Osteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA). Recently, Notch receptors have been implicated in the development of osteoclasts. However, the responsible Notch ligands have not been identified yet. This study was undertaken to determine the role of individual Notch receptors and ligands in osteoclastogenesis. Mouse bone marrow-derived macrophages or human peripheral blood monocytes were used as osteoclast precursors and cultured with receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) to induce osteoclasts. Osteoclasts were detected by tartrate-resistant acid phosphatase (TRAP) staining. K/BxN serum-induced arthritic mice and ovariectomized mice were treated with anti-mouse Delta-like 1 (Dll1) blocking monoclonal antibody (mAb). Blockade of a Notch ligand Dll1 with mAb inhibited osteoclastogenesis and, conversely, immobilized Dll1-Fc fusion protein enhanced it in both mice and humans. In contrast,
Transfection with siN1 and siN2 selectively suppressed the expression of Notch1 and Notch2 mRNA and protein, respectively. In T-ALL cell lines, NOTCH1 knockdown as well as NOTCH2 knockdown suppressed cell proliferation and induced apoptosis. Immunoblot analysis showed that Myc expression was downregulated in NOTCH1-knockdown cells but not affected in NOTCH2-knockdown cells. In AML cell lines, cell proliferation was not significantly affected by NOTCH siRNAs. NOTCH2 knockdown increased the level of cleaved Notch1 fragment without increasing Notch1 expression. The knockdown of NOTCH1 and NOTCH2 reduced the expression and phosphorylation of mTOR protein in THP-1 cells. To confirm this finding, we examined the effects of activation of Notch by the recombinant Notch ligands, Jagged1 and Delta1, on the expression of mTOR protein. The activation of Notch resulted in an increase in the level of the mTOR protein and its phosphorylation in THP-1 cells. Thus, siRNA-transfection and ligand stimulation of ...
Alagille syndrome is an autosomal dominant disorder with high penetrance but variable expressivity. Alagille syndrome 1 (ALGS1; MIM 118450) is caused by mutations in the JAG1 gene, encoding jagged-1, a ligand for the Notch receptors. Alagille syndrome 2 (ALGS2; MIM 610205) is caused by mutations in NOTCH2, which encodes a transmembrane Notch receptor. Interactions between Notch ligands and receptors regulate signaling pathways important for cell fate determination. The main clinical findings of Alagille syndrome include cholestasis due to bile duct paucity, congenital heart defects, skeletal abnormalities, a characteristic facial appearance, eye abnormalities, and renal disease. Cardiovascular findings include tetralogy of Fallot, peripheral pulmonary artery stenosis, atrial and/or ventricular septal defects, and coarctation of the aorta. Butterfly vertebra is the most common skeletal finding, particularly in individuals with JAG1 mutations. Other findings include narrowing of interpeduncular ...
Alagille syndrome is an autosomal dominant disorder with high penetrance but variable expressivity. Alagille syndrome 1 (ALGS1; MIM 118450) is caused by mutations in the JAG1 gene, encoding jagged-1, a ligand for the Notch receptors. Alagille syndrome 2 (ALGS2; MIM 610205) is caused by mutations in NOTCH2, which encodes a transmembrane Notch receptor. Interactions between Notch ligands and receptors regulate signaling pathways important for cell fate determination. The main clinical findings of Alagille syndrome include cholestasis due to bile duct paucity, congenital heart defects, skeletal abnormalities, a characteristic facial appearance, eye abnormalities, and renal disease. Cardiovascular findings include tetralogy of Fallot, peripheral pulmonary artery stenosis, atrial and/or ventricular septal defects, and coarctation of the aorta. Butterfly vertebra is the most common skeletal finding, particularly in individuals with JAG1 mutations. Other findings include narrowing of interpeduncular ...
Members of the Notch family of transmembrane receptors are found on primitive hematopoietic precursors, and Notch ligand expression has been demonstrated on the surface of stromal cells, suggesting a role for Notch signaling in mammalian blood cell development. The current report examines the expression of Notch receptors and their ligands in murine hematopoietic tissues to determine: A) which blood cell lineages in the adult are influenced by Notch activity, and B) whether fetal hematopoiesis in the embryo involves the Notch pathway. In the adult mouse, a combination of flow cytometry, immunohistochemistry and Northern analysis was used to examine Notch receptor or ligand expression in bone marrow and spleen. In the embryo, Northern analysis and in situ hybridization were used to characterize Notch receptor and ligand expression in fetal liver on embryonic day 12 (E12) through E17, an active period encompassing both erythropoiesis and granulopoeisis. Flow cytometry demonstrated the presence of ...
Notch is a transmembrane receptor for the transmembrane ligands Delta and Jagged (also known as Serrate). Signaling by Notch is important for establishing boundaries during development (see accompanying article by Fortini). Fringe modifies Notch signaling when expressed in Notch-expressing cells. Two groups, Brückner et al. and Moloney et al., show that Fringe is a glycosyltransferase that catalyzes the elongation of O-linked fucose residues on the epidermal growth factor repeats of the Notch receptor. Brückner et al. show that coexpression of Fringe and Notch enhances the interaction between Notch and Delta and that the glycosyltransferase activity of Fringe is essential for this activity. Moloney et al. show that when Notch is modified by Fringe, activation of Notch by Jagged1 is inhibited. Thus, carbohydrate modification of the Notch receptor fine-tunes the cellular responsiveness to Notch ligands, allowing the establishment of discrete boundaries of Notch signaling. Carbohydrate ...
1. Alagille syndrome: spectrum of clinical presentation in India. http://www.ncbi.nlm.nih.gov/pubmed/22692667. Gupta P, Bhakhri BK, Paul P.. Indian J Gastroenterol.2012Jun;31(3):149-50.doi:10.1007/s12664-012-0199-8. No abstract available.. PMID: 22692667 [PubMed - indexed for MEDLINE]. 2. Alagille syndrome: a rare disease in an adolescent.. http://www.ncbi.nlm.nih.gov/pubmed/22678460. Guru Murthy GS, Rana BS, Das A, Thapa BR, Duseja AK, Dhiman RK, Chawla YK.. Dig Dis Sci. 2012Nov;57(11):3035-7. doi:10.1007/s10620-012-2226-0.Epub 2012Jun 8. No abstract. available.. PMID: 22678460 [PubMed - indexed for MEDLINE]. 3. Alagille syndrome with prominent skin manifestations.. http://www.ncbi.nlm.nih.gov/pubmed/16394388. Sengupta S, Das JK, Gangopadhyay A.. Indian J Dermatol Venereol Leprol. 2005 Mar-Apr;71(2):119-21.. PMID: 16394388 [PubMed - indexed for MEDLINE] Free Article. 4. Alagille syndrome.. http://www.ncbi.nlm.nih.gov/pubmed/12420920. Shendge H, Tullu MS, Shenoy A, Chaturvedi R, Kamat JR, Khare ...
Specific functional consequences of mutated Notch receptors and ligands are largely not yet experimentally defined, but the clustering of mutations in known functional elements invites speculation with regard to whether the specific Notch receptor likely functions as a tumor suppressor or oncogene in a specific cancer type (Fig. 2).. More NOTCH1 gene mutations were observed than mutations in the other NOTCH receptor genes. This was in part, but not entirely, due to the greater number of tumors with NOTCH1 sequencing data. For HNSCC, lung SCC, and breast, NOTCH1 mutations were relatively frequent, with 5% to 15% of tumors harboring protein coding changes. Many of these missense mutations occurred at or near identified important domains such as the ligand-binding domain (EGF repeats 11 and 12) or the ankyrin domains (Fig. 2). Nonsense mutations observed in HNSCC would be predicted to result in truncated Notch1 proteins lacking domains important for transcription activation. The data suggest that ...
In this study, we formally tested the hypothesis that ADAM10 regulates B cell development. The generation and analysis of B cell-specific ADAM10 knockout mice revealed that ADAM10 critically regulates development of the entire MZB lineage by initiating Notch2 signaling.. The rate-limiting step in Notch2 signaling is cleavage within the receptors negative regulatory region (NRR) located in the membrane-proximal portion of the extracellular domain. The structure of the NRR prevents ligand-independent Notch cleavage. Mutations in the NRR can allow cleavage in the absence of ligand, leading to constitutive Notch signaling. In the case of Notch1, this leads to the formation of T cell acute lymphocytic leukemia (Kopan and Ilagan, 2009). Brou et al. (2000) and Mumm et al. (2000) identified the Notch1 cleavage site in the NRR between Ala-1710 and Val-1711, just 13 amino acids upstream of the transmembrane domain. These studies, in combination with more recent reports, have demonstrated that ADAM10, ...
Following injury, smooth muscle cells in the wall of the blood vessel can switch from a quiescent, contractile phenotype to a migratory, proliferative phenotype which contributes to lesion formation and vascular occlusive disease. Important regulators of vascular smooth muscle cell phenotype include serum response factor and its cofactor myocardin, growth factors, Krüppel-like factors, microRNA-143/145 and Notch signaling. The Notch signaling pathway is highly conserved and plays a critical role in both vascular development and disease. In mammals, there are five Notch ligands (Jagged1, Jagged2, Delta-like 1, Delta-like 3, and Delta-like 4) and four Notch receptors (Notch1-4). Knockout mouse models of most of the Notch ligand and receptor components display early embryonic lethality due to abnormal vasculogenesis, indicating their essential role in cardiovascular development. Following injury, the vascular remodeling response incorporates unique contributions from several of the Notch ligand and
In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p ≤ 0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with ...
Notch intercellular communication instructs tissue-specific T-cell development and function. In this study, we explored the roles of dendritic cell (DC)-expressed Notch ligands in the regulation of T-cell effector function. We generated mice with CD11c lineage-specific deletion of Notch Delta-like ligand (Dll)1 and Jagged (Jag)2. Using these genetically-ablated mice and engineered pharmacological Notch ligand constructs, the roles of various Delta-like and Jagged ligands in the regulation of T-cell-mediated immunity were investigated. We assessed tumor growth, mouse survival, cytokine production, immunophenotyping of myeloid and lymphoid populations infiltrating the tumors, expression of checkpoint molecules and T-cell function in the experimental settings of murine lung and pancreatic tumors and cardiac allograft rejection. Correlative studies were also performed for the expression of NOTCH ligands, NOTCH receptors and PD-1 on various subsets of myeloid and lymphoid cells in tumor-infiltrating immune
TY - JOUR. T1 - Notch and NOXA-related pathways in melanoma cells.. AU - Nickoloff, Brian J.. AU - Hendrix, Mary J.C.. AU - Pollock, Pamela M.. AU - Trent, Jeffrey M.. AU - Miele, Lucio. AU - Qin, Jian Zhong. PY - 2005/11. Y1 - 2005/11. N2 - Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small ...
The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch proteins (Notch1-Notch4 in vertebrates) are single-pass receptors that are activated by the Delta (or Delta-like) and Jagged/Serrate families of membrane-bound ligands. They are transported to the plasma membrane as cleaved, but otherwise intact polypeptides. Interaction with ligand leads to two additional proteolytic cleavages that liberate the Notch intracellular domain (NICD) from the plasma membrane. The NICD translocates to the nucleus, where it forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from CSL. Components of an activation complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to the NICD-CSL complex, leading to the transcriptional activation of Notch target genes ...
Notch1 and IL-7R signaling are both critical in early T cell development (27), but a functional relationship between both pathways has not been established. Supporting such a direct link, in this paper we identified IL-7Rα as a new transcriptional Notch1 target and showed that IL-7Rα expression is regulated by Notch1 in a T-lineage- and developmental stage-specific manner. We also provided evidence that developmental regulation of IL-7Rα expression by Notch1 during human thymopoiesis is critical to controling expansion of the early T cell progenitor compartment in response to IL-7. Moreover, we found that active Notch1 also regulated IL-7Rα expression and IL-7-dependent proliferation of human T-ALLs, suggesting that cross talk of both pathways may be relevant for leukemogenesis.. Active Notch1 was shown to specifically transactivate the IL7R promoter in a CSL/MAML-dependent manner. This finding provides the molecular basis for understanding the differential transcriptional regulation of IL7R ...
Alagille syndrome is a genetic disorder affecting heart, liver and other body systems. Alagille syndrome pictures, symptoms, causes and treatment explained.
Notch signaling can regulate cell-to-cell communication and control cell fate decisions in a variety of cell types. In the vascular endothelium, signaling between Dll4 and Notch1 in tip and stalk cells, respectively, prevents stalk cell sprouting.16 This Notch-dependent homotypic interaction helps to pattern blood vessels. In this study, we asked how Notch signaling might facilitate heterotypic interactions between mural cells and endothelial cells that help shape the vasculature. Previous work has suggested an important role for pericytes in modulating tube formation,50,51 and an in vitro study by our laboratory demonstrated that mural cell-expressed Notch3 affects angiogenesis.30 Here, we show that under physiological conditions, Notch3 deletion decreases vascularization in the mouse retina at early developmental stages. These angiogenic defects are not a result of enhanced regression, which points to growth retardation as the likely cause. The decline in angiogenesis is associated with a ...
The specific focus of this project is to understand how Notch responds to inherent changes in the tumour environment or changes occuring as a consequence of treatment, and how such "tumour stress" influence Notch activity to drive the disease. We have recently identified a Notch-hypoxia crosstalk of relevance for tumor progression (Sahlgren et al., 2008). We have shown that Notch signaling converts hypoxia inherent to the tumor microenvironment into epithelial mesenchymal transition (EMT) required for the hypoxia-induced invasiveness of epithelial tumor cells. We have participated in a project to elucidate the Notch-hypoxia transcriptome to gain insight in how such a crosstalk is manifested on the transcriptome level and to obtain a molecular platform to better understand the intersection between the two signaling cascades in normal development and cancer (Main et al., 2010). More recent data from the lab show that there is an elaborate crosstalk between Notch and cell metabolism and that Notch ...
NOTCH ligands DLL1, DLL4, JAG1 and JAG2 undergo ubiquitination and endocytosis after binding NOTCH2 in trans. Integrity of the intracellular domain of DLL1 was shown to be essential for the successful release of NOTCH2 intracellular domain, NICD2, in response to DLL1 binding (Shimizu et al. 2002). In Drosophila, ubiquitination of Delta and Serrate ligands is performed by either Mindbomb or Neuralized ubiquitin ligase. In mammals, there are two Mindbomb homologues, MIB1 and MIB2 and two Neuralized homologues, NEURL (also known as NEUR1) and NEURL1B (also known as NEUR2). Although both Mib1 and Mib2 ubiquitinate Delta (Koo et al. 2005), only Mib1 was shown to be essential for normal development in mice, with Mib1 deficient mice exhibiting typical Notch deficiency phenotypes (Koo et al. 2007). This could be due to different expression patterns of Mib1 and Mib2. While Mib1 is abundantly expressed in embryos and adult tissues, Mib2 expression is limited to adult tissues only (Koo et al. 2005). Mouse ...
NOTCH ligands DLL1, DLL4, JAG1 and JAG2 undergo ubiquitination and endocytosis after binding NOTCH2 in trans. Integrity of the intracellular domain of DLL1 was shown to be essential for the successful release of NOTCH2 intracellular domain, NICD2, in response to DLL1 binding (Shimizu et al. 2002). In Drosophila, ubiquitination of Delta and Serrate ligands is performed by either Mindbomb or Neuralized ubiquitin ligase. In mammals, there are two Mindbomb homologues, MIB1 and MIB2 and two Neuralized homologues, NEURL (also known as NEUR1) and NEURL1B (also known as NEUR2). Although both Mib1 and Mib2 ubiquitinate Delta (Koo et al. 2005), only Mib1 was shown to be essential for normal development in mice, with Mib1 deficient mice exhibiting typical Notch deficiency phenotypes (Koo et al. 2007). This could be due to different expression patterns of Mib1 and Mib2. While Mib1 is abundantly expressed in embryos and adult tissues, Mib2 expression is limited to adult tissues only (Koo et al. 2005). Mouse ...
Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a rare autosomal dominant genetic disorder caused by mutations in the Notch signalling pathway
In mice, Dll4 is the primary Notch ligand required for vascular development. Similarly to Vegfa+/- heterozygous mouse embryos, Dll4+/- heterozygous embryos on inbred genetic backgrounds exhibit embryonic lethal haploinsufficiency due to vascular defects (Duarte et al., 2004; Gale et al., 2004; Krebs et al., 2004). However, some Dll4+/- mice are viable on an outbred background, permitting the examination of Dll4-/- embryos. The phenotype of Dll4-/- homozygotes was similar, although more severe, than that of Dll4+/- heterozygous embryos (Duarte et al., 2004; Gale et al., 2004). Similar to that which is observed in Notch signaling-deficient zebrafish embryos, both Dll4-deficient embryos and other types of Notch signaling-deficient mouse embryos, such as Rbpj mutant and Hey1; Hey2 double-mutant embryos, do not express arterial markers (Duarte et al., 2004; Fischer et al., 2004; Gale et al., 2004; Kokubo et al., 2005; Krebs et al., 2004). In support of a direct role for Notch signaling in regulating ...
Describes Alagille syndrome, a rare, inherited disorder that affects the liver. Covers the causes, symptoms, diagnosis, treatment, and long-term outlook.
When activated by its ligand Dll4, Notch1 signaling acts as a negative regulator of angiogenic sprout initiation. Conversely, the Notch ligand Jagged1 has been discovered to be pro-angiogenic. Endothelial-specific Jagged1 loss leads to reduced angiogenesis during retinal development, wound healing, and tumor angiogenesis. How Jagged1 mediates its pro-angiogenic function is currently not well understood. Several models for Jagged1 function have been proposed: Jagged1 may be a competitor of Dll4, or a unique Notch signal activator. We hypothesize that Jagged1 interacts with another Notch protein, Notch4, to promote angiogenesis and that this signaling is distinct from the role of Dll4/Notch1 signaling. This project aims to describe a new signaling pair (Jagged1-Notch4) and to develop new approaches to promote wound healing through regulation of Jagged1 or Notch4 activities ...
Notch receptors are frequently deregulated in several human malignancies including human breast cancer. Activation of Notch has been reported to cause mammary carcinomas in mice. However, the...
NOTCH signaling is an evolutionary conserved pathway involved in tissue patterning and cell specification during normal development. It is initiated following interaction of a cell surface expressed ligand (JAG1, JAG2, DLL1, 3 and 4) with a transmembrane monomeric NOTCH receptor (NOTCH1-4). Binding of the ligand is followed by two successive proteolytic cleavage steps catalyzed by TNFα-converting enzyme and the presenilin-γ secretase complex that release the NOTCH intracellular domain (NICD) to the cytoplasm. Upon translocation to the nucleus, NICD activates the transcription factor CSL. The amplitude and duration of the NOTCH response are regulated by acetylation of NICD on specific lysine residues (1). Only few CSL targets are known, most prominently the HES and HEY family of transcriptional repressors. In many mammalian cell types, the NOTCH pathway enhances stem cell potential and suppresses differentiation, whereas in others, it exerts an opposite role suppressing tumor development (2). ...
