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Putative tumor suppressor EDD interacts with and up‐regulates APC
Author(s) -
Ohshima Ryuichi,
Ohta Tomohiko,
Wu Wenwen,
Koike Ayaka,
Iwatani Tsuguo,
Henderson Michelle,
Watts Colin K. W.,
Otsubo Takehito
Publication year - 2007
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2007.01138.x
Subject(s) - adenomatous polyposis coli , biology , wnt signaling pathway , suppressor , axin2 , microbiology and biotechnology , beta catenin , signal transduction , cancer research , gene , genetics , cancer , colorectal cancer
Adenomatous polyposis coli (APC), whose mutation causes colorectal cancers, is a key player in the Wnt signaling pathway. While the role of APC in inhibition of β‐catenin/LEF1‐dependent activation of transformation‐inducing genes has been intensively studied and well established, regulation of APC expression at the protein level is only partially understood. Here we report that APC is up‐regulated by EDD, the mammalian orthologue of Drosophila melanogaster “hyperplastic discs” gene ( hyd ) that is considered to be a putative tumor suppressor. Screening of APC immunocomplexes by mass spectrometry identified EDD as a putative APC‐interacting protein. Exogenously expressed and endogenous APC interacted with EDD in vivo . Indirect immunofluorescent analyses demonstrated that APC and EDD co‐localized in the cytoplasm of the cell. Over‐expression of EDD enhanced the protein expression level of APC and its binding partner Axin, resulting in inhibition of Wnt signaling downstream of β‐catenin. Conversely, siRNA knock‐down of EDD down‐regulated APC at the protein level without altering its mRNA level, causing enhanced protein expression of β‐catenin. Thus, through protein–protein interaction, EDD stabilizes APC and up‐regulates APC's function to inhibit β‐catenin, suggesting that EDD could act as a colorectal tumor suppressor.