Receptors, Notch: A family of conserved cell surface receptors that contain EPIDERMAL GROWTH FACTOR repeats in their extracellular domain and ANKYRIN repeats in their cytoplasmic domains. The cytoplasmic domain of notch receptors is released upon ligand binding and translocates to the CELL NUCLEUS where it acts as transcription factor.Receptor, Notch1: 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.Receptor, Notch2: A notch receptor that plays an important role in CELL DIFFERENTIATION in a variety of cell types. It is the preferentially expressed notch receptor in mature B-LYMPHOCYTES.Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.Basic Helix-Loop-Helix Transcription Factors: A family of DNA-binding transcription factors that contain a basic HELIX-LOOP-HELIX MOTIF.Amyloid Precursor Protein Secretases: Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.Intercellular Signaling Peptides and Proteins: Regulatory proteins and peptides that are signaling molecules involved in the process of PARACRINE COMMUNICATION. They are generally considered factors that are expressed by one cell and are responded to by receptors on another nearby cell. They are distinguished from HORMONES in that their actions are local rather than distal.Drosophila Proteins: Proteins that originate from insect species belonging to the genus DROSOPHILA. The proteins from the most intensely studied species of Drosophila, DROSOPHILA MELANOGASTER, are the subject of much interest in the area of MORPHOGENESIS and development.Gene Expression Regulation, Developmental: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action during the developmental stages of an organism.Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: A leukemia/lymphoma found predominately in children and young adults and characterized LYMPHADENOPATHY and THYMUS GLAND involvement. It most frequently presents as a lymphoma, but a leukemic progression in the bone marrow is common.Intracellular Signaling Peptides and Proteins: Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors.Receptors, Cell Surface: Cell surface proteins that bind signalling molecules external to the cell with high affinity and convert this extracellular event into one or more intracellular signals that alter the behavior of the target cell (From Alberts, Molecular Biology of the Cell, 2nd ed, pp693-5). Cell surface receptors, unlike enzymes, do not chemically alter their ligands.Homeodomain Proteins: Proteins encoded by homeobox genes (GENES, HOMEOBOX) that exhibit structural similarity to certain prokaryotic and eukaryotic DNA-binding proteins. Homeodomain proteins are involved in the control of gene expression during morphogenesis and development (GENE EXPRESSION REGULATION, DEVELOPMENTAL).Drosophila: A genus of small, two-winged flies containing approximately 900 described species. These organisms are the most extensively studied of all genera from the standpoint of genetics and cytology.WingTranscription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.

Alzheimer's disease: clues from flies and worms. (1/3418)

Presenilin mutations give rise to familial Alzheimer's disease and result in elevated production of amyloid beta peptide. Recent evidence that presenilins act in developmental signalling pathways may be the key to understanding how senile plaques, neurofibrillary tangles and apoptosis are all biochemically linked.  (+info)

Dynamic expression of lunatic fringe suggests a link between notch signaling and an autonomous cellular oscillator driving somite segmentation. (2/3418)

The metameric organization of the vertebrate trunk is a characteristic feature of all members of this phylum. The origin of this metamerism can be traced to the division of paraxial mesoderm into individual units, termed somites, during embryonic development. Despite the identification of somites as the first overt sign of segmentation in vertebrates well over 100 years ago, the mechanism(s) underlying somite formation remain poorly understood. Recently, however, several genes have been identified which play prominent roles in orchestrating segmentation, including the novel secreted factor lunatic fringe. To gain further insight into the mechanism by which lunatic fringe controls somite development, we have conducted a thorough analysis of lunatic fringe expression in the unsegmented paraxial mesoderm of chick embryos. Here we report that lunatic fringe is expressed predominantly in somite -II, where somite I corresponds to the most recently formed somite and somite -I corresponds to the group of cells which will form the next somite. In addition, we show that lunatic fringe is expressed in a highly dynamic manner in the chick segmental plate prior to somite formation and that lunatic fringe expression cycles autonomously with a periodicity of somite formation. Moreover, the murine ortholog of lunatic fringe undergoes a similar cycling expression pattern in the presomitic mesoderm of somite stage mouse embryos. The demonstration of a dynamic periodic expression pattern suggests that lunatic fringe may function to integrate notch signaling to a cellular oscillator controlling somite segmentation.  (+info)

Reverse genetic analysis of Caenorhabditis elegans presenilins reveals redundant but unequal roles for sel-12 and hop-1 in Notch-pathway signaling. (3/3418)

Mutations in the human presenilin genes PS1 and PS2 cause early-onset Alzheimer's disease. Studies in Caenorhabditis elegans and in mice indicate that one function of presenilin genes is to facilitate Notch-pathway signaling. Notably, mutations in the C. elegans presenilin gene sel-12 reduce signaling through an activated version of the Notch receptor LIN-12. To investigate the function of a second C. elegans presenilin gene hop-1 and to examine possible genetic interactions between hop-1 and sel-12, we used a reverse genetic strategy to isolate deletion alleles of both loci. Animals bearing both hop-1 and sel-12 deletions displayed new phenotypes not observed in animals bearing either single deletion. These new phenotypes-germ-line proliferation defects, maternal-effect embryonic lethality, and somatic gonad defects-resemble those resulting from a reduction in signaling through the C. elegans Notch receptors GLP-1 and LIN-12. Thus SEL-12 and HOP-1 appear to function redundantly in promoting Notch-pathway signaling. Phenotypic analyses of hop-1 and sel-12 single and double mutant animals suggest that sel-12 provides more presenilin function than does hop-1.  (+info)

Requirement for the Drosophila COE transcription factor Collier in formation of an embryonic muscle: transcriptional response to notch signalling. (4/3418)

During Drosophila embryogenesis, mesodermal cells are recruited to form a stereotyped pattern of about 30 different larval muscles per hemisegment. The formation of this pattern is initiated by the specification of a special class of myoblasts, called founder cells, that are uniquely able to fuse with neighbouring myoblasts. We report here the role of the COE transcription factor Collier in the formation of a single muscle, muscle DA3([A])(DA4([T])). Col expression is first observed in two promuscular clusters (in segments A1-A7), the two corresponding progenitors and their progeny founder cells, but its transcription is maintained in only one of these four founder cells, the founder of muscle DA3([A]). This lineage-specific restriction depends on the asymmetric segregation of Numb during the progenitor cell division and involves the repression of col transcription by Notch signalling. In col mutant embryos, the DA3([A]) founder cells form but do not maintain col transcription and are unable to fuse with neighbouring myoblasts, leading to a loss-of-muscle DA3([A]) phenotype. In wild-type embryos, each of the DA3([A])-recruited myoblasts turns on col transcription, indicating that the conversion, by the DA3([A]) founder cell, of 'naive' myoblasts to express its distinctive pattern of gene expression involves activation of col itself. We find that muscles DA3([A]) and DO5([A]) (DA4([T]) and DO5([T])) derive from a common progenitor cell. Ectopic expression of Col is not sufficient, however, to switch the DO5([A]) to a DA3([A]) fate. Together these results lead us to propose that specification of the DA3([A]) muscle lineage requires both Col and at least one other transcription factor, supporting the hypothesis of a combinatorial code of muscle-specific gene regulation controlling the formation and diversification of individual somatic muscles.  (+info)

The Enhancer of split complex of Drosophila melanogaster harbors three classes of Notch responsive genes. (5/3418)

Many cell fate decisions in higher animals are based on intercellular communication governed by the Notch signaling pathway. Developmental signals received by the Notch receptor cause Suppressor of Hairless (Su(H)) mediated transcription of target genes. In Drosophila, the majority of Notch target genes known so far is located in the Enhancer of split complex (E(spl)-C), encoding small basic helix-loop-helix (bHLH) proteins that presumably act as transcriptional repressors. Here we show that the E(spl)-C contains three additional Notch responsive, non-bHLH genes: m4 and ma are structurally related, whilst m2 encodes a novel protein. All three genes depend on Su(H) for initiation and/or maintenance of transcription. The two other non-bHLH genes within the locus, m1 and m6, are unrelated to the Notch pathway: m1 might code for a protease inhibitor of the Kazal family, and m6 for a novel peptide.  (+info)

T-cell development: What does Notch do for T cells? (6/3418)

During their development, T cells are rescued from apoptotic cell death to follow distinct lineage fates. Recent data concerned with the role of the Notch transmembrane receptor in these events are interpreted to show that Notch promotes survival, but contrary to earlier reports has no function in lineage commitment.  (+info)

A developmental pathway controlling outgrowth of the Xenopus tail bud. (7/3418)

We have developed a new assay to identify factors promoting formation and outgrowth of the tail bud. A piece of animal cap filled with the test mRNAs is grafted into the posterior region of the neural plate of a host embryo. With this assay we show that expression of a constitutively active Notch (Notch ICD) in the posterior neural plate is sufficient to produce an ectopic tail consisting of neural tube and fin. The ectopic tails express the evenskipped homologue Xhox3, a marker for the distal tail tip. Xhox3 will also induce formation of an ectopic tail in our assay. We show that an antimorphic version of Xhox3, Xhox3VP16, will prevent tail formation by Notch ICD, showing that Xhox3 is downstream of Notch signalling. An inducible version of this reagent, Xhox3VP16GR, specifically blocks tail formation when induced in tailbud stage embryos, comfirming the importance of Xhox3 for tail bud outgrowth in normal development. Grafts containing Notch ICD will only form tails if placed in the posterior part of the neural plate. However, if Xwnt3a is also present in the grafts they can form tails at any anteroposterior level. Since Xwnt3a expression is localised appropriately in the posterior at the time of tail bud formation it is likely to be responsible for restricting tail forming competence to the posterior neural plate in our assay. Combined expression of Xwnt3a and active Notch in animal cap explants is sufficient to induce Xhox3, provoke elongation and form neural tubes. Conservation of gene expression in the tail bud of other vertebrates suggests that this pathway may describe a general mechanism controlling tail outgrowth and secondary neurulation.  (+info)

LvNotch signaling mediates secondary mesenchyme specification in the sea urchin embryo. (8/3418)

Cell-cell interactions are thought to regulate the differential specification of secondary mesenchyme cells (SMCs) and endoderm in the sea urchin embryo. The molecular bases of these interactions, however, are unknown. We have previously shown that the sea urchin homologue of the LIN-12/Notch receptor, LvNotch, displays dynamic patterns of expression within both the presumptive SMCs and endoderm during the blastula stage, the time at which these two cell types are thought to be differentially specified (Sherwood, D. R. and McClay, D. R. (1997) Development 124, 3363-3374). The LIN-12/Notch signaling pathway has been shown to mediate the segregation of numerous cell types in both invertebrate and vertebrate embryos. To directly examine whether LvNotch signaling has a role in the differential specification of SMCs and endoderm, we have overexpressed activated and dominant negative forms of LvNotch during early sea urchin development. We show that activation of LvNotch signaling increases SMC specification, while loss or reduction of LvNotch signaling eliminates or significantly decreases SMC specification. Furthermore, results from a mosaic analysis of LvNotch function as well as endogenous LvNotch expression strongly suggest that LvNotch signaling acts autonomously within the presumptive SMCs to mediate SMC specification. Finally, we demonstrate that the expansion of SMCs seen with activation of LvNotch signaling comes at the expense of presumptive endoderm cells, while loss of SMC specification results in the endoderm expanding into territory where SMCs usually arise. Taken together, these results offer compelling evidence that LvNotch signaling directly specifies the SMC fate, and that this signaling is critical for the differential specification of SMCs and endoderm in the sea urchin embryo.  (+info)

*Proneural genes

... which binds and activate Notch receptors expressed in neighboring cells. Once Notch is activated, the activity of proneural ... preventing cells from getting into the differentiation cascade regulated by proneural genes and Notch. Although notch signaling ... On the other hand, the Notch signaling pathway is capable of promoting gliogenesis in stem cells through the inhibition of ... Yun, K; Fischman, S; Johnson, J; Hrabe De Angelis, M; Weinmaster, G; Rubenstein, J. L. (2002). "Modulation of the notch ...

*DmX gene

Signals are transduced by the cell-surface receptor Notch. During Notch synthesis there are three independent cleavage events. ... When Rbcn-3A or Rbcn-3B are absent, Notch synthesis is disrupted between the second and third cleavage events, and Notch is ... The rabconnectin-3 complex is involved in regulating Notch signalling, although its exact function is unclear. Notch signalling ... The third cleavage event in Notch synthesis is carried out by γ-secretase. This process requires the proton pump V-ATPase which ...

*EGFL7

The first EGF-like domain has a region similar to the DSL (Delta/Serrate/Lag-2) domain found in ligands of the Notch receptors ... Egfl7 interacts with the four Notch receptors, with Dll4, but not with jagged1. Moreover, recombinant Egfl7 competes with ... Fleming RJ (December 1998). "Structural conservation of Notch receptors and ligands". Semin. Cell Dev. Biol. 9 (6): 599-607. ... Egfl7 knockdown stimulates the Notch pathway and Egfl7 over-expression inhibits the Notch pathway in HUVEC and neural stem ...

