Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 437, pages 281–285 (2005)Cite this article

Abstract

The proto-oncoprotein c-Jun is a component of the AP-1 transcription factor, the activity of which is augmented in many tumour types1. 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)2. 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 cancer6, genetic abrogation of c-Jun N-terminal phosphorylation3 or gut-specific conditional c-jun inactivation4,5 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TCF4 interacts with phosphorylated c-Jun.
Figure 2: JNK-dependent interaction between c-Jun and TCF4 regulates the c- jun promoter.
Figure 3: Absence of c-Jun N-terminal phosphorylation attenuates intestinal cancer development in Apc Min mice.
Figure 4: c-Jun is required for intestinal cancer development in Apc Min/+ mice.

Similar content being viewed by others

References

  1. Eferl, R. & Wagner, E. F. AP-1: a double-edged sword in tumorigenesis. Nature Rev. Cancer 3, 859–868 (2003)

    Article  CAS  Google Scholar 

  2. Davis, R. J. Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252 (2000)

    Article  CAS  Google Scholar 

  3. Behrens, A., Sibilia, M. & Wagner, E. F. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nature Genet. 21, 326–329 (1999)

    Article  CAS  Google Scholar 

  4. Behrens, A. et al. Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J. 21, 1782–1790 (2002)

    Article  CAS  Google Scholar 

  5. el Marjou, F. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186–193 (2004)

    Article  CAS  Google Scholar 

  6. Moser, A. R. et al. ApcMin, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias. Proc. Natl Acad. Sci. USA 90, 8977–8981 (1993)

    Article  ADS  CAS  Google Scholar 

  7. Giles, R. H., van Es, J. H. & Clevers, H. Caught up in a Wnt storm: Wnt signalling in cancer. Biochim. Biophys. Acta 1653, 1–24 (2003)

    CAS  PubMed  Google Scholar 

  8. Fodde, R. The APC gene in colorectal cancer. Eur. J. Cancer 38, 867–871 (2002)

    Article  CAS  Google Scholar 

  9. Veeman, M. T., Axelrod, J. D. & Moon, R. T. A second canon. Functions and mechanisms of β-catenin-independent Wnt signalling. Dev. Cell 5, 367–377 (2003)

    Article  CAS  Google Scholar 

  10. Angel, P., Hattori, K., Smeal, T. & Karin, M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP1. Cell 55, 875–885 (1988)

    Article  CAS  Google Scholar 

  11. Behrens, A., Jochum, W., Sibilia, M. & Wagner, E. F. Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation. Oncogene 19, 2657–2663 (2000)

    Article  CAS  Google Scholar 

  12. Nateri, A. S., Riera-Sans, L., Da Costa, C. & Behrens, A. The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signalling. Science 303, 1374–1378 (2004)

    Article  ADS  CAS  Google Scholar 

  13. Stein, B. et al. Ultraviolet-radiation induced c-jun gene transcription: two AP-1 like binding sites mediate the response. Photochem. Photobiol. 55, 409–415 (1992)

    Article  CAS  Google Scholar 

  14. Staal, F. J. et al. Wnt target genes identified by DNA microarrays in immature CD34 + thymocytes regulate proliferation and cell adhesion. J. Immunol. 172, 1099–1108 (2004)

    Article  CAS  Google Scholar 

  15. Mann, B. et al. Target genes of β-catenin-T cell-factor/lymphoid-enhancer-factor signalling in human colorectal carcinomas. Proc. Natl Acad. Sci. USA 96, 1603–1608 (1999)

    Article  ADS  CAS  Google Scholar 

  16. He, T. C. et al. Identification of c-MYC as a target of the APC pathway. Science 281, 1509–1512 (1998)

    Article  ADS  CAS  Google Scholar 

  17. Wada, T. et al. MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nature Cell Biol. 6, 215–226 (2004)

    Article  CAS  Google Scholar 

  18. Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999)

    Article  ADS  CAS  Google Scholar 

  19. Raivich, G. et al. The AP-1 transcription factor c-Jun is required for efficient axonal regeneration. Neuron 43, 57–67 (2004)

    Article  CAS  Google Scholar 

  20. Wielenga, V. J. et al. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am. J. Pathol. 154, 515–523 (1999)

    Article  CAS  Google Scholar 

  21. Sansom, O. J. et al. Loss of Apc in vivo immediately perturbs Wnt signalling, differentiation, and migration. Genes Dev. 18, 1385–1390 (2004)

    Article  CAS  Google Scholar 

  22. Bogoyevitch, M. A., Boehm, I., Oakley, A., Ketterman, A. J. & Barr, R. K. Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential. Biochim. Biophys. Acta 1697, 89–101 (2004)

    Article  CAS  Google Scholar 

  23. Borsello, T. et al. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nature Med 9, 1180–1186 (2003)

    Article  CAS  Google Scholar 

  24. Alberts, A. S., Geneste, O. & Treisman, R. Activation of SRF-regulated chromosomal templates by Rho-family GTPases requires a signal that also induces H4 hyperacetylation. Cell 92, 475–487 (1998)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank T. Akiyama, K. Niemann, G. Peters and F. Watt for providing essential reagents. We are grateful to A. Gilkar, W. Jochum, E. Nye and G. Stamp for technical help and advice on histology. We thank K. Sabapathy, I. Tomlinson and R. Treisman for critical reading of the manuscript. The London Research Institute is funded by CR UK.

Author information

Authors and Affiliations

  1. Mammalian Genetics Laboratory,

    Abdolrahman S. Nateri & Axel Behrens

  2. Experimental Pathology Laboratory, CR UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, WC2A 3PX, London, UK

    Bradley Spencer-Dene

  3. Department of Histopathology, Imperial College, London, UK

    Bradley Spencer-Dene

Authors
  1. Abdolrahman S. Nateri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bradley Spencer-Dene
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Axel Behrens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Axel Behrens.

Ethics declarations

Competing interests

A.S.N. and A.B. are named as inventors on a patent application proposing inhibition of the c-Jun–TCF4 interaction as a therapeutic strategy for intestinal neoplastic disease.

Supplementary information

Supplementary Figures S1-S7

This file contains seven Supplementary Figures. Supplementary Figure S1: Determination of the c-Jun phosphorylation sites required for TCF4 binding. Supplementary Figure S2: Comparable expression of c-Jun and c-Jun4A in HCT 116 cells. Supplementary Figure S3: Nuclear β-catenin protein levels in several cell lines. Supplementary Figure S4: Luciferase assays showing cooperative activation of the c-jun promoter by c-Jun/TCF4 in HCT 116 colon cancer cells, but not NIH3T3 fibroblasts. Supplementary Figure S5: Luciferase assays showing cooperative activation of the c-jun promoter by c-Jun/TCF4 in SW480 colon cancer cells. Supplementary Figure S6: Quantification of tumor number in ApcMin/+;c-jun+/+, ApcMin/+; junAA/+ and ApcMin/+; junAA/AA mice. Supplementary Figure S7: Decreased BrdU incorporation in ApcMin/+; junAA/AA adenomas. The file also includes legends to accompany the above Supplementary Figures. (PDF 636 kb)

Supplementary Methods

Additional information on methods used in this study. (PDF 61 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03914

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing