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JNK signalling modulates intestinal homeostasis and tumourigenesis in mice
Author(s) -
Sancho Rocio,
Nateri Abdolrahman S,
de Vinuesa Amaya Garcia,
Aguilera Cristina,
Nye Emma,
SpencerDene Bradley,
Behrens Axel
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.153
Subject(s) - biology , homeostasis , microbiology and biotechnology , signalling , signal transduction , cancer research
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.