Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development

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Abstract
A previously unknown link between the molecular pathways involving the transcription factors c-Jun and TCF4 may be important in bowel cancer development. Phosphorylated c-Jun interacts with TCF4 to form a complex that regulates gene promoters responsive to both WNT and JNK signalling. Blocking this interaction in the ApcMin mouse model of intestinal cancer delays tumorigenesis and reduces the number and size of tumours produced. It is particularly interesting that JNK may be a promising strategy to treat colon cancer, as small- molecule JNK inhibitors are already in clinical trials. The proto-oncoprotein c-Jun is a component of the AP-1 transcription factor, the activity of which is augmented in many tumour types1. An important mechanism in the stimulation of AP-1 function is amino-terminal phosphorylation of c-Jun by the c-Jun N-terminal kinases (JNKs)2. Phosphorylated c-Jun is biologically more active, partially because it acquires the ability to interact with binding partners. Here we show that phosphorylated c-Jun interacts with the HMG-box transcription factor TCF4 to form a ternary complex containing c-Jun, TCF4 and β-catenin. Chromatin immunoprecipitation assays revealed JNK-dependent c-Jun–TCF4 interaction on the c-jun promoter, and c-Jun and TCF4 cooperatively activated the c-jun promoter in reporter assays in a β-catenin-dependent manner. In the ApcMin mouse model of intestinal cancer6, genetic abrogation of c-Jun N-terminal phosphorylation3 or gut-specific conditional c-jun inactivation4,5 reduced tumour number and size and prolonged lifespan. Therefore, the phosphorylation-dependent interaction between c-Jun and TCF4 regulates intestinal tumorigenesis by integrating JNK and APC/β-catenin, two distinct pathways activated by WNT signalling.