*Notch 3

... gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse ... "Human ligands of the Notch receptor". Am. J. Pathol. 154 (3): 785-94. doi:10.1016/S0002-9440(10)65325-4. PMC 1866435 . PMID ... is a transcriptional co-activator for NOTCH receptors". Nat. Genet. 26 (4): 484-9. doi:10.1038/82644. PMID 11101851. Beatus P, ... Neurogenic locus notch homolog protein 3 is a protein that in humans is encoded by the NOTCH3 gene. This gene encodes the third ...

*JAG2

Members of the Notch gene family encode transmembrane receptors that are critical for various cell fate decisions. The protein ... "Human Ligands of the Notch Receptor". Am. J. Pathol. 154 (3): 785-94. doi:10.1016/S0002-9440(10)65325-4. PMC 1866435 . PMID ... Lindner V, Booth C, Prudovsky I, Small D, Maciag T, Liaw L (2001). "Members of the Jagged/Notch Gene Families Are Expressed in ... The Notch signaling pathway is an intercellular signaling mechanism that is essential for proper embryonic development. ...

*Delta-like 1

Lewis AK, Frantz GD, Carpenter DA, de Sauvage FJ, Gao WQ (1999). "Distinct expression patterns of notch family receptors and ... Karlström H, Beatus P, Dannaeus K, Chapman G, Lendahl U, Lundkvist J (2003). "A CADASIL-mutated Notch 3 receptor exhibits ... "Human Ligands of the Notch Receptor". Am. J. Pathol. 154 (3): 785-94. doi:10.1016/S0002-9440(10)65325-4. PMC 1866435 . PMID ... "Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane". Cell. 90 (2): 281-91. doi:10.1016/ ...

*JAG1

... that interact with 4 receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved ... Once the JAG1-NOTCH (receptor-ligand) interactions take place, a cascade of proteolytic cleavages is triggered resulting in ... Human JAG1 is one of five ligands for receptors in the NOTCH signaling pathway which helps to determine cellular fate and is ... The extracellular component of the JAG1 protein physically interacts with its respective Notch receptor. This interaction kicks ...

*Notch 2

Kojika S, Griffin JD (2001). "Notch receptors and hematopoiesis". Exp. Hematol. 29 (9): 1041-52. doi:10.1016/S0301-472X(01) ... Neurogenic locus notch homolog protein 2 also known as notch 2 is a protein that in humans is encoded by the NOTCH2 gene. ... Notch 2 is a member of the notch family. Members of this Type 1 transmembrane protein family share structural characteristics ... Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch ...

*ADAM10

1999). "Localization of ADAM10 and Notch receptors in bone". Bone. 25 (1): 9-15. doi:10.1016/S8756-3282(99)00099-X. PMID ... 1995). "The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage". J. Biol. ... Lemjabbar H, Basbaum C (2002). "Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in ...

*Semagacestat

γ-Secretase has other targets, for example the notch receptor. It is not known whether this could cause long-term side effects ...

*ENU

Delta 1 is a ligand for the Notch receptor. A homozygous loss-of-function of Delta 1 (Dll1lacZ/lacZ) is embryonically lethal. ... 35 mutant lines were generated in G1 of which 7 revealed modifiers of the Notch signaling pathway. In the case of genetic ... A genetic screen for modifiers of the delta1-dependent notch signaling function in the mouse. Genetics 175, 1451-1463 (2007) ... performed a dominant modifier screen using ENU-induced mice to identify modifiers of the Notch signaling pathway. ...

*RBPJ

"Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H)". Current ... Beatus P, Lundkvist J, Oberg C, Pedersen K, Lendahl U (Jun 2001). "The origin of the ankyrin repeat region in Notch ... Beatus P, Lundkvist J, Oberg C, Pedersen K, Lendahl U (Jun 2001). "The origin of the ankyrin repeat region in Notch ... "A histone deacetylase corepressor complex regulates the Notch signal transduction pathway". Genes & Development. 12 (15): 2269- ...

*Neurogenic locus notch homolog protein 4

1999). "Human ligands of the Notch receptor". Am. J. Pathol. 154 (3): 785-94. doi:10.1016/S0002-9440(10)65325-4. PMC 1866435 . ... Neurogenic locus notch homolog 4 also known as notch 4 is a protein that in humans is encoded by the NOTCH4 gene located on ... 2001). "MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors". Nat. Genet. ... Kojika S, Griffin JD (2001). "Notch receptors and hematopoiesis". Exp. Hematol. 29 (9): 1041-52. doi:10.1016/S0301-472X(01) ...

*Ubiquitin C

"AIP4/Itch regulates Notch receptor degradation in the absence of ligand". PLoS One. 3 (7): e2735. doi:10.1371/journal.pone. ... "Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ... "Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB ... "Agonist-promoted Lys63-linked polyubiquitination of the human kappa-opioid receptor is involved in receptor down-regulation". ...

*Notch signaling pathway

Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a ... The Notch cascade consists of Notch and Notch ligands, as well as intracellular proteins transmitting the notch signal to the ... Notch signaling is initiated when Notch receptors on the cell surface engage ligands presented in trans on opposing cells. ... "Specific EGF repeats of Notch mediate interactions with Delta and serrate: Implications for notch as a multifunctional receptor ...

*Demcizumab

... blocks Delta-like ligand 4 (DLL4), a ligand of Notch receptors. Notch signaling has been implicated as a key ... The tumors must not have an epidermal growth factor receptor or anaplastic lymphoma kinase. The primary objective of this study ...

*Mastermind-like 3 (drosophila)

"Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors". Molecular and ... "Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling". ... translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway". Nature ...

*MAML2

"Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors". Mol Cell Biol. 22 ( ... Enlund F, Behboudi A, Andrén Y, Oberg C, Lendahl U, Mark J, Stenman G (2004). "Altered Notch signaling resulting from ... "Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling". J ... translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway". Nat. Genet. ...

*MAML1

There is in vitro evidence that the human homolog forms a complex with the intracellular portion of human Notch receptors and ... is a transcriptional co-activator for NOTCH receptors". Nat Genet. 26 (4): 484-9. doi:10.1038/82644. PMID 11101851. Kitagawa M ... "Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors". Mol. Cell. Biol. 22 ... "SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation". Mol. Cell. Biol. 21 ( ...

*WWE protein domain

... a cytosolic effector of Notch signalling thought to bind the N-terminal of the Notch receptor. It is also found as an ... Zweifel ME, Leahy DJ, Barrick D (November 2005). "Structure and Notch receptor binding of the tandem WWE domain of Deltex". ...

*MIPEP

A recent study showed that mitochondrial intermediate peptidase can degrade the transmembrane receptor Notch at its S5 site and ... "Gamma-secretase-regulated proteolysis of the Notch receptor by mitochondrial intermediate peptidase". The Journal of Biological ... assist Notch protein maturation. Since MIPEP plays critical roles in mitochondrial protein maturation, it has been linked to ...

*FABP7

... is expressed, during development, in radial glia by the activation of Notch receptors. Reelin was shown to induce FABP7 ... "Brain lipid-binding protein is a direct target of Notch signaling in radial glial cells". Genes & Development. 19 (9): 1028-33 ... "Reelin induces a radial glial phenotype in human neural progenitor cells by activation of Notch-1". BMC Developmental Biology. ... expression in neural progenitor cells via Notch-1 activation. According to one study, FABP7 binds DHA with the highest affinity ...

*DTX2

2002). "Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor". J. Biol. Chem. 276 (48): 45031-40. ... 1995). "Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats". ... 2001). "Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis". Int. J. ...

*EP300

"Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor". J. Biol. Chem. 276 (48): 45031-40. doi: ... and thyroid hormone receptor-retinoid X receptor". Biochem. J. 369 (Pt 3): 477-84. doi:10.1042/BJ20020057. PMC 1223100 . PMID ... "Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein". J. ... The p300 interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor interaction ...

*Calponin 2

Morrow D, Sweeney C, Birney YA, Cummins PM, Walls D, Redmond EM, Cahill PA (2005). "Cyclic strain inhibits Notch receptor ... HES-1 is known to function downstream of the Notch-RBP J signaling pathway, which has been suggested to mediate cellular ... "Mechanoregulation of h2-calponin gene expression and the role of Notch signaling". The Journal of Biological Chemistry. 289 (3 ...

*PSEN1

In Notch signaling, critical proteolytic reactions takes place during maturation and activation of Notch membrane receptor. ... Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly ... In the prenilin 1 null mutant drosophila, Notch signaling is abolished and it displays a notch-like lethal phenotype. Moreover ... Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israël A (July 1998). "The Notch1 receptor is cleaved ...

