Skip to main content

Thank you for visiting 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.

c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex


AP-1 (activator protein 1) activity is strongly induced in response to numerous signals, including growth factors, cytokines and extracellular stresses1. The proto-oncoprotein c-Jun belongs to the AP-1 group of transcription factors and it is a crucial regulator of intestinal progenitor proliferation and tumorigenesis2,3,4. An important mechanism of AP-1 stimulation is phosphorylation of c-Jun by the Jun amino-terminal kinases (JNKs)1. N-terminal phosphorylation of the c-Jun transactivation domain increases target gene transcription5,6, but a molecular explanation was elusive. Here we show that unphosphorylated, but not N-terminally phosphorylated c-Jun, interacts with Mbd3 and thereby recruits the nucleosome remodelling and histone deacetylation (NuRD) repressor complex. Mbd3 depletion in colon cancer cells increased histone acetylation at AP-1-dependent promoters, which resulted in increased target gene expression. The intestinal stem cell marker lgr5 was identified as a novel target gene controlled by c-Jun/Mbd3. Gut-specific conditional deletion of mbd3 (mbd3ΔG/ΔG mice) stimulated c-Jun activity and increased progenitor cell proliferation. In response to inflammation, mdb3 deficiency resulted in colonic hyperproliferation and mbd3ΔG/ΔG mice showed markedly increased susceptibility to colitis-induced tumorigenesis. Notably, concomitant inactivation of a single allele of c-jun reverted physiological and pathological hyperproliferation, as well as the increased tumorigenesis in mbd3ΔG/ΔG mice. Thus the transactivation domain of c-Jun recruits Mbd3/NuRD to AP-1 target genes to mediate gene repression, and this repression is relieved by JNK-mediated c-Jun N-terminal phosphorylation.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Mbd3 interacts with unphosphorylated c-Jun through its MBD.
Figure 2: Mbd3 represses c-jun transcription.
Figure 3: lgr5 is regulated by c-Jun-Mbd3/NuRD.
Figure 4: Mbd3 antagonises c-Jun/AP-1 function in vivo.


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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  3. Sancho, R. et al. JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. EMBO J . 28, 1843–1854 (2009)

    CAS  Article  Google Scholar 

  4. Nateri, A. S., Spencer-Dene, B. & Behrens, A. Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 437, 281–285 (2005)

    ADS  CAS  Article  Google Scholar 

  5. Pulverer, B. J., Kyriakis, J. M., Avruch, J., Nikolakaki, E. & Woodgett, J. R. Phosphorylation of c-jun mediated by MAP kinases. Nature 353, 670–674 (1991)

    ADS  CAS  Article  Google Scholar 

  6. 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)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  8. Le Guezennec, X. et al. MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol. Cell. Biol. 26, 843–851 (2006)

    CAS  Article  Google Scholar 

  9. Denslow, S. A. & Wade, P. A. The human Mi-2/NuRD complex and gene regulation. Oncogene 26, 5433–5438 (2007)

    CAS  Article  Google Scholar 

  10. Ahringer, J. NuRD and SIN3 histone deacetylase complexes in development. Trends Genet. 16, 351–356 (2000)

    CAS  Article  Google Scholar 

  11. Bowen, N. J., Fujita, N., Kajita, M. & Wade, P. A. Mi-2/NuRD: multiple complexes for many purposes. Biochim. Biophys. Acta 1677, 52–57 (2004)

    CAS  Article  Google Scholar 

  12. Saito, M. & Ishikawa, F. The mCpG-binding domain of human MBD3 does not bind to mCpG but interacts with NuRD/Mi2 components HDAC1 and MTA2. J. Biol. Chem. 277, 35434–35439 (2002)

    CAS  Article  Google Scholar 

  13. Hendrich, B. & Tweedie, S. The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet. 19, 269–277 (2003)

    CAS  Article  Google Scholar 

  14. D'Orazio, D. et al. Cooperation of two PEA3/AP1 sites in uPA gene induction by TPA and FGF-2. Gene 201, 179–187 (1997)

    CAS  Article  Google Scholar 

  15. Angel, P., Hattori, K., Smeal, T. & Karin, M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell 55, 875–885 (1988)

    CAS  Article  Google Scholar 

  16. Clayton, A. L., Rose, S., Barratt, M. J. & Mahadevan, L. C. Phosphoacetylation of histone H3 on c-fos- and c-jun-associated nucleosomes upon gene activation. EMBO J. 19, 3714–3726 (2000)

    CAS  Article  Google Scholar 

  17. Hendrich, B., Guy, J., Ramsahoye, B., Wilson, V. A. & Bird, A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 15, 710–723 (2001)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  19. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5 . Nature 449, 1003–1007 (2007)

    ADS  CAS  Article  Google Scholar 

  20. van der Flier, L. G. et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136, 903–912 (2009)

    CAS  Article  Google Scholar 

  21. Kaji, K. et al. The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nature Cell Biol. 8, 285–292 (2006)

    CAS  Article  Google Scholar 

  22. Kaji, K., Nichols, J. & Hendrich, B. Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development 134, 1123–1132 (2007)

    CAS  Article  Google Scholar 

  23. Baichwal, V. R., Park, A. & Tjian, R. The cell-type-specific activator region of c-Jun juxtaposes constitutive and negatively regulated domains. Genes Dev. 6, 1493–1502 (1992)

    CAS  Article  Google Scholar 

  24. Weiss, C. et al. JNK phosphorylation relieves HDAC3-dependent suppression of the transcriptional activity of c-Jun. EMBO J. 22, 3686–3695 (2003)

    CAS  Article  Google Scholar 

  25. Arias, J. et al. Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature 370, 226–229 (1994)

    ADS  CAS  Article  Google Scholar 

  26. Nelson, J. D., Denisenko, O. & Bomsztyk, K. Protocol for the fast chromatin immunoprecipitation (ChIP) method. Nature Protocols 1, 179–185 (2006)

    CAS  Article  Google Scholar 

  27. Neufert, C., Becker, C. & Neurath, M. F. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nature Protocols 2, 1998–2004 (2007)

    CAS  Article  Google Scholar 

  28. Floer, M. et al. Enoxaparin improves the course of dextran sodium sulfate-induced colitis in syndecan-1-deficient mice. Am. J. Pathol. 176, 146–157 (2010)

    CAS  Article  Google Scholar 

Download references


We are grateful to the LRI Animal Unit, Equipment Park, FACS, Peptide synthesis and the Experimental Histopathology unit for technical help and O. S. Gabrielsen for reagents. We thank C. Hill and H. Van Dam for critical reading of the manuscript. C.A. and R.S. were funded by Marie Curie Intraeuropean Fellowships (PIEF-GA-2008-220566 and MEIF-CT-2006-041119). The London Research Institute is funded by Cancer Research UK.

Author information

Authors and Affiliations



C.A. designed and performed most of the experiments, analysed data, and co-wrote the paper. K.N. identified Mbd3 as binding specifically to unphosphorylated c-Jun using the yeast three-hybrid screen, generated reagents and provided Fig. 1a, c and Supplementary Fig. 3. R.S. helped with all in vivo experiments and provided Fig. 3a and Supplementary Fig. 7a. A.C. provided Fig. 1f–i. B.H. generated the mbd3 floxed mouse line. A.B. supervised all aspects of this work and wrote the paper.

Corresponding author

Correspondence to Axel Behrens.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-9 with legends. (PDF 4889 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Aguilera, C., Nakagawa, K., Sancho, R. et al. c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature 469, 231–235 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


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.


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