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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review 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) 120 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. 121