JNK signalling modulates intestinal homeostasis and tumourigenesis in mice.
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/beta-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.
Sancho
Rocio
R
Mammalian Genetics Laboratory, CRUK London Research Institute, Lincoln's Inn Fields Laboratories, London, UK.
Nateri
Abdolrahman S
AS
de Vinuesa
Amaya Garcia
AG
Aguilera
Cristina
C
Nye
Emma
E
Spencer-Dene
Bradley
B
Behrens
Axel
A
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002277:Carcinoma / Q000503:physiopathology*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic; D007422:Intestines / Q000166:cytology / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D051820:TCF Transcription Factors / Q000235:genetics; D000073940:Transcription Factor 4; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D009419:Nerve Tissue Proteins; D016755:Proto-Oncogene Proteins c-jun; D051820:TCF Transcription Factors; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D018808:Transcription Factor AP-1; D051153:Wnt Proteins; D048031:JNK Mitogen-Activated Protein Kinases