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

TY - JOUR

T1 - c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex

AU - Aguilera, Cristina

AU - Nakagawa, Kentaro

AU - Sancho, Rocio

AU - Chakraborty, Atanu

AU - Hendrich, Brian

AU - Behrens, Axel

PY - 2011/1/13

Y1 - 2011/1/13

N2 - AP-1 (activator protein 1) activity is strongly induced in response to numerous signals, including growth factors, cytokines and extracellular stresses. 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 tumorigenesis. An important mechanism of AP-1 stimulation is phosphorylation of c-Jun by the Jun amino-terminal kinases (JNKs). N-terminal phosphorylation of the c-Jun transactivation domain increases target gene transcription, 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 (mbd3(ΔG/ΔG) mice) stimulated c-Jun activity and increased progenitor cell proliferation. In response to inflammation, mdb3 deficiency resulted in colonic hyperproliferation and mbd3(ΔG/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 mbd3(ΔG/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.

AB - AP-1 (activator protein 1) activity is strongly induced in response to numerous signals, including growth factors, cytokines and extracellular stresses. 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 tumorigenesis. An important mechanism of AP-1 stimulation is phosphorylation of c-Jun by the Jun amino-terminal kinases (JNKs). N-terminal phosphorylation of the c-Jun transactivation domain increases target gene transcription, 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 (mbd3(ΔG/ΔG) mice) stimulated c-Jun activity and increased progenitor cell proliferation. In response to inflammation, mdb3 deficiency resulted in colonic hyperproliferation and mbd3(ΔG/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 mbd3(ΔG/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.

KW - Acetylation

KW - Animals

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Colonic Neoplasms

KW - DNA-Binding Proteins

KW - Gene Expression Regulation, Neoplastic

KW - Histones

KW - Intestines

KW - JNK Mitogen-Activated Protein Kinases

KW - Mi-2 Nucleosome Remodeling and Deacetylase Complex

KW - Mice

KW - Phosphorylation

KW - Promoter Regions, Genetic

KW - Protein Binding

KW - Proto-Oncogene Proteins c-jun

KW - Receptors, G-Protein-Coupled

KW - Stem Cells

KW - Transcription Factors

U2 - 10.1038/nature09607

DO - 10.1038/nature09607

M3 - Article

C2 - 21196933

SN - 0028-0836

VL - 469

SP - 231

EP - 235

JO - NATURE

JF - NATURE

IS - 7329

M1 - N/A

ER -