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

Cristina Aguilera, et al. Nature 469, :231-5 (2011)

Speaker: Wei-Min Hung (洪偉珉)                                 Time: 15:00 ~ 16:00, Sep. 14, 2011

Commentator: Dr. Li-Jin Hsu (徐麗君 老師)                Place: Room 601

Abstract

The proto-oncoprotein c-Jun is a component of the AP-1 transcription factor, which is in response to many signals, including growth factors, cytokines and extracellular stresses¹. The mechanism of c-Jun activation is phosphorylation within its N-terminus by the Jun amino-terminal kinases(JNKs). c-Jun controls numerous cellular processes including cell proliferation, differentiation, survival and apoptosis². c-Jun is a critical regulator, so the authors tried to identify proteins that interact with c-Jun depending on its phosphorylation status. In this study, the authors found that methyl-CpG-binding domain protein 3 (Mbd3) binds to unphosphorylated c-Jun, and Mbd3 thereby recruits the nucleosome remodeling and histone deacetylation (NuRD) repressor complex which mediates gene repression through histone deacetylation at the AP-1 promoter. Deletion of Mbd3 increased histone acetylation and target gene expression. Thus, Mbd3 contributes to the epigenetic regulation of the c-jun promoter. Previous studies have shown that c-Jun has an important function in regulating intestinal epithelial homeostasis and intestinal cancer³. The authors generated a mouse line that specifically inactivate Mbd3 in the gut (mbd3^△G/△G). mbd3 deficiency stimulated c-Jun activity and increased progenitor cell proliferation. mbd3^△G/△G mice were more susceptible to colitis-induced tumorigenesis. But after one c-jun allele was deleted inmbd3^△G/△G mice, the hyper-proliferation phenotype was rescued. Therefore, in the intestine, Mbd3 controls cellular proliferation by antagonizing c-Jun activity. Collectively, the unphosphorylated c-Jun recruits Mbd3/NuRD repressor complex to AP-1 target genes to mediate gene repression, and this interaction is disrupted by JNK-mediated phosphorylation.

References

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

3.    Nateri, A. S., et al. Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 437, 281–285 (2005).