NOTCH3, PE, clone: HMN3-133, eBioscience™ 100μg; PE NOTCH3, PE, clone: HMN3-133, eBioscience™ Primary Antibodies Nj to No
Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature β cells is unclear. We found that islets derived from lean mice show modest β cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with β cell-specific-deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with β cell-specific Notch gain of function (β-NICD) had a progressive loss of β cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active β cells had increased proliferative capacity, leading to increased but dysfunctional β cell mass. These studies demonstrate a dynamic role for Notch in developed β cells for simultaneously regulating β cell function and proliferation.. ...
Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature β cells is unclear. We found that islets derived from lean mice show modest β cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with β cell-specific-deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with β cell-specific Notch gain of function (β-NICD) had a progressive loss of β cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active β cells had increased proliferative capacity, leading to increased but dysfunctional β cell mass. These studies demonstrate a dynamic role for Notch in developed β cells for simultaneously regulating β cell function and proliferation.. ...
Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature β cells is unclear. We found that islets derived from lean mice show modest β cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with β cell-specific-deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with β cell-specific Notch gain of function (β-NICD) had a progressive loss of β cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active β cells had increased proliferative capacity, leading to increased but dysfunctional β cell mass. These studies demonstrate a dynamic role for Notch in developed β cells for simultaneously regulating β cell function and proliferation.. ...
Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature β cells is unclear. We found that islets derived from lean mice show modest β cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with β cell-specific-deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with β cell-specific Notch gain of function (β-NICD) had a progressive loss of β cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active β cells had increased proliferative capacity, leading to increased but dysfunctional β cell mass. These studies demonstrate a dynamic role for Notch in developed β cells for simultaneously regulating β cell function and proliferation.. ...
Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature β cells is unclear. We found that islets derived from lean mice show modest β cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with β cell-specific-deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with β cell-specific Notch gain of function (β-NICD) had a progressive loss of β cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active β cells had increased proliferative capacity, leading to increased but dysfunctional β cell mass. These studies demonstrate a dynamic role for Notch in developed β cells for simultaneously regulating β cell function and proliferation.. ...
Rabbit polyclonal antibody raised against synthetic peptide of Notch1. A synthetic peptide corresponding to residues surrounding amino acids 1760 of mouse Notch1. (PAB8872) - Products - Abnova
Notch1 Receptor: A notch receptor that interacts with a variety of ligands and regulates SIGNAL TRANSDUCTION PATHWAYS for multiple cellular processes. It is widely expressed during EMBRYOGENESIS and is essential for EMBRYONIC DEVELOPMENT.
The highly-conserved Notch signaling pathway is unique, as both the Notch receptor and most of its respective ligands (canonically the DSL or Delta/Serrate/...
View Jag1/Jag1<+> Notch2/Notch2<+> involves: 129S1/Sv * C57BL/6J: phenotypes, images, diseases, and references.
NOTCH3 - NOTCH3 - Human, 4 unique 29mer shRNA constructs in retroviral untagged vector shRNA available for purchase from OriGene - Your Gene Company.
Plasmid NOTCH3-bio-His from Dr. Gavin Wrights lab contains the insert NOTCH3 and is published in Mol Cell Proteomics. 2015 Feb 23. pii: mcp.M114.046946. This plasmid is available through Addgene.
J:98284 Kitamoto T, Takahashi K, Takimoto H, Tomizuka K, Hayasaka M, Tabira T, Hanaoka K, Functional redundancy of the Notch gene family during mouse embryogenesis: Analysis of Notch gene expression in Notch3-deficient mice. Biochem Biophys Res Commun. 2005 Jun 17;331(4):1154-62 ...