*DTX1

"Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor". The Journal of Biological Chemistry. 276 (48 ... "Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor". The Journal of Biological Chemistry. 276 (48 ... "Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane". Cell. 90 (2): 281-91. doi:10.1016/ ... "Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats". Development. 121 ( ...
Notch signalling regulates cell fate in most tissues, promoting precursor cell proliferation in some, but differentiation in others. Accordingly, downregulation or overactivity variously contributes to cancer development. So far, little is known about Notch pathway activity and function in the normal urothelium and in urothelial carcinoma (UC). We have therefore investigated expression of Notch pathway components in UC tissues and cell lines and studied the function of one receptor, NOTCH1, in detail. Expression of canonical Notch pathway components were studied in UC and normal bladder tissues by immunohistochemistry and quantitative RT-PCR and in UC cell lines and normal cultured urothelial cells by qRT-PCR, immunocytochemistry and Western blotting. Pathway activity was measured by reporter gene assays. Its influence on cell proliferation was investigated by γ-secretase inhibition. Effects of NOTCH1 restoration were followed by measuring cell cycle distribution, proliferation, clonogenicity and
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 ...
The Notch signaling pathway is activated in many cell types, but its effects are cell type- and stage-specific. In the immune system, Notch activity is required for the differentiation of T cell progenitors, but it is reduced in more mature thymocytes, in which Notch is oncogenic. Studies based on single-gene models have suggested that the tumor suppressor protein Ikaros plays an important role in repressing the transcription of Notch target genes. We used genome-wide analyses, including chromatin immunoprecipitation sequencing, to identify genes controlled by Notch and Ikaros in gain- and loss-of-function experiments. We found that Ikaros bound to and directly repressed the expression of most genes that are activated by Notch. Specific deletion of Ikaros in thymocytes led to the persistent expression of Notch target genes that are essential for T cell maturation, as well as the rapid development of T cell leukemias in mice. Expression of Notch target genes that are normally silent in T cells, ...
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
Notch proteins are receptors that are important in mediating several developmental processes. Notch receptors are activated upon binding transmembrane ligands, the DSL proteins. Notch is cleaved at several sites and activation of Notch leads to the cleavage of the intracellular domain, which then is translocated to the nucleus and regulates the transcription of target genes. Krämer discusses how binding of Notch to the DSL ligand, Delta, leads to cleavage and trans-endocytosis of the Notch extracellular domain into the Delta-expressing cell. This trans-endocytosis event contributes to the cleavage and release of the active Notch intracellular domain. The Perspective is accompanied by a movie illustrating the trans-endocytosis of Notch.. ...
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 ...
coreceptor Cripto-1. Coimmunoprecipitation analysis confirmed the binding of Cripto-1 with all four mammalian Notch receptors. Deletion analyses revealed that the binding of Cripto-1 and Notch1 is mediated by the Cripto-1/FRL-1/Cryptic domain of Cripto-1 and the C-terminal region of epidermal growth factor-like repeats of Notch1. Binding of Cripto-1 to Notch1 occurred mainly in the endoplasmic reticulum-Golgi network. Cripto-1 expression resulted in the recruitment of Notch1 protein into lipid raft microdomains and enhancement of the furin-like protein convertase-mediated proteolytic maturation of Notch1(S1 cleavage). Enhanced S1 cleavage resulted in the sensitization to ligand-induced activation of Notch signaling ...
Notch signaling is a ubiquitously used signaling pathway that is highly conserved and used throughout metazoan development. Understanding the regulation of Notch signaling is becoming increasingly important in determining the mechanism and treatment for the myriad of human Notch-related diseases. In Drosophila. melanogaster, the development of external sensory organs provides a context in which Notch can be manipulated and phenotypes can be easily interpreted. Here, we expand upon the growing field of Notch regulation through endocytic trafficking by examining the role of Numb and Sara endosomes. Numb is a potent Notch inhibitor whose function is conserved in higher organisms, but whose mechanism of action has remained elusive. In this study, we dispel a previous hypothesis that Numb promotes Notch internalization and instead demonstrate that Numb is a suppressor of Notch endocytic recycling. In support of this, we show that Numb is necessary and sufficient for Notch trafficking to late endosomes
The Notch gene encodes a receptor protein that is involved in many processes during development. Its best understood role is during neurogenesis in a process called "lateral inhibition." However, it has been proposed that Notch also has a role in defining the proneural clusters in the first place. This raises the possibility that the Notch protein is acting as a multifunctional receptor. To test this hypothesis, we have carried out a genetic analysis of molecularly characterized Notch alleles to identify alleles that affect only one of the two proposed functions. Here we present evidence that Notch alleles can be identified that appear to affect the function of Notch during either lateral inhibition or the definition of proneural clusters. In addition our results indicate that there may be discrete regions of the Notch protein required for each function.. ...
TY - JOUR. T1 - Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development. T2 - Implications for the Treatment of Vein Graft Failure. AU - Koga, Jun Ichiro. AU - Nakano, Toshiaki. AU - Dahlman, James E.. AU - Figueiredo, Jose Luiz. AU - Zhang, Hengmin. AU - Decano, Julius. AU - Khan, Omar F.. AU - Niida, Tomiharu. AU - Iwata, Hiroshi. AU - Aster, Jon C.. AU - Yagita, Hideo. AU - Anderson, Daniel G.. AU - Keith Ozaki, C.. AU - Aikawa, Masanori. PY - 2015/11/1. Y1 - 2015/11/1. N2 - Objective-Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease. Approach and Results-We used 2 biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: (1) blocking antibody and (2) macrophage-or endothelial cell (EC)-targeted small-interfering RNA. Dll4 antibody administration for 28 days inhibited vein graft lesion ...
Drug resistance is one of the major problems in multiple myeloma (MM) clinical treatment. It is reported that Notch pathway was involved in drug resistance. In this study, we demonstrated that Notch activation by Dll1 simulation could induce drug resistance to bortezomib in murine and human MM cells. Blocking Notch pathway by DAPT (Notch inhibitor) could reverse the effect and increased the sensitivity to bortezomib. Notch activation decreased the cell apoptosis which was induced by bortezomib treatment as measured by flow cytometry. Further investigation showed that Dll1 simulation could down-regulate CD138, Blimp-1 and XBP-1 mRNA expression and shifts MM cells to a more resistant CD138- phenotype with a significant increase of CD138- subpopulation as detected by flow cytometry both in murine and human MM cells. Meanwhile, by MACS and FACS sorting of CD138+ subpopulation, we found that Notch activation could up-regulates anti-apoptotic proteins (Bcl-xL, Mcl-1 and Bcl-2) in CD138+ MM ...
TY - JOUR. T1 - The cell giveth and the cell taketh away. T2 - An overview of Notch pathway activation by endocytic trafficking of ligands and receptors. AU - Pratt, Emily B.. AU - Wentzell, Jill S.. AU - Maxson, Julia. AU - Courter, Lauren. AU - Hazelett, Dennis. AU - Christian, Jan L.. PY - 2011/5/1. Y1 - 2011/5/1. N2 - Notch signaling is firmly established as a form of cell-to-cell communication that is critical throughout development. Dysregulation of Notch has been linked to cancer and developmental disorders, making it an important target for therapeutic intervention. One aspect of this pathway that sets it apart from others is its apparent reliance on endocytosis by signal-sending and signal-receiving cells. The subtle details of endocytosis-mediated molecular processing within both ligand- and receptor-presenting cells that are required for the Notch signal to maintain fidelity remain unclear. The endosomal system has long been known to play an important role in terminating signal ...
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 ...
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 ...
This study sheds light into a previously unappreciated role for COMMD9 in vesicular sorting and the delivery of Notch proteins to the cell surface. Absent COMMD9, Notch is mislocalized in intracellular early endosomes, and the response to Notch ligands is substantially attenuated. Furthermore, our studies indicate that Notch is not only mislocalized but also undergoes lysosomal degradation. Interestingly, we found that similar phenotypes are observed in cells deficient in CCC components CCDC93 and C16orf62 and the retromer subunit VPS35. This latter complex, which is critically important for the endosomal recycling of a large number of receptors (Seaman et al., 2013), has not been previously linked to Notch trafficking (Steinberg et al., 2013).. The observation that COMMD9-dependent effects on Notch trafficking can dramatically affect signaling is in line with a large body of literature that demonstrates that trafficking through the endolysosomal system is an evolutionarily conserved mechanism ...
As a previous work has suggested the potential for cross-talk between the Notch and Hedgehog signaling cascades (14), we focused on the upregulation of Hedgehog signaling in response to MRK-003. Increased levels of Notch pathway components are seen in Hedgehog-driven medulloblastoma models (15, 42) and it was initially suggested that these tumors may be dependent on Notch signaling for survival (15). More recent studies, however, indicate that Hedgehog-driven medulloblastomas can grow in the absence of canonical Notch activity (43, 44). Additionally, several groups have demonstrated that Hedgehog pathway components Gli1 and Gli2 are able to positively regulate Hes1 independently of Notch (45, 46). However, when we treated several GBM neurosphere lines with the Hedgehog inhibitor cyclopamine we did not observe decreases in Hes1 or other Notch pathway targets, suggesting that Hedgehog does not play a significant role regulating Notch targets in malignant gliomas (Supplementary Fig. S2A).. We ...
Introduction: Notch ligands of the Delta-like (Dll) family regulate embryonic and postnatal arteriogenesis. However, the role of notch signaling in coronary arteries, especially in the endothelium, is poorly characterized. We have analyzed the role of Notch ligand Dll1 in coronary arteries and myocardial infarction.. Methods and Results: Analysis of Dll1 expression by immunofluorescence and Dll1-lacZ reporter gene studies in adult mouse hearts revealed selective endocardial and coronary endothelial, but not venous or capillary Dll1 expression. Hearts of mice heterozygous for Dll1 (Dll1+/−) were significantly smaller than wildtype (wt) hearts (heart weight (g)/femur length (cm), wt: 0.13± 0.02 vs. het: 0.09± 0.02, n=10, p,0.05) while body weight and survival over 18 months was comparable. Furthermore, the number of medium (,50 -100 um) and large (,100 um) coronary arteries was significantly reduced in Dll1+/− hearts (p,0.01). Reduced coronary numbers were also apparent in neonatal hearts, ...
Delta and Notch function are required for cell fate specification in numerous tissues during embryonic and postembryonic Drosophila development. Delta is expressed by all members of interacting cell populations within which fates are being specified and is subsequently down-regulated as cells stably adopt particular fates. Multiphasic expression in the derivatives of many germ layers implies successive requirements for Delta function in a number of tissues. At the cellular level, Delta and Notch expression are generally coincident within developing tissues. At the subcellular level, Delta and Notch are localized in apparent endocytic vesicles during down-regulation from the surfaces of interacting cells, implying an interaction consistent with their proposed roles as signal and receptor in cellular interactions during development.. ...
The present study affirms our hypothesis that the Notch pathway plays an important role in macrophages, a key cell type in inflammation and atherosclerosis. Evidence that supports this idea includes the expression of multiple Notch receptors and ligands in human macrophages; markedly increased Dll4 expression in human macrophages stimulated with LPS, mmLDL, or IL-1β, an event that likely involves TLR4 and NF-κB; the ability of Dll4 to bind to macrophages and trigger Notch signaling; the induction of the MAPK, Akt, and NF-κB pathways in macrophages stimulated with Dll4; the Dll4-induced transcription of iNOS, PTX3, Id1, and Dll4 itself; and the presence of Notch pathway components, such as Dll4 and Notch3, in human atherosclerotic plaques rich in macrophages.. Dll4 expression induced in human primary macrophages by proinflammatory stimuli (LPS, IL-1β, and mmLDL) (Figures 2 through 4⇑⇑) and the detection of immunoreactive Dll4 in human atherosclerotic plaques (Figure 8) indicate possible ...
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
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 ...
High expression of Notch-1 and/or Jagged-1 has negative prognostic significance in breast cancer ( 14, 15), and Notch-1 can transform HMECs ( 16). Our data confirm that Notch-1 and Notch-4 are commonly coexpressed in infiltrating breast cancers of ductal and lobular histologies, which also express Notch ligands Jagged-1 and Delta-1. However, our observations on breast cancer cell lines suggest that there may not be a simple correlation between protein levels of Notch receptor and ligands and Notch pathway activity level. Our data suggest that estrogen inhibits Notch signaling through an ERα-dependent effect, which is at least in part mediated by inhibition of Notch cleavage by γ-secretase. Inhibition of Notch activation by estrogen is observed under physiologic, ligand-induced Notch activation conditions, but it is independent of Notch ligands. Estradiol did not affect expression of Jagged-1, the most abundant Notch ligand in these cells (data not shown). The membrane accumulation of uncleaved ...
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 ...
Differentiation of arteries and veins is essential for the development of a functional circulatory system. In vertebrate embryos, genetic manipulation of Notch signaling has demonstrated the importance of this pathway in driving artery endothelial cell differentiation. However, when and where Notch activation occurs to affect endothelial cell fate is less clear. Using transgenic zebrafish bearing a Notch-responsive reporter, we demonstrate that Notch is activated in endothelial progenitors during vasculogenesis prior to blood vessel morphogenesis and is maintained in arterial endothelial cells throughout larval stages. Furthermore, we find that endothelial progenitors in which Notch is activated are committed to a dorsal aorta fate. Interestingly, some arterial endothelial cells subsequently downregulate Notch signaling and then contribute to veins during vascular remodeling. Lineage analysis, together with perturbation of both Notch receptor and ligand function, further suggests several distinct
Notch1 has been regarded as a fundamental regulator in tissue differentiation and stem cell properties. Recently, Notch1 mutations have been reported intensively both in solid tumors and in hematopoietic malignancies. However, little is known about the biological effect and the clinical implication of these reported mutations. Previously, we discovered several missense mutations in the Notch1 receptor in a Chinese population with oral squamous cell carcinoma (OSCC). We selected a hotspot mutation in the Abruptex domain (C1133Y). The expression of Notch1 was determined by western blot and real-time qPCR in OSCC cell lines transfected with pcDNA3.1-Notch1WT, pcDNA3.1-Notch1C1133Y, or pcDNA3.1 empty vector. CCK-8 assays were used to assess cell proliferation. Flow cytometry and western blot were used to confirm the alteration of cell cycle after transfection. Transwell assays and the detection of Epithelial-to-mesenchymal transition (EMT) markers were used to determine the invasive ability. The effects
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
A recent study has shown that Cr-1 controls processing of the Nodal proprotein by recruiting proprotein convertases such as furin or PACE4 (Blanchet et al., 2008). Because processing by furin-like convertases (S1 cleavage) is also a prerequisite to generate mature heterodimerized Notch receptors (Logeat et al., 1998), we hypothesized that CR-1 may affect this processing step. Similar to the sequestration of the Nodal precursor protein into lipid rafts (Blanchet et al., 2008), forced expression of CR-1 in CR-1-deficient CHO cells enhanced the localization of the FL Notch1 protein in the lipid raft fraction in which glycosylphosphatidylinositol-anchored proteins such as CR-1 are enriched (Fig. 4 B). Furthermore, we assessed the effect of CR-1 expression on S1 cleavage of Notch1 in the presence of the γ-secretase inhibitor DAPT to exclude the effect on ligand-induced S3 cleavage (Fig. 4, C and D). CR-1 expression caused a dose-dependent increase in enhancement of the cleaved form of Notch1. This ...
Purpose: : To explore the role of Notch signaling in corneal endothelial-mesenchymal transformation (EnMT). Methods: : EnMT was induced in rat corneal endothelial cells (RCECs) by serial passages or TGF-β treatment, with or without 10µM DAPT. Cell phenotype and transformation were evaluated by EnMT markers, growth curve, scratch test, immunostaining and RT-qPCR. An in vivo EnMT rat model was induced by transcorneal freezing, with or without topical treatment of 50µM DAPT for 14 days. The wound endothelium was evaluated by slit lamp, stereomicroscope, immunostaining and RT-qPCR. Results: : Corneal EnMT in vitro was evidenced by changed morphology, downregulated tight junctions (ZO-1, Cx43 and N-cadherin), increased α-SMA and Notch signaling (Notch1, Notch2, Jag1 and Hes1). DAPT blocked EnMT induction, also reversed the phenotype, morphology and hyperplasia of the transformed RCECs. In rat, DAPT treatment blocked the EnMT process, with normal tight junction and suppressed α-SMA and Notch ...
The NOTCH signaling pathway is evolutionally conserved and critical in stem cell differentiation and cell fate determination in development. Its roles in malignant initiation and progression, however, are complex and appear organ/cell-type dependent.. Four NOTCH receptors (NOTCH 1-4) exist in mammals with a different number of EGF-like repeats and are activated upon binding to ligands (1). The activation requires two sequential protein cleavage steps by ADAM10/17 metalloproteases and presenilin-γ-secretase complex (γ-secretase) to release the intracellular portion of the NOTCH, also known as ICN, which is translocated into the nucleus and mediates activation of the NOTCH pathway (2-4). Therefore, NOTCH pathway activities can be impacted by not only NOTCH receptors themselves but also their ligands, the protein cleavage steps, and ICN nuclear translocation.. Genetic alterations of genes in the NOTCH pathway have been noted in a number of human malignancies both in hematopoietic and solid tumors ...
Wnt signaling is important for T-cell differentiation at the early CD4(-)CD8(-) stage and is subsequently downregulated with maturation. To assess the importance of this downregulation, we generated a mouse line (R26-βcat) in which high levels of active β-catenin are maintained throughout T-cell development. Young R26-βcat mice show a differentiation block at the CD4(+)CD8(+) double-positive (DP) stage. These DP cells exhibit impaired apoptosis upon irradiation or dexamethasone treatment. All R26-βcat mice develop T-cell leukemias at 5 to 6 months of age. R26-βcat leukemias remain dependent on β-catenin function but lack Notch pathway activation. They exhibit recurrent secondary genomic rearrangements that lead to Myc overexpression and loss of Pten activity. Because β-catenin activation and Myc translocations were previously found in murine T-cell acute lymphoblastic leukemias (T-ALLs) deficient for Pten, our results suggest that activation of the canonical Wnt pathway is associated with a
