title: c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex.
abstract: 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.
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Aguilera
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Rocio
authors.initials: R
authors.lastname: Sancho
authors.forename: Atanu
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Brian
authors.initials: B
authors.lastname: Hendrich
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
mesh_terms: D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C493597:Lgr5 protein, mouse; C492013:Mbd3 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex