoyu Li, Wenling Li
JournalThe international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 55 Pg. 79-86 (Oct 2014) ISSN: 1878-5875 [Electronic] Netherlands
PMID25150829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • Adenomatous Polyposis Coli Protein
  • Peptide Fragments
  • beta Catenin
  • Green Fluorescent Proteins
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Histone Deacetylases
Topics
  • Adenomatous Polyposis Coli Protein (chemistry, genetics, metabolism)
  • Animals
  • Blotting, Western
  • Cilia (genetics, metabolism, pathology)
  • Dogs
  • Gene Expression
  • Glycogen Synthase Kinase 3 (metabolism)
  • Glycogen Synthase Kinase 3 beta
  • Green Fluorescent Proteins (genetics, metabolism)
  • Histone Deacetylases (genetics, metabolism)
  • Humans
  • Madin Darby Canine Kidney Cells
  • Mice
  • Microscopy, Confocal
  • Mutation
  • NIH 3T3 Cells
  • Peptide Fragments (genetics, metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • beta Catenin (genetics, metabolism)

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