N-terminal truncation mutations of adenomatous polyposis coli are associated with primary cilia defects

Li Song, Yuxin Jia, Wensi Zhu, Ian P. Newton, Zhuoyu Li (Lead / Corresponding author), Wenling Li

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    2 Citations (Scopus)

    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 ß-catenin/PI3K/AKT/GSK-3ß feedback signal cascade is responsible for causing N-terminal APC fragment-induced cilia defects. In this cascade, dysfunctions of both ß-catenin and GSK-3ß 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.

    Original languageEnglish
    Pages (from-to)79-86
    Number of pages8
    JournalInternational Journal of Biochemistry & Cell Biology
    Volume55
    Early online date21 Aug 2014
    DOIs
    Publication statusPublished - Oct 2014

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