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Review

Notch: a unique therapeutic target for immunomodulation

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Pages 395-410 | Published online: 22 Apr 2005

Bibliography

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  • ••Definitive review of Notch biology,particularly its role in cell fate determination.
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  • •Together, these two reviews [4,5] provide definitive coverage of the Treg field.
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  • •The first molecular characterisation of the Notch receptor and associated signalling mutants.
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  • •Identifies ground-breaking new Notch mutants which defme the CSL-independent signalling mode.
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  • ••Shows that absence of Notchl hasdramatic effect on B/T decision making: mice have striking phenotype of B-cells developing in the thymus.
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  • ••Study showingNotch3-IC transgenic miceare resistant to induced autoimmunity through enhanced Treg functionality.
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  • ••This important study links Notch signalsto peripheral CD4+ Treg activity for the first time.
  • WONG KK, CARPENTER MJ, YOUNG LL et al.: Notch ligation by Deltal inhibits peripheral immune responses to transplantation antigens by a CD8+ cell-dependent mechanism. Clin. Invest. (2003) 112:1741–1750.
  • ••Extending their previous findings, theauthors show that Notch can also regulate CD8+ T-cell responses, blocking transplant rejection.
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  • •These two papers {55,56] from the same group describe Notch-dependent generation of Treg cells and show that these cells express enhanced IL-10 and TGF13.
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  • •Important study linking Notch to TH1/ TH2 differentiation, though may overlook dose-dependent effects of Notch ligand-induced signals. Provides strong evidence for Notch regulation of IL-4 production.
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  • ••Provides the first molecular mode of actionfor Notch function in T-cells, Akt inhibition.
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  • •Provides molecular insight into an in vitro tolerance model.
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  • •Describes in vitro generation of Treg cells which can cure colitis in vivo.
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  • •• secreted and transmembrane DSL proteins. Dev. Cell (2004) 6:183–192.
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  • ••Together, these two studies [85,86]demonstrate that tumours subvert can T, function to evade immune surveillance; provides key validation for T„-directed therapies in oncology.
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  • •Excellent all-round review of RNAi biology and therapeutic potential.
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  • •Fascinating study linking Notch, Numb and Itch; has implications for Notch and anergy.
  • HEISSMEYER V, MACIAN F, IM SH et al: Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signalling proteins. Nat. Immunol (2004) 5:255–265.
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  • NARAMURA M, JANG IK, KOLE H, HUANG F, HAINES D, GU H: c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat. Immunol. (2002) 3:1192–1199.
  • JEHN BM, DITTERT I, BEYER S, VON DER MARK K, BIELKE W: c-Cbl binding and ubiquitin-dependent lysosomal degradation of membrane- associated Notchl. J. Biol. Chem. (2002) 277:8033–8040.
  • PAVLOPOULOS E, PITSOULI C, KLUEG KM, MUSKAVITCH MA,
  • •• MOSCHONAS NK, DELIDAKIS C: neuralized Encodes a peripheral membrane protein involved in delta signaling and endocytosis. Dev. Cell (2001) 1:807–816.
  • DEBLANDRE GA, LAI EC, KINTNER C: Xenopus neuralized is a ubiquitin ligase that interacts with XDeltal and regulates Notch signaling. Dev. Cell (2001) 1:795–806.
  • YEH E, DERMER M, COMMISSO C, ZHOU L, MCGLADE CJ, BOULIANNE GL: Neuralized functions as an E3 ubiquitin ligase during Drosophila development. Curr. Biol. (2001) 11:1675–1679.
  • ITOH M, KIM CH, PALARDY G et al: Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev. Cell (2003) 4:67–82.
  • •Proposes a novel transendocytosis mechanism for Notch signalling mediated by ubiquitin ligases.
  • OVERSTREET E, FITCH E, FISCHER JA: Fat facets and Liquid facets promote Delta endocytosis and Delta signaling in the signaling cells. Development (2004) 131:5355–5366.
  • WANG W, STRUHL G: Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch. Development (2004) 131:5367–5380.
  • TIAN X, HANSEN D, SCHEDL T, SKEATH JB: Epsin potentiates Notch pathway activity in Drosophila and C. elegans. Development (2004) 131:5807–5815.
  • ••These three important papers [114-116]provide compelling data which extends the transendocytosis model of Notch signalling by identifying Epsin/Lqf and its regulator Far as a core component of the pathway.
  • WENDLAND B: Epsins: adaptors in endocytosis? Nat. Rev Mol. Cell Biol. (2002) 3:971–977.
  • SUN Y: Targeting E3 ubiquitin ligases for cancer therapy. Cancer. Biol. Ther. (2003) 2:623–629.
  • ROBINSON PA, ARDLEY HC: Ubiquitin-protein ligases-novel therapeutic targets? Curr. Protein Pept. Sci. (2004) 5:163–176.
  • ROBEY EA, BLUESTONE JA: Notch signaling in lymphocyte development and function. Curr. Opin. Immunol. (2004) 16:360–366.
  • RADTKE F, WILSON A, MANCINI SJ, MACDONALD HR: Notch regulation of lymphocyte development and function. Nat. Immunol. (2004) 5:247-253. Affiliation

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