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Putative tumor suppressor EDD interacts with and up-regulates APC

Abstract

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 beta-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 beta-catenin. Conversely, siRNA knock-down of EDD down-regulated APC at the protein level without altering its mRNA level, causing enhanced protein expression of beta-catenin. Thus, through protein-protein interaction, EDD stabilizes APC and up-regulates APC's function to inhibit beta-catenin, suggesting that EDD could act as a colorectal tumor suppressor.

Type Journal
ISBN 1356-9597 (Print)
Authors Ohshima, R.; Ohta, T.; Wu, W.; Koike, A.; Iwatani, T.; Henderson, M.; Watts, C. K.; Otsubo, T.:
Publisher Name GENES CELLS
Published Date 2007-10-01 00:00:00
Published Volume 12
Published Issue 12
Published Pages 1339-45
URL http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18076571
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?10099_10852/07 Oshima GC.pdf