JNK/c-Jun信號(hào)作用通道被發(fā)現(xiàn)與包括神經(jīng)退化、糖尿病和癌癥在內(nèi)的各種不同疾病有關(guān),，而JNK抑制因子則被看作是潛在的治療藥物?，F(xiàn)在激酶JNK激發(fā)c-Jun的機(jī)制已被發(fā)現(xiàn)。c-Jun的“N-端磷酸化”被發(fā)現(xiàn)拮抗c-Jun 與 Mbd3（阻遏因子復(fù)合物NuRD的一個(gè)成分）的相互作用,。c-Jun 與 Mbd3之間的相互作用被發(fā)現(xiàn)在調(diào)控小鼠小腸先祖細(xì)胞的增殖中有重要作用,。（生物谷 Bioon.com）
生物谷推薦原文出處：
Nature doi:10.1038/nature09607
c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex
Cristina Aguilera,Kentaro Nakagawa,Rocio Sancho,Atanu Chakraborty,Brian Hendrich& Axel Behrens
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.