Sonic hedgehog (Shh) is an established morphogen critical to the development of the vascular system15,16 and is known to cooperate with vascular-specific growth factors during arterial differentiation.8,9 In adult blood vessels, Shh is angiogenic in the ischemic hindlimb,9 stimulates the production of angiogenic factors, including VEGF-A and angiopoietin-1 by interstitial fibroblasts,9 and promotes endothelial cell chemotaxis and tube formation.26 A restricted domain of Shh signaling has recently been localized to the arterial adventitia27 and may play an important role in cell maintenance within the artery wall after injury. While medial SMCs at the adventitial boundary express Ptc1 receptors,9,27 the role of Hh in SMCs, particularly after injury, remains unclear. We therefore examined whether recapitulation of Hh components occurred in SMCs after injury in vivo and further whether there is a specific functional role for Shh in activating Notch signaling in vitro to control SMC growth and ...
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 ...
Signaling through the Notch1 receptor is essential for T cell development in the thymus. Stromal OP9 cells ectopically expressing the Notch ligand Delta-like1 mimic the thymic environment by inducing hemopoietic stem cells to undergo in vitro T cell development. Notch1 is also expressed on Pax5-/- pro-B cells, which are clonable lymphoid progenitors with a latent myeloid potential. In this study, we demonstrate that Pax5-/- progenitors efficiently differentiate in vitro into CD4+CD8+ alphabeta and gammadelta T cells upon coculture with OP9-Delta-like1 cells. In vitro T cell development of Pax5-/- progenitors strictly depends on Notch1 function and progresses through normal developmental stages by expressing T cell markers and rearranging TCRbeta, gamma, and delta loci in the correct temporal sequence. Notch-stimulated Pax5-/- progenitors efficiently down-regulate the expression of B cell-specific genes, consistent with a role of Notch1 in preventing B lymphopoiesis in the thymus. At the same ...
Gradients of vascular endothelial growth factor (VEGF) induce single endothelial cells to become leading tip cells of emerging angiogenic sprouts. Tip cells then suppress tip-cell features in adjacent stalk cells via Dll4/Notch-mediated lateral inhibition. We report here that Smad1/Smad5-mediated BMP signaling synergizes with Notch signaling during selection of tip and stalk cells. Endothelium-specific inactivation of Smad1/Smad5 in mouse embryos results in impaired Dll4/Notch signaling and increased numbers of tip-cell-like cells at the expense of stalk cells. Smad1/5 downregulation in cultured endothelial cells reduced the expression of several target genes of Notch and of other stalk-cell-enriched transcripts (Hes1, Hey1, Jagged1, VEGFR1, and Id1-3). Moreover, Id proteins act as competence factors for stalk cells and form complexes with Hes1, which augment Hes1 levels in the endothelium. Our findings provide in vivo evidence for a regulatory loop between BMP/TGFβ-Smad1/5 and Notch signaling that
Author Summary Multicellular development requires tightly regulated spatial pattern formation, frequently including the generation of sharp differences over short length scales. Classic examples include boundary formation in the Drosophila wing veins and lateral inhibition patterning in the differentiation of sensory cells. These processes and a diverse variety of others are mediated by the Notch signaling system which allows neighboring cells to exchange information, via interaction between the Notch receptor on one cell and its ligands such as Delta, on another. Interestingly, recent evidence has shown that Notch and Delta within the same cell (in cis) also interact, mutually inactivating each other. However, the significance of this interaction for pattern formation has remained unclear. Here we show, by analytical and computational modeling, how this cis interaction intrinsically generates a difference-promoting logic that optimizes the system for use in fine-grained pattern formation. Specifically,
Objective(s): NOTCH signaling pathway is well known for its role in cell fate, cell survival, cell differentiation, and apoptosis. Some of the NOTCH signaling genes are critical for endometrial function and implantation in animals and appear to play a similar role in humans. The purpose of the current study was to investigate the potential roles of some main components of the NOTCH family in human endometrium during implantation period in common gynecological diseases.Materials and Methods: Endometrial NOTCH receptors NOTCH1, 3, 4 and ligand JAG1, 2 and survivin mRNA expression were investigated using the Q-PCR technique and the amount of the JAG1, 2 proteins was also determined by Western blot. Samples were obtained from 12 patients with endometriosis, 12 patients with repeated implantation failure (RIF), 12 patients with Polycystic Ovary Syndrome (PCOS) and 10 healthy fertile women as a control group. Data were analyzed using SPSS version 18. Group comparisons were performed by one-way ANOVA or
Signaling through the Notch1 receptor is essential for the control of numerous developmental processes during embryonic life as well as in adult tissue homeostasis and disease. Since the outcome of Notch1 signaling is highly context-dependent, and its precise physiological and pathological role in many organs is unclear, it is of great interest to localize and identify the cells that receive active Notch1 signals in vivo. Here, we report the generation and characterization of a BAC-transgenic mouse line, N1-Gal4VP16, that when crossed to a Gal4-responsive reporter mouse line allowed the identification of cells undergoing active Notch1 signaling in vivo. Analysis of embryonic and adult N1-Gal4VP16 mice demonstrated that the activation pattern of the transgene coincides with previously observed activation patterns of the endogenous Notch1 receptor. Thus, this novel reporter mouse line provides a unique tool to specifically investigate the spatial and temporal aspects of Notch1 signaling in vivo. ...
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, ...
In this study, the research team investigated NOTCH1 mutations in keratinocyte lines derived from OSCC biopsies that had been subjected to whole exome sequencing.. One line, SJG6, was found to have truncating mutations in both NOTCH1 alleles, resulting in loss of NOTCH1 expression.. Overexpression of the NOTCH1 intracellular domain in SJG6 cells promoted cell adhesion and differentiation, while suppressing proliferation, migration and clonal growth, consistent with the previously reported tumour suppressive function of NOTCH1 in OSCC.. Dr. Fiona M. Watt from the Centre for Stem Cells and Regenerative Medicine, Kings College London; Tower Wing, Guys Hospital, London, UK said "Notch1 is a heterodimeric and multifunctional transmembrane receptor that regulates key cellular processes, including cell fate determination, maintenance of stem cells, cell survival, proliferation and apoptosis.". Notch1 is a heterodimeric and multifunctional transmembrane receptor that regulates key cellular processes, ...
In this study, we have shown that ligand-induced Notch activation in multipotent hematopoietic precursor cells regulates lineage expression in a density-dependent manner. Our data suggest that the enhanced formation of B and T precursors occurs in the presence of lower densities of Delta1ext-IgG because of the effects on multipotent precursors. In addition, higher densities of ligand lead mainly to T cell differentiation because of the inhibition of early B cell and myeloid differentiation by multipotent precursors and the promotion of T cell differentiation by lymphoid committed precursors. These results represent the first evidence that a single Notch ligand can enhance the development of cells that adopt either a B or a T cell fate.. Previous studies of cell fate outcomes induced by Delta1 have used cell-expressed ligands and were thus unable to address quantitative differences in ligand expression (11, 21, 26). However, our studies suggest that lower densities of Delta1 induce Notch ...
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 receptors modulate transcriptional targets following the proteolytic release of the Notch intracellular domain (NotchIC). Phosphorylated forms of NotchIC have been identified within the nucleus and have been associated with CSL members, as well as correlated with regions of the receptor that are required for activity. Genetic studies have suggested that Shaggy, the Drosophila homolog of glycogen synthase kinase-3ß (GSK3ß) may act as a positive modulator of the Notch signaling. GSK3ß is a serine/threonine kinase and is a component of the Wnt/wingless signaling cascade. GSK3ß is able to bind and phosphorylate Notch1IC in vitro, and attenuation of GSK3ß activity reduces phosphorylation of NotchIC in vivo. Functionally, ligand-activated signaling through the endogenous Notch1 receptor is reduced in GSK3ß null fibroblasts, implying a positive role for GSK3ß in mammalian Notch signaling. As a possible mechanistic explanation of the effect of GSK3ß on Notch signaling, it was observed that ...
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 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 ...
Asymmetric cell division is a conserved mechanism by which cell fate diversity is generated during Metazoan development. How one cell can generate two daughter cells with different identities and how defects in this asymmetry can contribute to cancer are the fundamental questions we are addressing in Drosophila. We are investigating this process in the context of asymmetric cell division of neural precursor cells, called Sensory Organ Precursor (SOP). These latter undergo four rounds of asymmetric divisions, in which mother cells generate distinct daughters via the unequal segregation of the cell-fate determinants Numb and Neuralized at mitosis. At each division binary cell fate decision are regulated by Delta-Notch dependent cell-cell signalling. Numb is an endocytic protein that can bind to Notch and a four pass transmembrane protein named Sanpodo (Spdo), a protein required for Notch activation in SOP lineage, thereby preventing Notch activation in this cell. Neur acts in SOPs and pIIb cells ...
Asymmetric cell division is a conserved mechanism by which cell fate diversity is generated during Metazoan development. How one cell can generate two daughter cells with different identities and how defects in this asymmetry can contribute to cancer are the fundamental questions we are addressing in Drosophila. We are investigating this process in the context of asymmetric cell division of neural precursor cells, called Sensory Organ Precursor (SOP). These latter undergo four rounds of asymmetric divisions, in which mother cells generate distinct daughters via the unequal segregation of the cell-fate determinants Numb and Neuralized at mitosis. At each division binary cell fate decision are regulated by Delta-Notch dependent cell-cell signalling. Numb is an endocytic protein that can bind to Notch and a four pass transmembrane protein named Sanpodo (Spdo), a protein required for Notch activation in SOP lineage, thereby preventing Notch activation in this cell. Neur acts in SOPs and pIIb cells ...
In this report, we have provided new insight into the relationship between the Notch and FGF pathways during prosensory induction in the cochlea. (1) we showed that the expression of Fgf20 is dependent on Notch signaling. At the time of prosensory induction, Notch inhibition led to a decline in Fgf20 expression, as shown by RT-qPCR and in situ hybridization. Jag1 cKO mutants also showed a loss of Fgf20 expression. (2) In addition, we found that FGF20 can rescue the inhibition of Notch in explant cultures. FGF20 added to E12.5 explants rescues Sox2 expression and in some cases sensory cells, while FGF9, a more potent member of the FGF20 subfamily, can rescue a substantial number of sensory cells in the presence of continuous Notch inhibition with DAPT. Also, FGF20 added to DAPT-treated E13.5 explants provides a consistent rescue of sensory cells in the apex. Together, these results support a model in which prosensory specification by Notch signaling acts at least in part via regulation of Fgf20 ...
The Notch pathway plays critical roles in the differentiation and polarized activation of macrophages; however, the downstream molecular mechanisms underlying Notch activity in macrophages remain elusive. Our previous study has identified a group of miRNAs that mediate Notch signaling to regulate macrophage activation and tumor-associated macrophages (TAMs). In this study, we demonstrated that miR-148a-3p functions as a novel downstream molecule of Notch signaling to promote the differentiation of monocytes into macrophages in the presence of granulocyte and macrophage colony stimulating factor (GM-CSF). Meanwhile, miR-148a-3p promoted M1 and inhibited M2 polarization of macrophages upon Notch activation. Macrophages overexpressing miR-148a-3p exhibited enhanced ability to engulf and kill bacteria, which was mediated by excessive production of reactive oxygen species (ROS). Further studies using reporter assay and Western blotting identified Pten as a direct target gene of miR-148a-3p in macrophages.
Notch receptors are a family of highly conserved transmembrane receptors crucial to cell development and fate: Notch-1 plays a critical role in normal T cell development, and is further involved in T cell activation and differentiation, while Notch-2 is known to be important to B cell development. The ability to influence T and B cell fate is of great interest in the field of transplantation; however, limited data exist on the importance of Notch-1 and Notch-2 in immune regulation. The primary aim of this study was to investigate the role of Notch-1 and Notch-2 in the alloimmune response using an in vivo mouse model of solid organ transplantation and selective human anti-Notch-1 (aNotch-1) and anti-Notch-2 (aNotch-2) antibodies, with particular reference to their roles in T and B cell development and behaviour, respectively.
In cancer, DNA methylation affects important signal transduction pathways leading to altered receptor function, disruption of normal cell-cell interaction, etc. Since methylation occurs at a very early stage, hypermethylated promoters hold great promise as biomarkers for early detection and an effective drug target for gene reactivation. The Notch signaling pathway is one such developmental pathway governing cell fate decisions. Dysregulated Notch signaling is found to have a prominent role in the development of various cancers. Glioblastoma is the most common primary brain tumor with a very poor prognosis. Therefore it is important to study genetic and epigenetic events leading to gliomagenesis and to guide new treatment strategies. The aim of this study was to detect Notch pathway genes potentially regulated by promoter methylation in human glioblastoma. We used real-time PCR and methylation-specific PCR to study gene expression and methylation status of seven Notch pathway genes (Notch1, ...
Notch signaling through the Notch2 receptor is essential for normal biliary tubulogenesis during liver development. However, the signaling events downstream of Notch2 critical for this process are less well defined. Furthermore, whether Notch signali
The present study is the first to examine the relation between CVD and the Notch3 polymorphism. The Japanese population has a higher C allele frequency in T6746C polymorphism than European populations.3 Our study shows that the Notch3 polymorphism is not associated with CVD, even in low risk subjects.. Mutations in the Notch3 gene are missense mutations characteristically leading to the loss or gain of a cysteine residue in one of the EGF-like domains of the protein.3 The abnormal Notch3 allele may encode for a protein product with an abnormal conformation due to disruption of the disulphide bonding of cysteine residues. Five genetic polymorphisms, which lead to amino acid substitutions, have been reported in the coding sequence of Notch 3.3 Among them, the most common polymorphism, T6746C, results in an amino acid dimorphism (Val/Ala) at residue 2223, which is located in the intracellular domain. Because the intracellular domain of Notch3 is thought to be involved in signal transduction,2 this ...
Formation of a regularly branched blood vessel network is crucial in development and physiology. Here we show that the expression of the Notch ligand Dll4 fluctuates in individual endothelial cells within sprouting vessels in the mouse retina in vivo and in correlation with dynamic cell movement in mouse embryonic stem cell-derived sprouting assays. We also find that sprout elongation and branching associates with a highly differential phase pattern of Dll4 between endothelial cells. Stimulation with pathologically high levels of Vegf, or overexpression of Dll4, leads to Notch dependent synchronization of Dll4 fluctuations within clusters, both in vitro and in vivo. Our results demonstrate that the Vegf-Dll4/Notch feedback system normally operates to generate heterogeneity between endothelial cells driving branching, whilst synchronization drives vessel expansion. We propose that this sensitive phase transition in the behaviour of the Vegf-Dll4/Notch feedback loop underlies the morphogen ...
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 ...
In the present report, we show that PF-03084014 has broad antitumor activity against Notch receptor-driven tumors via its potent inhibition of γ-secretase. This novel orally available small molecule, PF-03084014, was identified as a selective reversible, noncompetitive inhibitor of γ-secretase. PF-03084014 potently modulated the Notch receptor signaling pathway and inhibited the growth of a panel of T-ALL cells potentially through the induction of cell cycle arrest and apoptosis. This compound also displayed significant antitumor activity in a broad spectrum of Notch-driven xenograft models.. Previous studies have shown that activated Notch signaling causes aberrant cell cycle progression of T-ALL cells and GSI treatments lead to cell cycle arrest and exit (3, 12, 13, 23, 24). We confirm and extend these findings by showing that PF-03084014 completely inhibited Notch activity (NICD levels) and expression of Notch target genes Hes-1 and cMyc after 7 days of treatment. Notch inhibition caused a ...
Interphase fluorescence in situ hybridization (FISH) for detection of structural chromosomal abnormalities involving NOTCH2 was carried out on nuclei isolated from frozen tumor tissue of 23 of the MZL cases, 2 of which also showed NOTCH2 mutations. Several probes mapping to different segments of NOTCH2 were used. FISH was performed according to standard methods. For the quantitative detection of NOTCH2 mRNA expression and one of the Notch target gene HES-1 commercial primers and probes (PE Applied Biosystems, Hs00225747 and Hs00172878) were used. An ABI PRISM 7700 instrument (PE Applied Biosystems) was used for the PCR. Relative mRNA concentrations were calculated using the comparative CT method (PE Applied Biosystems, user bulletin No.2, 1997) with β-glucuronidase (GUS) as an internal control. All samples were compared to the relative mRNA level obtained in the SSK41 cell line. Immunoblot analysis was performed with frozen tissue sections lysed in lysis buffer, proteins were resolved by SDS ...
A humanized monoclonal antibody directed against the N-terminal epitope of Notch ligand DLL4 (delta-like 4) with potential antineoplastic activity. Anti-DLL4 monoclonal antibody OMP-21M18 binds to the membrane-binding portion of DLL4 and prevents its interaction with Notch-1 and Notch-4 receptors, thereby inhibiting Notch-mediated signaling and gene transcription, which may impede tumor angiogenesis. Activation of Notch receptors by DLL4 stimulates proteolytic cleavage of the Notch intracellular domain (NICD); after cleavage, NICD is translocated into the nucleus and mediates the transcriptional regulation of a variety of genes involved in vascular development. The expression of DLL4 is highly restricted to the vascular endothelium ...
