Nam Yunsun, Sliz Piotr, Pear Warren S, Aster Jon C, Blacklow Stephen C
Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2103-8. doi: 10.1073/pnas.0611092104. Epub 2007 Feb 6.
Notch receptors control differentiation and contribute to pathologic states such as cancer by interacting directly with a transcription factor called CSL (for CBF-1/Suppressor of Hairless/Lag-1) to induce expression of target genes. A number of Notch-regulated targets, including genes of the hairy/enhancer-of-split family in organisms ranging from Drosophila to humans, are characterized by paired CSL-binding sites in a characteristic head-to-head arrangement. Using a combination of structural and molecular approaches, we establish here that cooperative formation of dimeric Notch transcription complexes on promoters with paired sites is required to activate transcription. Our findings identify a mechanistic step that can account for the exquisite sensitivity of Notch target genes to variation in signal strength and developmental context, enable new strategies for sensitive and reliable identification of Notch target genes, and lay the groundwork for the development of Notch pathway inhibitors that are active on target genes containing paired sites.
Notch受体通过与一种名为CSL（CBF-1/无毛抑制因子/Lag-1）的转录因子直接相互作用来诱导靶基因表达，从而控制细胞分化并导致癌症等病理状态。许多Notch调控的靶基因，包括从果蝇到人类等生物中毛状/分裂增强子家族的基因，其特征是在典型的头对头排列中有成对的CSL结合位点。我们通过结构和分子方法相结合，在此确定在具有成对位点的启动子上形成二聚体Notch转录复合物的协同作用是激活转录所必需的。我们的研究结果确定了一个机制步骤，该步骤可以解释Notch靶基因对信号强度和发育环境变化的高度敏感性，为灵敏可靠地鉴定Notch靶基因提供了新策略，并为开发对含有成对位点的靶基因有活性的Notch信号通路抑制剂奠定了基础。
