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The Notch3 Receptor and Its Intracellular Signaling-Dependent Oncogenic Mechanisms

  • Diana Bellavia
  • Saula Checquolo
  • Rocco Palermo
  • Isabella Screpanti
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1066)

Abstract

During evolution, gene duplication of the Notch receptor suggests a progressive functional diversification. The Notch3 receptor displays a number of structural differences with respect to Notch1 and Notch2, most of which have been reported in the transmembrane and in the intracellular regions, mainly localized in the negative regulatory region (NRR) and trans-activation domain (TAD). Targeted deletion of Notch3 does not result in embryonic lethality, which is in line with its highly restricted tissue expression pattern. Importantly, deregulated Notch3 expression and/or activation, often results in disrupted cell differentiation and/or pathological development, most notably in oncogenesis in different cell contexts. Mechanistically this is due to Notch3-related genetic alterations or epigenetic or posttranslational control mechanisms. In this chapter we discuss the possible relationships between the structural differences and the pathological role of Notch3 in the control of mouse and human cancers. In future, targeting the unique features of Notch3-oncogenic mechanisms could be exploited to develop anticancer therapeutics.

Keywords

Notch3 T cell leukemogenesis Epigenetic regulation Post-translational modifications 

Abbreviations

ADAM

A Disintegrin And Metalloprotease

DSL

Delta, Serrate

ECD

Extracellular domain

HD

Heterodimerization domain

NICD

Notch intracellular domain

NRR

Negative regulatory region

TAD

Trans-activation domain

LAG-2

Notch Ligands or DSL ligands

T-ALL

T-cell acute lymphoblastic leukemia

Ptcra

Invariant preTα chain of the pre-T cell receptor

Tregs

T regulatory cells

IKK

Inhibitor of KAPPA-B kinase complex

PTM

Post-translational modification

IK

Ikaros

IK-DN

Ikaros dominant negative isoforms

HUD

RNA-binding protein D of the ELAV/Hu family

BORIS/CTCFL

Brother Of Regulator of Imprinted Sites/CTCF-like protein

TCR

T-cell receptor

NF-κB

Nuclear factor-κB

N1ICD

Notch1 intracellular domain

N2ICD

Notch2 intracellular domain

N3ICD

Notch3 intracellular domain.

Notes

Acknowledgments

We thank members of Screpanti’s laboratory, whose comments and work have contributed to the realization of this chapter. Work in the author’s laboratories is supported by Grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC), Institut Pasteur - Fondazione Cenci-Bolognetti and Sapienza University of Rome. This chapter is dedicated to the memory of Professor Alberto Gulino.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Diana Bellavia
    • 1
  • Saula Checquolo
    • 2
  • Rocco Palermo
    • 3
  • Isabella Screpanti
    • 1
  1. 1.Department of Molecular MedicineSapienza University of RomeRomeItaly
  2. 2.Department of Medico-Surgical Sciences and BiotechnologiesSapienza University of RomeRomeItaly
  3. 3.Center for Life Nano Science@SapienzaIstituto Italiano di TecnologiaRomeItaly

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