Real-time PCR of vasculogenic and Notch target genes in Notch112f/lbd yolk sac and embryo. Total RNA extracted from E10.5 yolk sac or embryonic head was reverse
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). ...
The NOTCH signaling pathway is mostly recognized for its role in determining cell fate, especially during development and tissue homeostasis.18 The pathway transduces signals between neighboring cells, emphasizing its participation in the 3-dimensional structuring of tissues. Here, we report that the NOTCH pathway is of disease relevance in large-vessel vasculitis, regulating the activity of vessel wall-infiltrating T cells that orchestrate tissue damage in blood vessels. Blocking NOTCH signaling has profound effects on T-cell-dependent immune responses and suppresses the production of proinflammatory cytokines, in particular IL-17. Both early and later stages of vasculitis are sensitive to disrupting NOTCH-NOTCH ligand interactions, suggesting that this pathway has potential as a therapeutic target in inflammatory vasculopathies.. In GCA, CD4 T-cell invasiveness, cytotoxicity, and in situ cytokine production lie at the core of the pathogenic process.19 Initiation of vascular inflammation ...
During early vertebrate eye development, a regulatory network of transcription factors regulates retinal cell differentiation (Ohsawa and Kageyama, 2008) and survival into adulthood, including Pax6, Six3, Rx, Chx10, Notch, and Notch pathway components (Badea and Nathans, 2011; Mu and Klein, 2004). KLFs including KLF4 regulate differentiation of other cell types throughout the body (Apara and Goldberg, 2014; Moore et al., 2011), and KLF4 is one of a set of four factors capable of reprogramming somatic cells into induced pluripotent stem cells (Hanna et al., 2008; Takahashi et al., 2007; Takahashi and Yamanaka, 2006; Welstead et al., 2008; Yu et al., 2007). KLF4 plays an important role in cell cycle arrest and growth inhibition (Choi et al., 2006; Wei et al., 2005, 2008), and is highly expressed in the postmitotic cells of both the gut and skin (Shields et al., 1996; Zheng et al., 2009). KLF4 has been found to be downregulated in many types of cancers, indicating its possible contribution to ...
21 Background: Inflammation-dominated sympathetic sprouting adjacent to the necrotic 22 region following myocardial infarction (MI) has been implicated in the etiology of 23 arrhythmias resulting in sudden cardiac death; however, the mechanisms responsible remain 24 to be elucidated. Although being a key immune mediator, the role of the Notch has yet to be 25 explored. 26 Objective: We investigated whether Notch regulates macrophage responses to 27 inflammation and affects cardiac sympathetic reinnervation in rats undergoing MI. 28 Methods and Results: MI was induced by coronary artery ligation. A high level of NICD 29 was observed in the macrophages that infiltrated the infarct area at 3 days post-MI. The 30 administration of the Notch inhibitor 31 N-N-(3,5-difluorophenacetyl-l-alanyl)-S-phenylglycine-t-butyl ester (DAPT) (i.v. 30 minutes 32 before MI and then daily until sacrifice) decreased the number of macrophages and 33 significantly increased the M2 macrophage activation profile in the early
Regulation of arterial development and branching morphogenesis The purpose of these studies is to elucidate molecular pathways leading to arterial specification of the endothelium and formation of arterial vasculature. We have recently demonstrated that knockout of synectin, a PDZ protein involved in endosomal trafficking of a number of TK receptor complexes leads to selective reduction in arterial morphogenesis and vascular branching (Chittenden et al Dev Cell, 2006). We have now demonstrated that synectin controls retrograde trafficking of VEGF-R2 containing endosomes via its binding to myosin-VI. Interestingly, myosin-VI knockout in mice or knockdown in zebrafish leads to the same arteriopenic phenotype. This abnormal receptor trafficking results in impaired activation of one of VEGF-R2 signaling pathways that appears to be crucial for arterial specification. Rescue of this aspect of VEGF signaling fully restores arterial morphogenesis not only in synectin null or myosin-VI null mice but in ...
EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It is generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, but contrary to this, we uncovered here that gefitinib and osimertinib increased STAT3 phosphorylation (p-STAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induced a p-STAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we showed that tyrosine kinase inhibitor-resistant tumors, with EGFRT790M and EGFRC797S mutations, were highly responsive to the combined treatment of Notch inhibitors with gefitinib or osimertinib, respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse ...
The Notch receptor is part of a core signalling pathway which is highly conserved in all metazoan species. It is required for various cell fate decisions at multiple stages of development and in the adult organism, with dysregulation of the pathway associated with genetic and acquired diseases including cancer. Although cellular and in vivo studies have provided considerable insight into the downstream consequences of Notch signalling, relatively little is known about the molecular basis of the receptor/ligand interaction and initial stages of activation. Recent advances in structure determination of the extracellular regions of human Notch-1 and one of its ligands Jagged-1 have given new insights into docking events occurring at the cell surface which may facilitate the development of new highly specific therapies. We review the structural data available for receptor and ligands and identify the challenges ahead.
Akt1 is well known for its role in regulating cell proliferation, differentiation, and apoptosis and is implicated in tumors and several neurological disorders. However, the role of Akt1 in neural development has not been well defined. We have isolated zebrafish akt1 and shown that this gene is primarily transcribed in the developing nervous system, and its spatiotemporal expression pattern suggests a role in neural differentiation. Injection of akt1 morpholinos resulted in loss of neuronal precursors with a concomitant increase in post-mitotic neurons, indicating that knockdown of Akt1 is sufficient to cause premature differentiation of neurons. A similar phenotype was observed in embryos deficient for Notch signaling. Both the ligand (deltaA) and the downstream target of Notch (her8a) were downregulated in akt1 morphants, indicating that Akt1 is required for Delta-Notch signaling. Furthermore, akt1 expression was downregulated in Delta-Notch signaling-deficient embryos and could be induced by
My laboratory focuses on the in vivo regulation of stem cell self-renewal and differentiation in the germline tissue of the small nematode C. elegans. In this system, Notch signaling from a single-celled mesenchymal niche promotes maintenance of germline stem cells (GSCs)(1). My talk will focus on two broadly important questions. First, what key downstream effectors of Notch signaling are transcriptionally activated in stem cells to maintain their totipotent state? Second, how does Notch-dependent transcriptional activation maintain a pool of stem cells? We have known for some time that an RNA regulatory network acts downstream of Notch signaling to drives the choice between self-renewal and differentiation. We recently identified two Notch-dependent direct target genes, lst-1 and sygl-1, that fully account for the role of GLP-1/Notch signaling in GSC control (2). My talk will report recent efforts to understand lst-1 and sygl-1, to identify additional direct Notch targets in GSCs and to ...
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.. ...
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/...
Msi1 is an RNA-binding protein that represses mRNA translation by binding specific consensus sites present in the 3′-UTR region of its targets (Imai et al., 2001). In fact, Msi1 competes with the translation initiation factor eIF4G to bind PABP, preventing the initiation of translation (Kawahara et al., 2008). A recent study identified new direct targets of Msi1 using a global RIP-Chip analysis (de Sousa Abreu et al., 2009). The authors showed that these targets preferentially participate in two major processes involved in tumorigenesis: proliferation versus apoptosis, and protein modifications. Another study described several mRNAs that are deregulated by Msi1 overexpression, which are therefore considered to be indirect targets (Wang et al., 2008). Interestingly, this study showed that the overexpression of Msi1 in a mammary cell line induces cell proliferation and activates Wnt and Notch pathways. Here we report similar results in a different cellular context. Indeed, we show that Msi1 ...
Notch receptors are core components of the Notch signaling pathway and play a central role in cell fate decisions during development as well as tissue homeostasis. Upon ligand binding, Notch is sequentially cleaved at the ...
The researchers found that the segmentation clock lies quiescent in individual embryonic cells that give rise to the vertebrae, then clicks on all at once, collectively, when the cells reach a critical mass.. The researchers further discovered that the clock is controlled by two signals, Notch and Yap, that are sent and received by these cells.. On its own, they found, Notch starts the clock ticking by triggering cellular oscillations that release instructions to build structures that will ultimately become vertebrae. But Notch isnt the only signal in town.. It turns out that the cells Yap chatter determines the amount of Notch required to activate the segmentation clock. If Yap is very low, then the clock runs on its own. If Yap levels are "medium," said Pourquié, then Notch is needed to start the clock. And if Yap levels are high, even a lot of Notch wont convince the clock to tick. Scientists call this an excitability threshold.. "If you stimulate the system a little, nothing happens. But ...
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Abstract The Notch signaling pathway is fundamental to proper cardiovascular development and is now recognized as an important player in tumor angiogenesis. Two key Notch ligands h..
View Jag1/Jag1<+> Notch2/Notch2<+> involves: 129S1/Sv * C57BL/6J: phenotypes, images, diseases, and references.
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
Sigma-Aldrich offers abstracts and full-text articles by [Yoshihito Taniguchi, Helena Karlström, Johan Lundkvist, Tomohiko Mizutani, Akira Otaka, Monica Vestling, Alan Bernstein, Dorit Donoviel, Urban Lendahl, Tasuku Honjo].
Find Non-Canonical Notch Signaling Molecules research area related information and Non-Canonical Notch Signaling Molecules research products from R&D Systems. Learn more.
NOTCH3 - NOTCH3 - Human, 4 unique 29mer shRNA constructs in retroviral untagged vector shRNA available for purchase from OriGene - Your Gene Company.
Mouse monoclonal antibody raised against a partial recombinant NOTCH3. NOTCH3 (NP_000426, 47 a.a. ~ 156 a.a) partial recombinant protein with GST tag. MW of the GST tag alone is 26 KDa. (H00004854-M01) - Products - Abnova
A piece of Armco iron wire was notched to a depth of .030 in., polished and etched, and then cycled by reversed plane bending. Plastic replicas were made of the notch root after the completion of each tensile stroke. A long trough or crack, about 20 microns deep and 20 microns wide was observed to develop during 7-1/4 cycles. Various effects of cyclic plastic flow were observed in detail at and near the notch root, including the formation of slip bands and subsequent fissuring in the slip bands, and the sinking of surface material to form troughs during cycling. (Author)(*IRON
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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:112461 Tang LS, Alger HM, Pereira FA, COUP-TFI controls Notch regulation of hair cell and support cell differentiation. Development. 2006 Sep;133(18):3683-93 ...
Gentaur molecular products has all kinds of products like :search , Prosci \ DTX2 is a regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. DTX2 probably acts both as a positive and \ 29-852 for more molecular products just contact us
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In this study, I have attempted to understand how Notch signals promote different stages of T cell maturation by examining the regulation of Notch signals on two levels. First, I have used an in vitro culture system to ...
BEN factors are conserved CSL co-repressors in Notch-mediated neural development. Our general goal is to understand how cell signaling pathways mediate accurate...
Sigma-Aldrich offers abstracts and full-text articles by [Lin Mi, Yaosheng Chen, Xueli Zheng, Youlei Li, Qiangling Zhang, Delin Mo, Gongshe Yang].
During embryogenesis, the Notch/RBPjk and Wnt/2-catenin signaling pathways regulate diverse cell fate decisions. Osteoblasts are the primary cell type responsib...
Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our cu
Rabbit polyclonal activated Notch1 antibody validated for WB, ICC/IF and tested in Human. Referenced in 1 publication. Immunogen corresponding to synthetic…
Buy NOTCH1 blocking peptide-NP_060087.3 (MBS8212478) product datasheet at MyBioSource, Blocking Peptides. Application: Blocking (BL)
The Notch signaling pathway plays a substantial role on human NK cell development, however the role of Notch on KIR upregulation and acquisition of effector function has not been explored. To evaluate how Notch influences terminal differentiation, cord blood derived NK cells or sorted KIR- peripheral blood NK cells were cultured with IL-15 for 7 days in the presence or absence of gamma-secretase inhibitor, known to inhibit Notch signaling. Inhibition of Notch signaling significantly decreased KIR expression. Conversely, co-culturing the same cells with OP9 cells bearing Notch ligands enhanced KIR expression. Overexpression of the active portion of Notch on cord blood derived NK cells after 28 days of culture resulted in a 2-fold increase in KIR expression indicating that Notch signaling plays a direct, cell intrinsic, role in KIR regulation. By knocking down delta-like 1 (DLL1) on NK cells and co-culturing them with OP9 cells expressing Notch ligands we show that DLL1 mediated cis-inhibition ...
RETIEF, Chris; SCHUTTE, Clara-Maria and BAKER, Malcolm Kevin. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). SAMJ, S. Afr. med. j. [online]. 2009, vol.99, n.6, pp.461-465. ISSN 2078-5135.. BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leuco-encephalopathy (CADASIL) is a hereditary autosomal dominant non-atherosclerotic non-amyloid cerebral arteriopathy. The disease was identified in 1993. We are not aware of reports in the literature of its occurrence in South Africa, and we present the clinical and laboratory features of 5 patients with CADASIL. METHODS: Patients with the characteristic radiological white matter disease and typical features (family history, ischaemic events, migraine or dementia) were evaluated for possible CADASIL by means of clinical examination, routine investigations for strokes, magnetic resonance imaging, skin biopsy electron microscopy, evoked potentials and ...
The Notch protein is a transmembrane signaling protein responsible for regulating several important pathways among all metazoans including cell proliferation, differentiation, and death. Notch exists as one protein in Drosophila, but has four homologs in mice and humans (Notch1- 4). A defining component of the Notch protein is the presence of 29-36 tandem epidermal growth factor-like (EGF) repeats, small protein motifs defined by the presence of six cysteines forming three disulfide bonds. Defects in Notch have been linked to various diseases like Alagille syndrome and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is responsible for early onset of dementia in patients aged 40-50, along with migraines and stroke. CADASIL is characterized by the presence and accumulation of granular osmiophilic material (GOMs) and Notch3 extracellular domain in close proximity to vascular smooth muscle cells, eventually leading to the degradation of ...
The Notch receptor of Drosophila and its homologues in other organisms mediate cell-cell interactions required for the correct partitioning of cell fates within equivalence groups. Genes related to Notch and other components of the Notch signaling pathway represent a well conserved system for signal transduction, having been isolated from organisms as diverse as flies, worms, sea urchins, frogs, fish, chickens, mice, rats, and humans (reviewed by Lardelli et al., 1995). The expression and requirements for Notch signaling are pleiotropic through development, in contrast to other tissue or cell type specific receptors. How the Notch signaling cascade mediates pattern formation in so many tissues and cell types is not well understood. The research contained herein increases the understanding of Notch signaling by studying its role during Drosophila oogenesis. Additionally, this research lends insight into several important processes that take place during Drosophila oogenesis, including ...
Notch signalling, SoxB and Group A bHLH proneural genes are conserved regulators of the neurogenic program in many bilaterians. However, the ancestry of their functions and interactions is not well understood. We address this question in the sea anemone Nematostella vectensis, a representative of the Cnidaria, the sister clade to the Bilateria. It has previously been found that the SoxB orthologue NvSoxB(2) is expressed in neural progenitor cells (NPCs) in Nematostella and promotes the development of both neurons and nematocytes, whereas Notch signalling has been implicated in the negative regulation of neurons and the positive regulation of nematocytes. Here, we clarify the role of Notch by reporting that inhibition of Notch signalling increases the numbers of both neurons and nematocytes, as well as increasing the number of NvSoxB(2)-expressing cells. This suggests that Notch restricts neurogenesis by limiting the generation of NPCs. We then characterise NvAth-like (Atonal/Neurogenin family) ...
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Podocyte apoptosis is a key process in the onset of diabetic nephropathy. A significant body of evidence shows that the Notch signaling pathway plays a central role in this process. We found that Rho-kinase mediates transforming growth factor β (TGF-β)-induced Notch ligand Jag1 expression. Importantly, TGF-β-mediated podocyte apoptosis was attenuated by Rho-kinase inhibition. Mechanistically, Rho-kinase regulated Jag1 induction via the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) but not Smad pathways. Consistently, the Rho-kinase inhibitor fasudil prevented albuminuria and the urinary excretion of nephrin in db/db mice and reduced the prevalence of podocyte apoptosis and Jag1 expression. Finally, the expression of Jag1 and apoptosis markers such as Bax and cyclin-dependent kinase inhibitor 1A (CDKN1A) was decreased in podocytes derived from db/db mice treated with fasudil. The present study provides evidence that Rho-kinase plays a key role in podocyte apoptosis.
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 ...
McKellar S.H., Tester D.J., Yagubyan M., Majumdar R., Ackerman M.J., Sundt T.M.. OBJECTIVES: Bicuspid aortic valve is a common condition and is associated with a significantly increased risk of developing thoracic aortic aneurysms and acute aortic dissection. Patient-specific prediction of the risk of developing thoracic aortic aneurysm, however, is imprecise. We hypothesize that genotypic variations in patients with bicuspid aortic valves contribute to this observed variability in aortic phenotype. We, therefore, investigated the potential relationship between mutations in regions of NOTCH1 recently reported to be associated with bicuspid aortic valve and the phenotype of bicuspid aortic valve and thoracic aortic aneurysms in unrelated patients undergoing surgical repair. METHODS: We performed a targeted mutational analysis of NOTCH1 using genomic DNA from 48 unrelated subjects with concomitant bicuspid aortic valve and thoracic aortic aneurysm using denaturing high-performance liquid ...

