Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Notch signaling is involved in many cell fate determination events in metazoans. Ligand binding results in proteolytic cleavage to release the signal-transducing Notch intracellular domain (NICD). The nuclear protein RBP-J kappa, when complexed with NICD, acts as a transcriptional activator which, in turn, induces a target gene of Notch such as the repressors HES/E(spl) and HERP2. Under physiological stimulation using co-culture with Notch ligand-expressing cells and target cells expressing Notch receptors, the HES1 gene and the HERP2 gene have been shown to be directly up-regulated by Notch ligand binding. However, expression of another member of the HERP family, HERP1, was not induced by ligand stimulation in any cells tested, leading to the suggestion that HERP1 may not be an immediate target of Notch or that Notch pathways can be cell type-specific. Because HERP1 appears to play a central role in the development of the aorta (Zhong, T. P., Rosenberg, M., Mohideen, M. A., Weinstein, B., and Fishman, M. C. (2000) Science 287, 1820-1824), we re-addressed the issue of its relationship with the Notch pathway by examining its expression in A10 smooth muscle cells derived from thoracic aorta. We show that in these specific cells HERP1 is also a direct target gene of Notch. NICD activates the HERP1 promoter in an RBP-J kappa-dependent manner, and induces expression of endogenous HERP1 mRNA as well as HERP1 protein in A10 cells. Co-culture with Notch ligand-bearing cells induces endogenous HERP1 mRNA expression in A10 cells, and these events occur even in the absence of de novo protein synthesis. In addition, RBP-J kappa proved essential for induction of HERP1 mRNA in Notch signaling because exogenous RBP-J kappa was sufficient to rescue HERP1 mRNA expression in RBP-J kappa-deficient cells. These findings provide the first solid evidence that HERP1 is a novel primary target of Notch and underscores the cell-specific complexity of the Notch regulatory pathway. Given that Notch signaling plays a crucial role in vascular development, Notch may derive its function via HERP family members.
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PMID:HERP1 is a cell type-specific primary target of Notch. 1174 89

Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis in metazoans. Multiple factors at each step-ligands, receptors, signal transducers and effectors-play critical roles in executing the pleiotropic effects of Notch signaling. Ligand-binding results in proteolytic cleavage of Notch receptors to release the signal-transducing Notch intracellular domain (NICD). NICD migrates into the nucleus and associates with the nuclear proteins of the RBP-Jkappa family (also known as CSL or CBF1/Su(H)/Lag-1). RBP-Jkappa, when complexed with NICD, acts as a transcriptional activator, and the RBP-Jkappa-NICD complex activates expression of primary target genes of Notch signaling such as the HES and enhancer of split [E(spl)] families. HES/E(spl) is a basic helix-loop-helix (bHLH) type of transcriptional repressor, and suppresses expression of downstream target genes such as tissue-specific transcriptional activators. Thus, HES/E(spl) directly affects cell fate decisions as a primary Notch effector. HES/E(spl) had been the only known effector of Notch signaling until a recent discovery of a related but distinct bHLH protein family, termed HERP (HES-related repressor protein, also called Hey/Hesr/HRT/CHF/gridlock). In this review, we summarize the recent data supporting the idea of HERP being a new Notch effector, and provide an overview of the similarities and differences between HES and HERP in their biochemical properties as well as their tissue distribution. One key observation derived from identification of HERP is that HES and HERP form a heterodimer and cooperate for transcriptional repression. The identification of the HERP family as a Notch effector that cooperates with HES/E(spl) family has opened a new avenue to our understanding of the Notch signaling pathway.
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PMID:HES and HERP families: multiple effectors of the Notch signaling pathway. 1254 45