HERP, a new primary target of notch regulated by ligand binding

作     者：Iso, T Sartorelli, V Chung, G Shichinohe, T Kedes, L Hamamori, Y 

作者机构：Univ So Calif Keck Sch Med Inst Med Genet Los Angeles CA 90089 USA Univ So Calif Keck Sch Med Dept Biochem & Mol Biol Los Angeles CA 90089 USA Univ So Calif Keck Sch Med Dept Pathol Los Angeles CA 90089 USA Univ So Calif Keck Sch Med Dept Med Los Angeles CA 90089 USA NIAMS Muscle Biol Lab Muscle Gene Express Grp IRPNIH Bethesda MD 20892 USA 

出 版 物：《MOLECULAR AND CELLULAR BIOLOGY》 (分子生物学与细胞生物学)

年 卷 期：2001年第21卷第17期

页      面：6071-6079页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

主　　题：.Notch Signaling Basic helix-loop-helix NICD Notch Receptor primary target regulated intramembrane HES spl 

摘      要：Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis in metazoans. Ligand binding initiates the signal through regulated intramembrane proteolysis of a transmembrane Notch receptor which releases the signal-transducing Notch intracellular domain (NICD). The HES/E(spl) gene family is a primary target of Notch and thus far the only known Notch effector. A newly isolated HER-P family, a HES-related basic helix-loop-helix protein family, has been proposed as a potential target of Notch, based on its induction following NICD overexpression. However, NICD is physiologically maintained at an extremely low level that typically escapes detection, and therefore, nonregulated overexpression of NICD-as in transient transfection-has the potential of generating cellular responses of little physiological relevance. Indeed, a constitutively active NICD indiscriminately up-regulates expression of both HERP1 and HERP2 mRNAs. However, physiological Notch stimulation through ligand binding results in the selective induction of HERP2 but not HERP1 mRNA and causes only marginal up-regulation of HES1 mRNA. Importantly, HERP2 is an immediate target gene of Notch signaling since HERP2 mRNA expression is induced even in the absence of de novo protein synthesis. HERP2 mRNA induction is accompanied by specific expression of HERP2 protein in the nucleus. Furthermore, using RBP-jk-deficient cells, we show that an RBP-Jk protein, a transcription factor that directly activates HES/E(spl) transcription, also is essential for HERP2 mRNA expression and that expression of exogenous RBP-jk is sufficient to rescue HERP2 mRNA expression. These data establish that HERP2 is a novel primary target gene of Notch that, together with HES, may effect diverse biological activities of Notch.