The Notch Receptor and Its Ligands Are Selectively Expressed During Hematopoietic Development in the Mouse - Walker - 2001 -...The Notch Receptor and Its Ligands Are Selectively Expressed During Hematopoietic Development in the Mouse - Walker - 2001 -...

Members of the Notch family of transmembrane receptors are found on primitive hematopoietic precursors, and Notch ligand ... as well as a selective use of Notch signaling in adult erythropoiesis and granulopoiesis. Notch receptors in the adult are most ... The Notch Receptor and Its Ligands Are Selectively Expressed During Hematopoietic Development in the Mouse. Authors. *. Liberty ... In the embryo, Northern analysis and in situ hybridization were used to characterize Notch receptor and ligand expression in ...
more infohttp://onlinelibrary.wiley.com/doi/10.1634/stemcells.19-6-543/abstract

The cell giveth and the cell taketh away: An overview of Notch pathway activation by endocytic trafficking of ligands and...The cell giveth and the cell taketh away: An overview of Notch pathway activation by endocytic trafficking of ligands and...

In receptor-presenting cells, endocytosis may be a prerequisite for Notch cleavage and thus activation and/or it could be a ... In receptor-presenting cells, endocytosis may be a prerequisite for Notch cleavage and thus activation and/or it could be a ... In receptor-presenting cells, endocytosis may be a prerequisite for Notch cleavage and thus activation and/or it could be a ... In receptor-presenting cells, endocytosis may be a prerequisite for Notch cleavage and thus activation and/or it could be a ...
more infohttps://ohsu.pure.elsevier.com/en/publications/the-cell-giveth-and-the-cell-taketh-away-an-overview-of-notch-pat

Critical role of endothelial Notch1 signaling in postnatal angiogenesi by K Takeshita, M Satoh et al."Critical role of endothelial Notch1 signaling in postnatal angiogenesi" by K Takeshita, M Satoh et al.