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Rabbit polyclonal activated Notch1 antibody validated for WB, ICC/IF and tested in Human. Referenced in 1 publication. Immunogen corresponding to synthetic…
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I had this piece of 1x2 aluminum with a notch cut in the center, so I enlarged the notch a bit and added dovetail cuts at the ends so I could clamp it to the dovetail on my milling machine. I drilled a 5/8 hole at each end and a setscrew for each hole. ...
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Here we report that Notch signaling controls gastric epithelial cell homeostasis by regulating antral stem cell function. Our lineage tracing studies in adult NIP1::CreERT2 mice showed that antral stem cells are actively signaling from the Notch1 receptor, thus demonstrating that the Notch pathway directly targets these cells under normal homeostatic conditions. Manipulation of Notch signaling showed that Notch functions to promote overall stem cell proliferation. Blocking Notch by pharmacologic or genetic means reduced stem cell proliferation, while genetic activation of Notch signaling in LGR5+ stem cells increased the number of proliferating stem cells. Expression of the Notch target gene Olfm4 paralleled the changes in stem cell proliferation, suggesting that it may be an antral stem cell marker, similar to what has been reported for LGR5+ stem cells in intestine (van der Flier et al, 2009; VanDussen et al, 2012). Analysis of gastric organoids demonstrated that Notch signaling is intrinsic ...
Notch receptors are important mediators of cell fate during embryogenesis, but their role in adult physiology, particularly in postnatal angiogenesis, remains unknown. Of the Notch receptors, only Notch1 and Notch4 are expressed in vascular endothelial cells. Here we show that blood flow recovery and postnatal neovascularization in response to hindlimb ischemia in haploinsufficient global or endothelial-specific Notch1(+/-) mice, but not Notch4(-/-) mice, were impaired compared with wild-type mice. The expression of vascular endothelial growth factor (VEGF) in response to ischemia was comparable between wild-type and Notch mutant mice, suggesting that Notch1 is downstream of VEGF signaling. Treatment of endothelial cells with VEGF increases presenilin proteolytic processing, gamma-secretase activity, Notch1 cleavage, and Hes-1 (hairy enhancer of split homolog-1) expression, all of which were blocked by treating endothelial cells with inhibitors of phosphatidylinositol 3-kinase/protein
Variations in the spatial localization of signaling components and crosstalk among signaling cascades are mechanisms through which diversity in signaling networks is generated. The receptor Notch provides an example of regulation by spatial localization: In the canonical Notch signaling pathway, Notch is cleaved to produce the Notch intracellular domain (NICD, also known as NIC), which translocates to the nucleus to regulate gene expression. We describe a T cell receptor-dependent, non-nuclear distribution and function of the processed receptor Notch, which was associated with the improved survival of regulatory T cells (Tregs) in vitro and in vivo and was compromised by T cell-specific deletion of Notch1. Unlike a nuclear-restricted mutant of NICD, mutant NICD that underwent nuclear export or was targeted to the plasma membrane protected Notch1−/− Tregs from apoptosis induced by nutrient deprivation and oxidative stress. Notch signaling integrated with phosphatidylinositol 3-kinase ...
Notch signaling is used for cell fate determination throughout the animal kingdom, and differences in Notch activity between two daughter cells determine their future fates. Thus, Notch signaling promotes progenitor cell identity at the expense of differentiated cell phenotypes (Jadhav et al., 2006; Mizutani et al., 2007). Differences in the Notch activities between two daughter cells can be specified by the asymmetric localization and inheritance of Numb, a negative regulator of the Notch pathway (Guo et al., 1996; Cayouette et al., 2001; Petersen et al., 2002; Shen et al., 2002). In the embryonic lung, Notch signaling controls cell fates in developing airways (Post et al., 2000; Tsao et al., 2008; Tsao et al., 2009), and Notch activation inhibits the differentiation of distal progenitors into alveolar cells (Guseh et al., 2009). Yet the role of asymmetric segregation of cell fate determinant/Notch inhibitor Numb during lung development, and the way the process might be regulated are still ...