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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli Protein / genetics
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Adenomatous Polyposis Coli Protein / metabolism
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Animals
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Cell Line
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Cell Line, Tumor
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Chromatin Immunoprecipitation
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Cytoskeletal Proteins / metabolism
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DNA-Binding Proteins / metabolism*
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Genes, APC
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Genes, jun / genetics
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Intestinal Neoplasms / metabolism*
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Intestinal Neoplasms / pathology*
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mice
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Mice, Inbred C57BL
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NIH 3T3 Cells
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Phosphorylation
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Promoter Regions, Genetic / genetics
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Protein Binding
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism*
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Signal Transduction
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TCF Transcription Factors
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Trans-Activators / metabolism
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Transcription Factor 7-Like 2 Protein
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Transcription Factors / metabolism*
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Wnt Proteins
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beta Catenin
Substances
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Adenomatous Polyposis Coli Protein
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins c-jun
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TCF Transcription Factors
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TCF7L2 protein, human
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Tcf7l2 protein, mouse
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Trans-Activators
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
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Wnt Proteins
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beta Catenin
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JNK Mitogen-Activated Protein Kinases