Of the Notch receptors, only Notch1 and Notch4 are expressed in vascular endothelial cells. Here we show that blood flow ... in response to ischemia was comparable between wild-type and Notch mutant mice, suggesting that Notch1 is downstream of VEGF ... Notch receptors are important mediators of cell fate during embryogenesis, but their role in adult physiology, particularly in ... Of the Notch receptors, only Notch1 and Notch4 are expressed in vascular endothelial cells. Here we show that blood flow ...
more infohttps://mouseion.jax.org/stfb2000_2009/1488/

HBD fusions - Picard Lab homeHBD fusions - Picard Lab home

FLP recombinase/estrogen receptor fusion proteins require the receptor D domain for responsiveness to antagonists, but not ... Ronchini, C. & Capobianco, A. J. Notch(ic)-ER chimeras display hormonedependent transformation, nuclear accumulation, ... EMBO J. 11, 4641-4652 (1992). Zurovec, M., Petrenko, O., Roll, R. & Enrietto, P. J. A chicken c-Rel-estrogen receptor chimeric ... 320, 113-121 (2008). Zuo, J., Niu, Q.-W. & Chua, N.-H. An estrogen receptor-based transactivator XVE mediates highly inducible ...
more infohttp://spotidoc.com/doc/695589/hbd-fusions---picard-lab-home

Prognostic values of Notch receptors in breast cancer | SpringerLinkPrognostic values of Notch receptors in breast cancer | SpringerLink

Activation of Notch has been reported to cause mammary carcinomas in mice. However, the... ... Notch receptors are frequently deregulated in several human malignancies including human breast cancer. ... Estrogen receptor (ER) Notch receptor Prognosis KM plotter Hazardous ratio (HR) This is a preview of subscription content, log ... Notch receptors are frequently deregulated in several human malignancies including human breast cancer. Activation of Notch has ...
more infohttps://link.springer.com/article/10.1007/s13277-015-3961-6

Trans-Endocytosis of Notch Receptors into Ligand-Expressing Cells | Science SignalingTrans-Endocytosis of Notch Receptors into Ligand-Expressing Cells | Science Signaling

Notch proteins are receptors that mediate several developmental processes. Notch receptors are activated upon binding ... Trans-Endocytosis of Notch Receptors into Ligand-Expressing Cells Message Subject. (Your Name) has forwarded a page to you from ... First, Notch is cleaved in its extracellular domain at the S2 site. The subsequent cleavage within Notchs transmembrane domain ... The animation shows a schematic representation of how trans-endocytosis of Notch into Delta-expressing cells contributes to ...
more infohttps://stke.sciencemag.org/content/2003/198/tr4

PLOS Computational Biology: Mutual Inactivation of Notch Receptors and Ligands Facilitates Developmental PatterningPLOS Computational Biology: Mutual Inactivation of Notch Receptors and Ligands Facilitates Developmental Patterning

... via interaction between the Notch receptor on one cell and its ligands such as Delta, on another. Interestingly, recent ... These processes and a diverse variety of others are mediated by the Notch signaling system which allows neighboring cells to ... Our results provide a foundation for understanding these and other Notch-dependent pattern formation processes. ... evidence has shown that Notch and Delta within the same cell (in cis) also interact, mutually inactivating each other. However ...
more infohttp://journals.plos.org/ploscompbiol/article/figure?id=10.1371/journal.pcbi.1002069.g006

An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye.  - PubMed - NCBIAn activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye. - PubMed - NCBI

An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye.. Fortini ME1, Rebay I, Caron LA, ... Truncation of the extracellular domain of the Drosophila Notch protein produces an activated receptor, as judged by its ability ... The Notch protein contains a large extracellular domain of 36 epidermal growth factor-like repeats as well as three Notch/Lin- ... The Notch locus of Drosophila melanogaster encodes a 2,703-amino-acid transmembrane protein required for a variety of ...
more infohttps://www.ncbi.nlm.nih.gov/pubmed/8413612?dopt=Abstract

Abstract 1004: Disruption of Notch Receptor Signaling Promotes Smooth Muscle Cell Differentiation | CirculationAbstract 1004: Disruption of Notch Receptor Signaling Promotes Smooth Muscle Cell Differentiation | Circulation

Abstract 1004: Disruption of Notch Receptor Signaling Promotes Smooth Muscle Cell Differentiation. Adewole S Adamson, Vaishnavi ... The objective of this study was to examine the role of Notch receptor signaling during VSMC lineage commitment in our ... To assess the effects of Notch specific receptor expression on VSMC differentiation, we utilized Notch1, or Notch3-specific ... Abstract 1004: Disruption of Notch Receptor Signaling Promotes Smooth Muscle Cell Differentiation ...
more infohttp://circ.ahajournals.org/content/114/Suppl_18/II_183.5

Distinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals | PNASDistinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals | PNAS

... a receptor with conserved function in cell-fate determination. Expression of constitutively active Notch [Notch intracellular ( ... Distinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals. Yina H. ... The Effect of Notch on TCR-Responsive Genes. The developmental fate regulator, Notch, has been reported to affect CD4 and CD8 ... To identify Notch-dependent transcription we used CD4+CD8+ from MHC-/- thymocytes expressing a constitutively activated Notch ...
more infohttps://www.pnas.org/content/101/14/4936?ijkey=3b09a4e0774a440b3d6978ca9be84e3bfdcf78ef&keytype2=tf_ipsecsha

Structural Insights into Notch Receptor-Ligand Interactions | Springer for Research & DevelopmentStructural Insights into Notch Receptor-Ligand Interactions | Springer for Research & Development

... the Artavanis-Tsakonas group in the late 1980s localized the core ligand recognition sequence in the DrosophilaNotch receptor ... Specific EGF repeats of notch mediate interactions with Delta and serrate-implications for notch as a multifunctional receptor ... Structural Insights into Notch Receptor-Ligand Interactions. In: Borggrefe T., Giaimo B. (eds) Molecular Mechanisms of Notch ... Becam I, Fiuza UM, Arias AM, Milan M (2010) A role of receptor Notch in ligand cis-inhibition in Drosophila. Curr Biol 20:554- ...
more infohttps://rd.springer.com/chapter/10.1007%2F978-3-319-89512-3_2

Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1 | JCBEnhancement of Notch receptor maturation and signaling sensitivity by Cripto-1 | JCB

cl., cleaved Notch proteins; fl., FL Notch proteins. (E) Nonquantitative RT-PCR for Notch receptor expression in NTERA2/D1 ... step is essential for the cell surface expression of Notch receptors and for ligand-induced activation of the Notch receptors, ... Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1. Kazuhide Watanabe, Tadahiro Nagaoka, Joseph M. ... 1 E and 5, A-C and G). F9 mouse EC cells express Cr-1 and several Notch receptors, as detected by RT-PCR and Western blot ...
more infohttp://jcb.rupress.org/content/187/3/343

Human Protein Phosphatase Inhibitor Activity to Human Notch Receptor Processing from Cell Signaling TechnologyHuman Protein Phosphatase Inhibitor Activity to Human Notch Receptor Processing from Cell Signaling Technology

Human Notch Receptor Processing Human Notch Receptor Processing: Monoclonal Antibody - Notch1 (D6F11) XP® Rabbit mAb, UniProt ... Category listing: Human Protein Phosphatase Inhibitor Activity to Human Notch Receptor Processing ... Human Peptide Receptor Activity Human Peptide Receptor Activity: Polyclonal Antibody - SHP-2 Antibody - Western Blotting, ...
more infohttps://www.cellsignal.com/1/4/indexd88.html

Maintenance of T Cell Specification and Differentiation Requires Recurrent Notch Receptor-Ligand Interactions | JEMMaintenance of T Cell Specification and Differentiation Requires Recurrent Notch Receptor-Ligand Interactions | JEM

Maintenance of T Cell Specification and Differentiation Requires Recurrent Notch Receptor-Ligand Interactions. Thomas M. ... Maintenance of T Cell Specification and Differentiation Requires Recurrent Notch Receptor-Ligand Interactions ... indicates that Notch receptor-ligand interactions are necessary for induction and maintenance of T cell lineage specification ... suggesting that the Notch-induced repression of the B cell fate is temporally separate from Notch-induced commitment to the T ...
more infohttp://jem.rupress.org/content/200/4/469.abstract

Cyclic Strain Inhibits Notch Receptor Signaling in Vascular Smooth Muscle Cells In Vitro | Circulation ResearchCyclic Strain Inhibits Notch Receptor Signaling in Vascular Smooth Muscle Cells In Vitro | Circulation Research

QRTPCR analysis of Notch 1 and Notch 3 receptors, Notch ligand, Jagged-1, and Notch target genes hrt-1, hrt-2, hrt-3, hes-1, ... Notch receptors 1 through 4; Notch ligands Delta, Serrate, and Jagged). Studies using constitutively activated Notch receptors ... Notch IC and the full-length receptor [Notch extracellular]) concomitant with a significant decrease in the expression of Notch ... Notch 3 Receptor Promotes SMC Proliferation and Inhibits Apoptosis Through Activation of Notch Target Genes in a CBF-1/RBP-Jκ- ...
more infohttp://circres.ahajournals.org/content/96/5/567

The vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor | DevelopmentThe vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor | Development

Lack of Notch signaling in V-ATPase mutant tissue could be due to effects on Notch ligands or the Notch receptor. To ... the Notch receptor is activated by S3 cleavage, a γ-secretase-mediated intramembrane proteolysis that liberates the Notch ... Activation of the Notch receptor following ligand binding requires a proteolytic cleavage called S3, which is mediated by γ- ... 2008). The big brain aquaporin is required for endosome maturation and notch receptor trafficking. Cell 133, 852-863. ...
more infohttp://dev.biologists.org/content/137/11/1825

Mutual inactivation of Notch receptors and ligands facilitates developmental patterningMutual inactivation of Notch receptors and ligands facilitates developmental patterning

... El meu compte ... Mutual inactivation of Notch receptors and ligands facilitates developmental patterning. PLoS Computational Biology. 2011; 7(6 ... Recent work has shown that Notch and Delta, the canonical metazoan juxtacrine signaling receptor and ligand, mutually ... Recent work has shown that Notch and Delta, the canonical metazoan juxtacrine signaling receptor and ligand, mutually ...
more infohttps://repositori.upf.edu/handle/10230/23702

JCI -
Blockade of individual Notch ligands and receptors controls graft-versus-host diseaseJCI - Blockade of individual Notch ligands and receptors controls graft-versus-host disease

... we demonstrate that Notch1/Notch2 receptors and the Notch ligands Delta-like1/4 mediate all the effects of Notch signaling in T ... Blockade of individual Notch ligands and receptors controls graft-versus-host disease. ... Blockade of individual Notch ligands and receptors controls graft-versus-host disease. ... We previously identified Notch signaling in T cells as a new therapeutic target for preventing GVHD. Notch-deprived T cells ...
more infohttps://www.jci.org/articles/view/65477/figure/5

JCI -
Blockade of individual Notch ligands and receptors controls graft-versus-host diseaseJCI - Blockade of individual Notch ligands and receptors controls graft-versus-host disease

... we demonstrate that Notch1/Notch2 receptors and the Notch ligands Delta-like1/4 mediate all the effects of Notch signaling in T ... Blockade of individual Notch ligands and receptors controls graft-versus-host disease. ... Blockade of individual Notch ligands and receptors controls graft-versus-host disease. ... We previously identified Notch signaling in T cells as a new therapeutic target for preventing GVHD. Notch-deprived T cells ...
more infohttps://www.jci.org/articles/view/65477/figure/9

Notch receptor-ligand binding and activation: insights from molecular studies. - Oxford NeuroscienceNotch receptor-ligand binding and activation: insights from molecular studies. - Oxford Neuroscience

Recent advances in structure determination of the extracellular regions of human Notch-1 and one of its ligands Jagged-1 have ... Although cellular and in vivo studies have provided considerable insight into the downstream consequences of Notch signalling, ... We review the structural data available for receptor and ligands and identify the challenges ahead. ... relatively little is known about the molecular basis of the receptor/ligand interaction and initial stages of activation. ...
more infohttps://www.neuroscience.ox.ac.uk/publications/254298

Bacterial expression and in vitro refolding of limited fragments of the Notch receptor and its ligands. - Oxford NeuroscienceBacterial expression and in vitro refolding of limited fragments of the Notch receptor and its ligands. - Oxford Neuroscience

... of the protocol for the production of these EGF-containing constructs we have focused on a limited fragment of human Notch 1 ... Prokaryotic expression of limited fragments of the Notch receptor and its ligands followed by in vitro refolding has been used ... Bacterial expression and in vitro refolding of limited fragments of the Notch receptor and its ligands. ... Prokaryotic expression of limited fragments of the Notch receptor and its ligands followed by in vitro refolding has been used ...
more infohttps://www.neuroscience.ox.ac.uk/publications/487115

Clinicopathological analysis of ATRX, DAXX and NOTCH receptor expression in angiosarcomas.  - PubMed - NCBIClinicopathological analysis of ATRX, DAXX and NOTCH receptor expression in angiosarcomas. - PubMed - NCBI

Clinicopathological analysis of ATRX, DAXX and NOTCH receptor expression in angiosarcomas.. Panse G1, Chrisinger JS1, Leung CH2 ... The aim of this study was to evaluate the immunohistochemical expression of ATRX, DAXX and NOTCH receptors (NOTCH1 and NOTCH2) ... Additionally, inhibition of NOTCH signalling induces the development of malignant vascular tumours in mice, indicating a tumour ... Multiple genetic alterations, including alternative lengthening of telomeres (ALT) and NOTCH mutations, have been described in ...
more infohttps://phgkb.cdc.gov/PHGKB/phgHome.action?action=forward&dbsource=huge&id=153699

The role of Notch receptors and ligands in regulation of immune respon by Gerard F. Hoyne"The role of Notch receptors and ligands in regulation of immune respon" by Gerard F. Hoyne

We are beginning to obtain a better understanding of the roles that the different Notch ligands and receptors play in both ... This review will examine the key findings that have emerged in relation to function of Notch in differentiation of T cells, B ... Notch signalling has an important role in the immune system in directing cell fate decisions in a range of diverse cell types. ... cells and dendritic cells and how modulation of Notch signalling seems to have potential for therapeutic applications in immune ...
more infohttps://researchonline.nd.edu.au/health_article/79/

Differential synergy of Notch and T cell receptor signaling determines ß versus lineage fate | JEMDifferential synergy of Notch and T cell receptor signaling determines ß versus lineage fate | JEM

Differential synergy of Notch and T cell receptor signaling determines ,IMG SRC="/math/agr.gif" ALT="{alpha}" BORDER="0",ß ... Differential synergy of Notch and T cell receptor signaling determines ,IMG SRC="/math/agr.gif" ALT="{alpha}" BORDER="0",ß ...
more infohttp://jem.rupress.org/content/early/2006/06/05/jem.20060474

Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma.  - PubMed...Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma. - PubMed...

Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma.. Yu T1, ... mRNA expression of Notch receptor genes in HCC tissues and adjacent normal tissues, and association with OS and RFS. (A) Notch1 ... Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus‐related hepatocellular carcinoma ... Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus‐related hepatocellular carcinoma ...
more infohttps://phgkb.cdc.gov/PHGKB/phgHome.action?action=forward&dbsource=huge&id=150932
  • We are beginning to obtain a better understanding of the roles that the different Notch ligands and receptors play in both cellular differentiation of precursor cells and the regulation of immune responses by mature lymphocytes in the periphery. (edu.au)
  • Flow cytometry demonstrated the presence of Notch1 and Notch2 receptors on bone marrow-derived myeloid cells but not on erythroid cells positive for the marker, Ter-119. (wiley.com)
  • The aim of this study was to evaluate the immunohistochemical expression of ATRX, DAXX and NOTCH receptors (NOTCH1 and NOTCH2) in a large cohort of angiosarcomas, and study their clinicopathological and prognostic significance. (cdc.gov)
  • Using newly developed humanized antibodies and conditional genetic models, we demonstrate that Notch1/Notch2 receptors and the Notch ligands Delta-like1/4 mediate all the effects of Notch signaling in T cells during GVHD, with dominant roles for Notch1 and Delta-like4. (jci.org)
  • Pioneering cell aggregation experiments from the Artavanis-Tsakonas group in the late 1980's localized the core ligand recognition sequence in the Drosophila Notch receptor to epidermal growth factor-like (EGF) domains 11 and 12. (springer.com)
  • Association between single nucleotide polymorphisms of delta/notch-like epidermal growth factor (EGF)-related receptor (DNER) and Delta-like 1 Ligand (DLL 1) with the risk of type 2 diabetes mellitus in a Chinese Han population. (nih.gov)
  • Thus, activating mutations in both invertebrate and vertebrate Notch family members can lead to tumor formation. (biologists.org)
  • Given these attributes of Notch signaling, we propose Notch agonists can enhance NK cell maturation and tumor killing in a post-transplant setting. (jimmunol.org)
  • Since then, advances in protein expression, structure determination methods and functional assays have enabled us to define the molecular basis of the core receptor/ligand interaction and given new insights into the architecture of the Notch complex at the cell surface. (springer.com)
  • Although cellular and in vivo studies have provided considerable insight into the downstream consequences of Notch signalling, relatively little is known about the molecular basis of the receptor/ligand interaction and initial stages of activation. (ox.ac.uk)
  • Mammals have four Notch receptors (Notch1-4) and five membrane-bound ligands (Dll1, -3, and -4 and Jagged-1 and -2). (rupress.org)
  • Using clonal analyses, we show that CD44 + CD25 + (DN2) cells, which appeared committed to the T cell lineage when cultured on Dll1-expressing stromal cells, nonetheless gave rise to natural killer cells with a progenitor frequency similar to that of CD44 + CD25 − (DN1) thymocytes when Notch signaling was absent. (rupress.org)
  • These data, together with the observation that Dll1 is expressed on stromal cells throughout the thymic cortex, indicates that Notch receptor-ligand interactions are necessary for induction and maintenance of T cell lineage specification at both the DN1 and DN2 stages of T cell development, suggesting that the Notch-induced repression of the B cell fate is temporally separate from Notch-induced commitment to the T lineage. (rupress.org)
  • Dll1 and Dll4 Notch ligands control the production of IFN-γ and IL-2 by alloreactive T cells, with dominant effects of Dll4. (jci.org)
  • By knocking down delta-like 1 (DLL1) on NK cells and co-culturing them with OP9 cells expressing Notch ligands we show that DLL1 mediated cis-inhibition controls KIR expression. (jimmunol.org)
  • More specifically, we investigated the prognostic value of four Notch receptors in breast cancer patients through "the Kaplan-Meier plotter" (KM plotter) database, in which updated gene expression data and survival information are from a total of 3554 breast cancer patients. (springer.com)
  • Here, Notch signaling activates expression of the Notch gene. (plos.org)
  • Notch1 (pN1-IC) and Notch3 (pN3-IC) expression vectors were employed to examine Notch signaling under constitutive activation. (ahajournals.org)
  • Here we use DNA microarray analysis to compare gene expression changes in CD4 + CD8 + double-positive thymocytes undergoing positive selection, TCR stimulation, and Notch activation. (pnas.org)
  • We also find that Notch activity potentiates the effects of TCR stimulation on gene expression. (pnas.org)
  • Expression of constitutively active Notch [Notch intracellular (NotchIC)] in DP thymocytes has dramatic effects on CD4 and CD8 T cell maturation, which have been interpreted by different groups as either effects on CD4 versus CD8 lineage commitment ( 2 - 4 ), promotion of thymocyte survival ( 5 , 6 ), or dampening of TCR signals ( 7 ). (pnas.org)
  • Although this microarray analysis represents an important first step to analyzing gene expression changes on TCR signaling in thymocytes, the relationship between the gene expression programs induced by positive selection, TCR signaling, and Notch signaling has yet to be addressed. (pnas.org)
  • In addition, knockdown of Cripto-1 expression in human and mouse embryonal carcinoma cells desensitized the ligand-induced Notch signaling activation. (rupress.org)
  • 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. (wiley.com)
  • 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. (wiley.com)
  • 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. (wiley.com)
  • In situ hybridization of E12 through E17 fetal liver demonstrated widespread expression of Jagged1 and Delta1 in a pattern similar to but less abundant than that of the erythropoietin receptor. (wiley.com)
  • Taken together with earlier functional results, the current expression data suggest a role for Notch activity in establishing definitive hematopoiesis in fetal liver, as well as a selective use of Notch signaling in adult erythropoiesis and granulopoiesis. (wiley.com)
  • Bacterial expression and in vitro refolding of limited fragments of the Notch receptor and its ligands. (ox.ac.uk)
  • Prokaryotic expression of limited fragments of the Notch receptor and its ligands followed by in vitro refolding has been used for the production of the significant amounts of protein required for structure determination by X-ray crystallography or nuclear magnetic resonance spectroscopy. (ox.ac.uk)
  • Clinicopathological analysis of ATRX, DAXX and NOTCH receptor expression in angiosarcomas. (cdc.gov)
  • We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. (aacrjournals.org)
  • Notch-4 expression in clinical specimens correlated with proliferation (Ki67). (aacrjournals.org)
  • Deregulated expression of wild-type Notch receptors, ligands, and targets has been described in several solid tumors ( 1 - 3 ). (aacrjournals.org)
  • In the same study, we detected expression of Notch-1 in seven cases of infiltrating ductal carcinoma, which seemed stronger in H-Ras-overexpressing cases ( 18 ). (aacrjournals.org)
  • We investigated the expression of Notch pathway components in human breast cancers and the regulation of Notch expression and activity by a novel cross-talk mechanism with estrogen. (aacrjournals.org)
  • PDGFR -β expression was upregulated by Notch ligand induction or by activated forms of the Notch receptor. (ahajournals.org)
  • Moreover, upregulation of PDGFR -β expression in response to Notch activation critically required the Notch signal integrator CSL. (ahajournals.org)
  • In primary VSMCs, PDGFR -β expression was robustly upregulated by Notch signaling, leading to an augmented intracellular response to PDGF stimulation. (ahajournals.org)
  • OUTCOME MEASURES Tissues were analyzed for Notch Intra-Cellular Domain 1 (NICD1) and Progesterone Receptor (PGR) protein expression by immunohistochemistry and for transcript levels of NICD1 target gene HES1, PGR, and PGR-B by qRT-PCR. (deepdyve.com)
  • Expression of Notch1 receptor and ligands in Lin-CD45RA-DC precusors was detected by Real-time PCR and was down-regulated by shRNA or γ-secretase inhibitor (GSI). (biomedcentral.com)
  • Expression of Notch1 receptors and ligands were detected in Lin-CD45RA-DC precursor cells. (biomedcentral.com)
  • Conversely, co-culturing the same cells with OP9 cells bearing Notch ligands enhanced KIR expression. (jimmunol.org)
  • Notch signaling also enhances CD16 upregulation that precedes KIR expression. (jimmunol.org)
  • More important than receptor expression is function. (jimmunol.org)
  • To disrupt global Notch signaling we utilized the gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t -butyl ester (DAPT). (ahajournals.org)
  • Stem like and non-stem like cells are treated with GSI (a Notch inhibitor) and tamoxifen. (eurekamag.com)
  • Lewis J. Notch signalling and the control of cell fate choices in vertebrates. (springer.com)
  • An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye. (nih.gov)
  • One contributing factor may be Notch, a receptor with conserved function in cell-fate determination. (pnas.org)
  • Notch signaling has been shown recently to regulate vascular cell fate in adult cells. (ahajournals.org)
  • Notch signalling has an important role in the immune system in directing cell fate decisions in a range of diverse cell types. (edu.au)
  • The Notch locus of Drosophila melanogaster encodes a 2,703-amino-acid transmembrane protein required for a variety of developmental processes, including neurogenesis, oogenesis and ommatidial assembly. (nih.gov)
  • Together, these results provide a framework for analysis of more complex Notch-dependent developmental systems. (upf.edu)
  • The objective of this study was to examine the role of Notch receptor signaling during VSMC lineage commitment in our multipotent P19 model system. (ahajournals.org)
  • In this report, we link Notch signaling to platelet-derived growth factor (PDGF) signaling, a key determinant of VSMC biology, and show that PDGF receptor ( PDGFR )-β is a novel immediate Notch target gene. (ahajournals.org)
  • Modulation of notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium. (springer.com)
  • Deregulation in stem cell self-renewal pathways such as Notch, Wnt and Hedgehog signaling have been implicated in mammary transformation. (eurekamag.com)
  • In vitro, egfl7 knockdown in HUVEC inhibits migration, probably by blocking the Notch pathway, although other groups reported that Egfl7 has no effect on HUVEC migration. (wikipedia.org)
  • Tamoxifen, a modulator of estrogen receptor (ER), is currently used for the treatment of both early and advanced ER+ breast cancer. (eurekamag.com)
  • It has also been proposed that Notch activity might promote CD8 T cell development by down-modulating TCR signals ( 7 ), thus linking Notch signaling to the quantitative TCR-signaling model for CD4 versus CD8 lineage commitment. (pnas.org)
  • Notch signaling has been shown to play a pivotal role in inducing T lineage commitment. (rupress.org)
  • However, T cell progenitors are known to retain other lineage potential long after the first point at which Notch signaling is required. (rupress.org)
  • The rabconnectin-3 complex is involved in regulating Notch signalling, although its exact function is unclear. (wikipedia.org)
  • The Notch ICD translocates to the cell nucleus, where it interacts with the DNA-binding protein CSL. (ahajournals.org)
  • NOTCH signaling as a novel cancer therapeutic target. (springer.com)
  • Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERα + breast cancers and that Notch signaling is a potential therapeutic target in ERα − breast cancers. (aacrjournals.org)
  • The Notch signaling pathway plays a substantial role on human NK cell development, however the role of Notch on KIR upregulation and acquisition of effector function has not been explored. (jimmunol.org)
  • Furthermore, structure determination of O -glycosylated variants of Notch alone or in complex with receptor fragments, has shown that these sugars contribute directly to the binding interface, as well as to stabilizing intra-molecular domain structure, providing some mechanistic insights into the observed modulatory effects of O -glycosylation on Notch activity. (springer.com)
  • Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for OS in HBV-related HCC patients. (cdc.gov)