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- Title
JNK signalling modulates intestinal homeostasis and tumourigenesis in mice.
- Authors
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.
- Subjects
COLON cancer; STEM cells; HOMEOSTASIS; INTESTINAL cancer; TRANSCRIPTION factors; CELLULAR signal transduction; NUCLEOPROTEINS
- Publication
EMBO Journal, 2009, Vol 28, Issue 13, p1843
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/emboj.2009.153