Disease relevance of JAG1

• We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome [1].
• We have studied a JAG1 missense mutation (JAG1-G274D) that was previously identified in 13 individuals from an extended family with cardiac defects of the type seen in patients with AGS (e.g., peripheral pulmonic stenosis and tetralogy of Fallot) in the absence of liver dysfunction [2].
• Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects but with variable expressivity in a large kindred, which demonstrates that mutation in JAG1 can cause hearing loss [3].
• We examined the JAG1 mutation in extrahepatic biliary atresia (EHBA), which is similar in phenotype to AGS, although a different pathogenesis is suggested [4].
• Human JAG1 mRNA was expressed in embryonic stem (ES) cells, neural tissues, lung carcinoid, gastric cancer, pancreatic cancer, colon cancer, and also in squamous cell carcinoma (SCC) of skin, oral cavity, esophagus, head and neck [5].

Psychiatry related information on JAG1

• Patients with "recently" diagnosed Huntington's Disease (RHD) were compared on a neuropsychological test battery to patients who have had the disease three to 15 years (AHD) and to intact controls [6].
• The present study was designed to assess effects of aversive stimuli on learning and memory in wild-caught Arctic ground squirrels (AGS, Spermophilus parryii) using an active avoidance learning paradigm [7].
• With its emphasis on friendship, the saliency of health, reinforcement of self-efficacy and control over one's health, health education, the ecological nature of health, and the need to preserve the quality of the future for children and grandchildren, the AHDP model has national and international implications [8].
• Eighty-one Shia Imami Nizari Ismaili Muslims living in Ontario, Canada, provided demographic data and completed the Bem Sex-Role Inventory (BSRI; Bem, 1981) and the Attitudes Toward Women Scale (AWS; Spence, Helmreich, & Stapp, 1973) [9].

High impact information on JAG1

• Mutations in JAG1, encoding a Notch ligand, cause the Alagille syndrome in humans, characterized by poor development of the biliary system, suggesting that the Notch pathway is also involved in normal biliary development [10].
• Increasing evidence suggests that, in addition to the inhibitory Jagged1/Notch1 signaling cascade, other pathways act via Notch to mediate oligodendrocyte differentiation [11].
• Determining the complete exon-intron structure of JAG1 allowed detailed mutational analysis of DNA samples from non-deletion AGS patients, revealing three frame-shift mutations, two splice donor mutations and one mutation abolishing RNA expression from the altered allele [12].
• During mammalian central nervous system (CNS) development, contact-mediated activation of Notch1 receptors on oligodendrocyte precursors by the ligand Jagged1 induces Hes5, which inhibits maturation of these cells [13].
• Experiments in vitro showed that Jagged1 signaling inhibited process outgrowth from primary human oligodendrocytes [13].

Chemical compound and disease context of JAG1

• Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1 [3].
• We show here that 17 beta-estradiol promoted a 6-fold increase in Jagged1 expression and an 8-fold increase in Notch1 expression by cDNA arrays in breast cancer MCF7 cells [14].
• In vitro experiments with the human gastric cancer cell line AGS were also performed to identify mechanisms underlying cancer chemoprevention by nimesulide [15].
• For screening the genes upregulated by the demethylating agent 5-aza-2'-deoxycytidine (DAC), cDNA microarray analysis (AceGene(R), containing 30,000 genes) was performed using gastric cancer cell lines (AGS, MKN74, MKN1, MKN45 and Kato3) treated with DAC [16].
• We examined in human gastric cancer AGS cells: (1) survivin expression, (2) localization of survivin and Aurora-B, (3) cell proliferation, and (4) effects of specific survivin siRNA and/or rebamipide (free radical scavenging drug) on survivin and Aurora-B expression and cell proliferation [17].

Biological context of JAG1

• The cardiac-specific phenotype associated with this mutation suggests that the developing heart is more sensitive than the developing liver to decreased dosage of JAG1 [2].
• JAG1 mutations in AGS include gene deletions and protein truncating, splicing, and missense mutations, suggesting that haploinsufficiency is the mechanism of disease causation [2].
• Of the remaining 51 patients, 35 (69%) had mutations within JAG1, identified by SSCP analysis [18].
• Evaluation of candidate loci in a large kindred segregating autosomal dominant ToF with reduced penetrance culminated in identification of a missense mutation (G274D) in JAG1, the gene encoding jagged1, a Notch ligand expressed in the developing right heart [19].
• We have isolated the human homolog of the rat Jagged1 gene, JAG1, from a CpG island in a YAC clone covering the Alagille syndrome critical region at chromosome 20p12 (tel-SNAP-D20S186-cen) [20].

