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

Nateri, Abdolrahman S.; Spencer-Dene, Bradley; Behrens, Axel

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 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 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/β-catenin, two distinct pathways activated by WNT signalling. © 2005 Nature Publishing Group.

Citation

Nateri, A. S., Spencer-Dene, B., & Behrens, A. (2005). Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature, 437(7056), 281-285. https://doi.org/10.1038/nature03914

• Journal Article Type: Article
• Acceptance Date: Jun 14, 2005
• Online Publication Date: Jul 10, 2005
• Publication Date: Sep 8, 2005
• Deposit Date: Sep 11, 2024
• Journal: Nature
• Print ISSN: 0028-0836
• Electronic ISSN: 1476-4687
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 437
• Issue: 7056
• Pages: 281-285
• DOI: https://doi.org/10.1038/nature03914
• Public URL: https://nottingham-repository.worktribe.com/output/39458141
• Publisher URL: https://www.nature.com/articles/nature03914