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MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm

Abstract

The mutated in colorectal cancer (MCC) is a multifunctional gene showing loss of expression in colorectal and liver cancers. MCC mutations can drive colon carcinogenesis in the mouse and in vitro experiments suggest that loss of MCC function promotes cancer through several important cellular pathways. In particular, the MCC protein is known to regulate beta-catenin (beta-cat) signaling, but the mechanism is poorly understood. Here we show that the beta-cat repressor function of MCC is strongly impaired by the presence of a disease-associated mutation. We also identify deleted in breast cancer 1 (DBC1) as a new MCC interacting partner and regulator of beta-cat signaling. RNA interference experiments show that DBC1 promotes beta-cat transcriptional activity and that the presence of DBC1 is required for MCC-mediated beta-cat repression. In contrast to all other DBC1 interacting partners, MCC does not interact through the DBC1 Leucine Zipper domain but with a glutamic-acid rich region located between the Nudix and EF-hand domains. Furthermore, MCC overexpression relocalizes DBC1 from the nucleus to the cytoplasm and reduces beta-cat K49 acetylation. Treatment of cells with the SIRT1 inhibitor Nicotinamide reverses MCC-induced deacetylation of beta-cat K49. These data suggest that the cytoplasmic MCC-DBC1 interaction sequesters DBC1 away from the nucleus, thereby removing a brake on DBC1 nuclear targets, such as SIRT1. This study provides new mechanistic insights into the DBC1-MCC axis as a new APC independent beta-cat inhibitory pathway.

Type Journal
ISBN 1097-0215 (Electronic) 0020-7136 (Linking)
Authors Pangon, L.; Mladenova, D.; Watkins, L.; Van Kralingen, C.; Currey, N.; Al-Sohaily, S.; Lecine, P.; Borg, J. P.; Kohonen-Corish, M. R.;
Garvan Authors Dr Dessislava Mladenova , Dr Laurent Pangon , A/Prof Maija Kohonen-Corish , Nicola Currey , Dr Sam Al-Sohaily
Publisher Name INT J CANCER
Published Date 2015-01-01 00:00:00
Published Volume 136
Published Pages 55-64
URL http://www.ncbi.nlm.nih.gov/pubmed/24824780
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12420_12923/Pangon 2015 ijc28967.pdf