Mechanical factors activate beta-catenin-dependent oncogene expression in APC1638N/+ mouse colon

Abstract : -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. -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 -catenin, are expressed in response to transient compression in APC deficient "APC1638N/+... colon tissue explants, but not in wild-type colon explants. Mechanical stimulation of APC1638N/+ tissue leads to the phosphorylation of -catenin at tyrosine 654, the site of interaction with E-cadherin, as well as to increased nuclear localization of -catenin. The mechanical activation of Myc and Twist1 expression in APC1638N/+ colon can be prevented by blocking -catenin phosphorylation using Src kinase inhibitors. Microenvironmental signals are known to cooperate with genetic lesions to promote the nuclear -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 -catenin dependent transcriptional program characteristic of cancer
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Submitted on : Tuesday, May 28, 2013 - 9:57:01 PM
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J. Whitehead, Danijela Vignjevic, C. Fütterer, Emmanuel Beaurepaire, Sylvie Robine, et al.. Mechanical factors activate beta-catenin-dependent oncogene expression in APC1638N/+ mouse colon. HFSP Journal, 2008, 2 (5), pp.286. ⟨10.2976/1.2955566⟩. ⟨hal-00824412⟩

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