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.
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Authors | Li Song, Yuxin Jia, Wensi Zhu, Ian P Newton, Zhuoyu Li, Wenling Li |
Journal | The international journal of biochemistry & cell biology
(Int J Biochem Cell Biol)
Vol. 55
Pg. 79-86
(Oct 2014)
ISSN: 1878-5875 [Electronic] Netherlands |
PMID | 25150829
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 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
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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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