Article
- The EMBO Journal (2009) 28, 1843 - 1854
- doi:10.1038/emboj.2009.153
Published online: 11 June 2009
Subject Categories:
JNK signalling modulates intestinal homeostasis and tumourigenesis in mice
Rocio Sancho1,a, Abdolrahman S Nateri1,2,a, Amaya Garcia de Vinuesa3, Cristina Aguilera1, Emma Nye4, Bradley Spencer-Dene4,5 and Axel Behrens1
- Mammalian Genetics Laboratory, CRUK London Research Institute, Lincoln's Inn Fields Laboratories, London, UK
- Cancer Genetics Lab, Wolfson Digestive Diseases Centre, School of Medical and Surgical Sciences, Nottingham, UK
- Departamento de Biologia Celular, Fisiologia e Inmunologia, Universidad de Cordoba, Cordoba, Spain
- Experimental Pathology Laboratory, CRUK London Research Institute, Lincoln's Inn Fields Laboratories, London, UK
- Department of Histopathology, Imperial College, London, UK
Correspondence to:
Axel Behrens, Mammalian Genetics Laboratory, Cancer Reasearch UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44, Lincoln's Inn Fields, London WC2A 3PX, UK. Tel.: 44 207 269 3361; Fax: 44 207 269 3581; E-mail: axel.behrens@cancer.org.uk
aThese authors contributed equally to this work
Received 2 March 2009; Accepted 12 May 2009
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/
-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.
Keywords:
- c-Jun,
- colon cancer,
- intestinal stem cell,
- JNK,
- TCF4
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