Download Gene Section NOTCH3 (Notch homolog 3 (Drosophila)) Atlas of Genetics and Cytogenetics

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NOTCH3 (Notch homolog 3 (Drosophila))
Tian-Li Wang
Departments of Gynecology/Obstetrics and Oncology Johns Hopkins Medical Institutions CRBII, Rm: 306
1550 Orleans Street Baltimore, MD 21231, USA
Published in Atlas Database: August 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/NOTCH3ID41557ch19p13.html
DOI: 10.4267/2042/38495
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Notch (NICD). The NICD translocates to the nucleus,
where it interacts with CSL (CBF1/RBP-J kappa,
Suppressor of Hairless, LAG-1). Binding of NICD to
CSL displaces corepressor complexes and recruits
coactivators, leading to transcription from promoters
containing CSL-binding elements. The Notch3 target
genes participate in wide spectrum of biological
processes such as differentiation, proliferation and
apoptosis.
Identity
Hugo: NOTCH3
Other names: CADASIL; CASIL
Location: 19p13.12
Local order: Gene orientation: telomere-3’ NOTCH3
5’-centromere.
DNA/RNA
Expression
Description
Expressed in certain types of fetal and adult tissues.
The Notch3 gene is encoded by 33 exons spanning
41.35 kb that are located on chromosome 19p13.12.
Localisation
Mainly located at cell membrane. Following proteolytic
events upon ligand binding, its intracellular domain is
translocated into the nuclei.
Transcription
8.089 kb mRNA, the coding sequence is from 77 bp7042 bp.
Function
Protein
Notch3 is a membrane receptor that mediates cell-cell
interactions to facilitate cell differentiation, growth and
cell death.
Note: 2321 amino acids with a predicted molecular
mass of 243.66 kD.
Single-pass type I membrane protein. Contain 1 signal
peptide, 36 extracellular EGF repeats, 1 single
transmembrane domain, and 2 PEST domains.
Synthesized in the endoplasmic reticulum as an
inactive form, which is cleaved by a furin-like
convertase in the trans-Golgi complex before it reaches
the plasma membrane to yield an active, ligandaccessible form. Cleavage results in a transmembrane
Notch subunit (NTM) and an extracellular Notch
subunit (ECN).
Mutations
Germinal
Mutation in NOTCH3 is associated with cerebral
autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL).
CADASIL is an adult-onset disorder characterized by
recurrent ischemic strokes, dementia, and premature
death. It affects predominantly the small cerebral
arteries, leads to progressive degeneration of
vasculature smooth-muscle cells.
Disease-associated mutations are distributed throughout
the epidermal growth factor-like repeats (EGFRs) that
compose the extracellular domain of the Notch3
receptor and result in a loss or a gain of a cysteine
residue in one of these EGFRs. Mutation hotspots were
Description
Notch3 is a cell surface receptor for membrane-bound
ligands including Jagged1, Jagged2, Delta-like1, Deltalike3 and Delta-like4. It is activated by ligand-receptor
interaction, which triggers two successive proteolytic
cleavages that release the active intracellular domain of
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2)
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NOTCH3 (Notch homolog 3 (Drosophila))
Wang TL
located at the two exons encoding the first five EGFRs.
The findings suggested that aberrant dimerization of
NOTCH3, due to abnormal disulfide bridging with
NOTCH3 molecule or another protein, may be
involved in the pathogenesis of CADASIL.
promoter/enhancer resulted in inhibited differentiation
of epithelial lung cell, altered lung morphology, and
perinatal lethality in the transgenic mice.
Ovarian cancer-serous type
Cytogenetics
Chromosome 19p13.12 amplification harboring the
Notch3 gene is frequently identified in ovarian cancer.
Oncogenesis
In vitro study demonstrated that cell lines with Notch3
over-expression are more sensitive to the antiproliferative effect of Notch3 signaling pathway
inhibitors including gamma-secretase inhibitor and
Notch3-specific siRNA.
Somatic
Somatic sequence mutations, gene translocation and
amplification of chromosomal locus involved Notch3
gene were identified in T-cell lymphoma, non-smallcell lung cancer and ovarian cancer, respectively.
Implicated in
Non-small-cell lung cancer
Cytogenetics
t(15;19)(q11;p13)
Hybrid/Mutated Gene
A breakpoint was localized to the cosmid R31546. The
breakpoint was found about 50 kilobases (kb) upstream
of the Notch3 and within the 3' untranslated region of a
putative gene, Hunk1, on 19p. Translocation of
chromosome 19p was also found in several other
chromosomes, including chromosomes 12q, 14q, 17q,
4q, and 6q. Overexpression of Notch3 full-length
mRNA is associated with a 19p translocation.
Oncogenesis
The translocation is associated with Notch3 overexpression. Transgenic mouse study by constitutive
expression of intracellular domain of Notch3 in lung
epithelium using surfactant protein C.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2)
References
Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR,
Minna JD, Roberts JR, Carbone DP. Chromosome 19
translocation, overexpression of Notch3, and human lung
cancer. J Natl Cancer Inst 2000;92:1355-1357.
Dang TP, Eichenberger S, Gonzalez A, Olson S, Carbone DP.
Constitutive activation of Notch3 inhibits terminal epithelial
differentiation in lungs of transgenic mice. Oncogene
2003;22:1988-1997.
Park JT, Li M, Nakayama K, Mao TL, Davidson B, Zhang Z,
Kurman RJ, Eberhart CG, Shih IeM, Wang TL. Notch3 gene
amplification in ovarian cancer. Cancer Res 2006;66:63126318.
This article should be referenced as such:
Wang TL. NOTCH3 (Notch homolog 3 (Drosophila)). Atlas
Genet Cytogenet Oncol Haematol.2008;12(2):120-121.
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