JNK signalling modulates intestinal homeostasis and tumourigenesis in mice

Sancho, Rocio; Nateri, Abdolrahman S.; De Vinuesa, Amaya Garcia; Aguilera, Cristina; Nye, Emma; Spencer-Dene, Bradley; Behrens, Axel

Abstract

Wnt signalling is a crucial signalling pathway controlling intestinal homeostasis and cancer. We show here that the JNK MAP kinase pathway and one of its most important substrates, the AP-1 transcription factor c-Jun, modulates Wnt signalling strength in the intestine. Transgenic gut-specific augmentation of JNK signalling stimulated progenitor cell proliferation and migration, resulting in increased villus length. In the crypt, c-Jun protein was highly expressed in progenitor cells and the absence of c-Jun resulted in decreased proliferation and villus length. In addition to several known c-Jun/AP-1 target genes, expression of Wnt target genes Axin2 and Lgr5 were stimulated by JNK activation, suggesting a cross talk of JNK to Wnt signalling. Expression of the Wnt pathway component TCF4 was controlled by JNK activity, and chromatin immunoprecipitation and reporter assays identified tcf4 as a direct c-Jun target gene. Consequently, increased JNK activity accelerated tumourigenesis in a model of colorectal carcinogenesis. As c-jun is a direct target of the TCF4/Β-catenin complex, the control of tcf4 expression by JNK/c-Jun leads to a positive feedback loop that connects JNK and Wnt signalling. This mechanism regulates the physiological function of progenitor cells and oncogenic transformation. © 2009 European Molecular Biology Organization. All Rights Reserved.

Citation

Sancho, R., Nateri, A. S., De Vinuesa, A. G., Aguilera, C., Nye, E., Spencer-Dene, B., & Behrens, A. (2009). JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. EMBO Journal, 28(13), 1843-1854. https://doi.org/10.1038/emboj.2009.153

• Journal Article Type: Article
• Acceptance Date: May 12, 2009
• Online Publication Date: Jun 11, 2009
• Publication Date: Jul 8, 2009
• Deposit Date: Sep 11, 2024
• Journal: EMBO Journal
• Print ISSN: 0261-4189
• Electronic ISSN: 1460-2075
• Publisher: EMBO Press
• Peer Reviewed: Peer Reviewed
• Volume: 28
• Issue: 13
• Pages: 1843-1854
• DOI: https://doi.org/10.1038/emboj.2009.153
• Public URL: https://nottingham-repository.worktribe.com/output/39458052
• Publisher URL: https://www.embopress.org/doi/full/10.1038/emboj.2009.153