PMID:16007074

Citation	Nateri, AS, Spencer-Dene, B and Behrens, A (2005) Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 437:281-5
Abstract	The proto-oncoprotein c-Jun is a component of the AP-1 transcription factor, the activity of which is augmented in many tumour types. 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). 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 beta-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 beta-catenin-dependent manner. In the Apc(Min) mouse model of intestinal cancer, genetic abrogation of c-Jun N-terminal phosphorylation or gut-specific conditional c-jun inactivation 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/beta-catenin, two distinct pathways activated by WNT signalling.
Links	PubMed Online version:10.1038/nature03914
Keywords	Adenomatous Polyposis Coli Protein/genetics; Adenomatous Polyposis Coli Protein/metabolism; Animals; Cell Line; Cell Line, Tumor; Chromatin Immunoprecipitation; Cytoskeletal Proteins/metabolism; DNA-Binding Proteins/metabolism; Genes, APC; Genes, jun/genetics; Humans; Intercellular Signaling Peptides and Proteins/metabolism; Intestinal Neoplasms/metabolism; Intestinal Neoplasms/pathology; JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases/metabolism; Mice; Mice, Inbred C57BL; NIH 3T3 Cells; Phosphorylation; Promoter Regions, Genetic/genetics; Protein Binding; Proto-Oncogene Proteins c-jun/genetics; Proto-Oncogene Proteins c-jun/metabolism; Signal Transduction; TCF Transcription Factors; Trans-Activators/metabolism; Transcription Factor 7-Like 2 Protein; Transcription Factors/metabolism; Wnt Proteins; beta Catenin
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