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

Nature. 2005 Sep 8;437(7056):281-5. doi: 10.1038/nature03914. Epub 2005 Jul 10.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Adenomatous Polyposis Coli Protein
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins c-jun
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Tcf7l2 protein, mouse
  • Trans-Activators
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • JNK Mitogen-Activated Protein Kinases