Journal Article

PreJuSER-2105

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mechanical factors activate ß-catenin-dependent oncogene expression in APC1638N/+ mouse colon

Whitehead, J. ; Vignjevic, D. ; Fütterer, C.FZJ* ; Beaurepaire, E. ; Robine, S. ; Farge, E.

2008
HFSP Publishing, PubMed Central HFSP Publishing

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Please use a persistent id in citations: doi:10.2976/1.2955566

Abstract: beta-catenin acts as a critical regulator of gastrointestinal homeostasis through its control of the Wnt signaling pathway, and genetic or epigenetic lesions which activate Wnt signaling are the primary feature of colon cancer. beta-catenin is also a key element of mechanotranscription pathways, leading to upregulation of master developmental gene expression during Drosophila gastrulation, or regulating mammalian bone development and maintenance. Here we investigate the impact of mechanical stimulation on the initiation of colon cancer. Myc and Twist1, two oncogenes regulated through beta-catenin, are expressed in response to transient compression in APC deficient (APC(1638N+)) colon tissue explants, but not in wild-type colon explants. Mechanical stimulation of APC(1638N+) tissue leads to the phosphorylation of beta-catenin at tyrosine 654, the site of interaction with E-cadherin, as well as to increased nuclear localization of beta-catenin. The mechanical activation of Myc and Twist1 expression in APC(1638N+) colon can be prevented by blocking beta-catenin phosphorylation using Src kinase inhibitors. Microenvironmental signals are known to cooperate with genetic lesions to promote the nuclear beta-catenin accumulation which drives colon cancer. Here we demonstrate that when APC is limiting, mechanical strain, such as that associated with intestinal transit or tumor growth, can be interpreted by cells of preneoplastic colon tissue as a signal to initiate a beta-catenin dependent transcriptional program characteristic of cancer.

Keyword(s): J

Note: JW was supported by a French Ministry of Education & Research fellowship and a Marie Curie Intra-European fellowship. This work was supported by grants from ARC (3536), INSERM (ITS2005), HSFP (RGP0014/2006-C) and Equipe Labellisee La Ligue (EL2008. LNCC/SR1). JW carried out the experimental work and imaging, and prepared the manuscript; DJ aided in tissue preparation; CF designed the apparatus; SR provided mice; EB carried out the 2PEF microscopy; EF initiated the project. JW & EF analyzed the data, and all authors contributed to project planning and manuscript preparation. Thanks to Francois Waharte (Cell and Tissue Imaging Facility, UMR144 CNRS/Institut Curie) for confocal imaging assistance, to Jacques Prost and Padra Ahmadi (UMR168 CNRS/Institut Curie) for experimental advice, and to Olivier Delattre, Xavier Sastre, Daniel Louvard, and members of the Robine lab for helpful discussions.

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Contributing Institute(s):

1. Zelluläre Biophysik (INB-1)

Research Program(s):

1. Funktion und Dysfunktion des Nervensystems (P33)

Appears in the scientific report 2008

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