期刊
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
卷 55, 期 -, 页码 79-86出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2014.08.010
关键词
Adenomatous polyposis coli; Tumor-associated N-terminal APC fragments; Primary cilia; Ciliogenesis; Gardner's syndrome
资金
- National Natural Sciences Foundation of China [31271516, 21207084]
- Research Fund for the Doctoral Program of Higher Education of China [20111401110011]
- China Postdoctoral Science Foundation [2012M521178]
- Natural Sciences Foundation of Shanxi [2014011027-5]
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 beta-catenin/PI3K/AKTIGSK-3 beta feedback signal cascade is responsible for causing N-terminal APC fragment-induced cilia defects. In this cascade, dysfunctions of both p-catenin and GSK-3 beta 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. (C) 2014 Elsevier Ltd. All rights reserved.
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