Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development.
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.
Mesh Terms:
Adenomatous Polyposis Coli Protein, Animals, Cell Line, Cell Line, Tumor, Chromatin Immunoprecipitation, Cytoskeletal Proteins, DNA-Binding Proteins, Genes, APC, Genes, jun, Humans, Intercellular Signaling Peptides and Proteins, Intestinal Neoplasms, JNK Mitogen-Activated Protein Kinases, Mice, Mice, Inbred C57BL, NIH 3T3 Cells, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-jun, Signal Transduction, TCF Transcription Factors, Trans-Activators, Transcription Factor 7-Like 2 Protein, Transcription Factors, Wnt Proteins, beta Catenin
Adenomatous Polyposis Coli Protein, Animals, Cell Line, Cell Line, Tumor, Chromatin Immunoprecipitation, Cytoskeletal Proteins, DNA-Binding Proteins, Genes, APC, Genes, jun, Humans, Intercellular Signaling Peptides and Proteins, Intestinal Neoplasms, JNK Mitogen-Activated Protein Kinases, Mice, Mice, Inbred C57BL, NIH 3T3 Cells, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-jun, Signal Transduction, TCF Transcription Factors, Trans-Activators, Transcription Factor 7-Like 2 Protein, Transcription Factors, Wnt Proteins, beta Catenin
Nature
Date: Sep. 08, 2005
PubMed ID: 16007074
View in: Pubmed Google Scholar
Download Curated Data For This Publication
111574
Switch View:
- Interactions 4