Anatomical context of JAG1

• By transfecting wild-type and mutant JAG1 into COS-7 cells in vitro, we found that HGF is a target gene of JAG1 downstream [21].
• In the developing heart, both Notch1 and Notch2 are expressed in the outflow tracts and the epicardium, in specific cell populations previously shown to express JAG1 [22].
• Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells [5].
• We conclude that JAG1 is expressed in the structures affected in Alagille syndrome, such as the pulmonary artery, anterior chamber of the eye, and face [23].
• JAG1 is expressed in the distal cardiac outflow tract and pulmonary artery, major arteries, portal vein, optic vesicle, otocyst, branchial arches, metanephros, pancreas, mesocardium, around the major bronchial branches, and in the neural tube [23].

Associations of JAG1 with chemical compounds

• A candidate-gene approach was undertaken and culminated in the identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the first cysteine of the first epidermal-growth-factor-like repeat domain of the protein [3].
• Finally, coculture of Dl-1-expressing cells with myogenic C2 cells suppresses differentiation of C2 cells into myotubes, as previously demonstrated for Jagged-1 and Jagged-2, and also leads to an increased level of endogenous HES-1 mRNA [24].
• BACKGROUND: Aspartyl (asparaginyl)-beta-hydroxylase (AAH) hydroxylates Asp and Asn residues within EGF-like domains of Notch and Jagged, which mediate cell motility and differentiation [25].
• Interestingly, addition of a beta1,4 galactose by beta4GalT-1 to the GlcNAc added by fringe is required for Jagged1-induced Notch signaling to be inhibited in a co-culture assay [26].
• Since PTH(1-34) activates both Adenylate Cyclase/Protein Kinase A (AC/PKA) and Protein Kinase C (PKC) downstream of the PTH1R in osteoblastic cells, we independently determined the effect of either pathway on Jagged1 [27].

Physical interactions of JAG1

• JAG1 then binds to the Notch receptor on adjacent stem cells to induce Notch receptor proteolyses for the release of Notch intracellular domain (NICD) [28].

Regulatory relationships of JAG1

• Thus, Dl-1 behaves as a functional ligand for Notch-1 and has the same ability to suppress cell differentiation as the Jagged proteins do [24].
• However, the decrease in Jagged1-triggered Notch2 signaling by mFng was again greater than that by lFng [29].
• The direct action of hJagged-1 was confirmed by the enhanced expression of the HES-1 (hairy enhancer of the split-1) gene [30].
• Down-regulation of Jagged-1 induces cell growth inhibition and S phase arrest in prostate cancer cells [31].

Other interactions of JAG1

• Activation of this signaling pathway by constitutive Notch-1 mutants and by Jagged-1 causes an angiogenic and invasive tumor phenotype [32].
• Transfection of PaCa cells with the constitutive active Notch-IC mutant and with Jagged-1 revealed increased levels for VEGF [32].
• Jagged1 increases the number of bipotent colony-forming unit-granulocyte macrophage (CFU-GM) and unipotent progenitors (CFU-granulocytes and CFU-macrophages), without quantitatively affecting terminal cell differentiation, whereas Delta1 reduces the number of CFU-GM and differentiated monocytic cells [33].
• Four Notch receptors have been identified in vertebrates and different ligands, divided into Delta-like and Serrate-like (Jagged) [34].
• Further, Jagged1 expression correlates with the rapid induction of PI3K-mediated epithelial-mesenchymal transition in both HaCaT cells and a human cervical tumor-derived cell line, suggestive of Delta1;Serrate/Jagged;Lag2 ligand-specific roles [35].

Analytical, diagnostic and therapeutic context of JAG1

• The JAG1 gene mutations were generally found in severely ill patients subjected to liver transplantation at less than 5 years of age [4].
• Notch1 and Notch3 expression overlapped with that of Jagged1, as determined by confocal microscopy [36].
• The results were correlated with the expression of Notch ligand JAG1 gene and the clinicopathologic features and the full-length p63 protein expression by immunohistochemistry [37].
• We investigated the JAG1 gene for genetic alterations in eight Japanese AGS patients, using fluorescence in situ hybridization (FISH), single strand conformation polymorphism (SSCP) analysis, and direct sequencing [38].
• The mRNA transcript levels of AAH, insulin receptor substrate (IRS), insulin and insulin-like growth factor (IGF) receptors and polypeptides, Notch, Jagged, and HES were measured in 15 paired samples of HCC and adjacent HCC-free human liver biopsy specimens using real-time quantitative RT-PCR and Western blot analysis [39].

References