Atlas of Genetics and Cytogenetics in Oncology and Haematology


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NOTCH1 (Notch homolog 1, translocation-associated (Drosophila))

Identity

Other namesTAN1
hN1
notch1
Notch1
HGNC (Hugo) NOTCH1
LocusID (NCBI) 4851
Location 9q34.3
Location_base_pair Starts at 139388896 and ends at 139440238 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Note History and Nomenclature: The notch1 gene, previously referred to as TAN1, was first described in 1917 by American giant of genetics and embryology Thomas Hunt Morgan in a strain of the fruit fly Drosophila melanogaster with "notches" apparent in their wings. Molecular study of the notch1 gene product and sequencing was carried out in the 1980s.
The following discussion will refer to the notch1 gene as "notch1" and the functional gene product (protein) as "NOTCH1".
Description Notch1 encompasses 51,418 bp of DNA on chromosome 9 (9q34.3) between 138,508,717 and 138,508,135 bp from pter.
Transcription The notch1 RNA transcript contains 34 exons and is 9,371 bp in length.

Protein

Description The notch1 gene product NOTCH1 (2,556 amino acids; 272,500 Da) consists of a large extracellular unit which associates in a calcium-dependent, non-covalent interaction with a second unit consisting of the following: a small extracellular region, a single transmembrane spanning region, and a small intracellular region.
The NOTCH1 extracellular domain is composed primarily of 36 small cysteine knot motifs called EGF-like repeats. Each EGF-like repeat is approximately 40 amino acids, and its structure is defined largely by six conserved cysteine residues that form three conserved disulfide bonds. This feature is critical in ligand binding. The extracellular domain also contains three cysteine-rich Notch/Lin12 (LN) repeats required for the blockage of signaling in the absence of ligand.
The NOTCH1 intracellular domain (NICD) contains a RAM23 domain, six ankyrin/cdc10 repeats involved in protein-protein interactions, two nuclear localization signals (N1 and N2), a transcriptional activation domain (TAD), and a PEST (proline-, glutamic acid-, serine-, and threonine- rich) sequence that negatively regulates protein stability. NOTCH1 undergoes an initial proteolytic cleavage by furin (PACE1) in the Golgi during trafficking to the cell surface.
NOTCH1 is subject to several important post-translational modifications. An O-glucose sugar may be added between the first and second conserved cysteine, and an O-fucose may be added between the second and third conserved cysteine. These sugars are added by an as yet unidentified O-glucosyltransferase, and GDP-fucose protein O-fucosyltransferase 1 (POFUT1) respectively. The addition of O-fucose by POFUT1 is crucial for NOTCH1 function, and without its addition NOTCH1 proteins fail to function properly. As yet, the manner in which the glycosylation of NOTCH1 affects function is not completely understood.
The O-glucose on NOTCH1 can be further elongated to a trisaccharide with the addition of two xylose sugars by xylosyltransferases, and the O-fucose can be elongated to a tetrasaccharide by the ordered addition of an N-acetylglucosamine (GlcNAc) sugar by an N-Acetylglucosaminyltransferase called Fringe, the addition of a galactose by a galactosyltransferase, and the addition of a sialic acid by a sialyltransferase.
The NOTCH1 ligands are single-pass transmembrane proteins and are members of the DSL (Delta/Serrate/LAG-2) family of proteins. In Drosophila there are two involved ligands named Delta and Serrate. In mammals, the corresponding names are Delta-like and Jagged. In mammals there are multiple Delta-like and Jagged ligands, as well as probably a variety of other ligands, such as F3/contactin.
Localisation NOTCH1: Cell membrane. Single pass type I membrane protein.
NICD: Internal surface of cell membrane translocating to the nucleus upon ligand binding.
Function The NOTCH1 cell signaling mechanism is conserved in most multicellular organisms including all metazoans (and thus vertebrates). NOTCH1 functions as a receptor for membrane-bound ligands Jagged1, Jagged2, and Delta1 in regulation of cell-fate determination.
Once the NOTCH1 extracellular domain interacts with a ligand, an ADAM-family metalloprotease called TACE (Tumor Necrosis Factor Alpha Converting Enzyme) cleaves the NOTCH1 protein just outside the membrane. Consequently, the extracellular portion of NOTCH1 is released and continues to interact with the ligand. The ligand plus the NOTCH1 extracellular domain is then endocytosed by the ligand-expressing cell. There may be signaling effects in the ligand-expressing cell after endocytosis, however currently these effects are not well understood.
Upon ligand activation and cleavage via gamma secretase, the released notch intracellular domain (NICD) forms a transcriptional activator complex via its RAM23 domain with the transcription factor CSL (CBF1 in humans, RBP-JK in mice, Suppressor of Hairless in Drosophila, LAG in Caenorhabditis elegans). In the absence of NOTCH1, CSL proteins bind to promoters of target genes and recruit histone deacetylases and corepressors (CoR) that inhibit transcription of these genes. Among known corepressor molecules are SMRT/NcoR and SHARP/MINT/SPEN. The NICD/CSL interaction converts CSL from a transcriptional repressor into a transcriptional activator (CBF1 binding complex in humans) by displacing the corepressor complex and recruiting coactivators such as Mastermind-Like 1 (MAM) and histone acetyltransferase. Several other proteins are known to affect NOTCH1 signaling, including the RING-domain E3 ubiquitin ligase deltex and the phosphotyrosine binding domain (PTB)-containing proteins numb and numblike, which act as context-dependent negative or positive Notch1 regulators.
In mammals there are three Fringe N-acetylglucosamine (GlcNAc)-transferase enzymes named Lunatic Fringe, Manic Fringe, and Radical Fringe, which are responsible for something called the "Fringe Effect" on NOTCH1 signaling. If Fringe adds a GlcNAc to the O-fucose sugar, then addition of a galactose and sialic acid will occur. In the presence of this tetrasaccharide, NOTCH1 signals strongly when it interacts with the Delta ligand, but is inhibited when interacting with the Jagged ligand. The means by which this addition of sugar inhibits signaling through one ligand, and potentiates signaling through another is not clearly understood.
Known target genes of NOTCH1 signaling include: members of the basic helix-loop-helix (bHLH) hairy/enhancer of split (Hes) family, the related HRT/Herp (Hes-related repressor protein) transcription factor family, the cell cycle regulator p21, the Notch pathway element Notch-regulated ankyrin repeat protein (Nrarp), deltex1, and the pre-T cell receptor-alpha gene. The NOTCH1 signaling pathway is important for cell-cell communication, involving gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life. NOTCH1 signaling is known to play a role in the following processes:

  • Neuronal function and development: Via lateral inhibition, NOTCH1 in the embryo generates molecular differences between adjacent cells. In the central nervous system, NOTCH1 activity maintains the neural progenitor state and inhibits differentiation. During gliogenesis, NOTCH1 has an instructive role, directly promoting the differentiation of different glial subtypes. More detailed analyses have also revealed that Notch regulates progenitor pool diversification and neuronal maturation. New data suggests that NOTCH1 activity has a role in neuronal function of the adult brain.
  • Modulating arterial endothelial fate and angiogenesis: Expression of NOTCH1 and its ligand in vascular endothelium and defects in vascular phenotypes of targeted mutants in the NOTCH1 pathway suggest a critical role for NOTCH1 signaling in vasculogenesis and angiogenesis. Vascular endothelial growth factor (VEGF) can induce gene expression of NOTCH1 and its ligand, Delta-like 4 (Dll4), in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 (FLT1/VEGFR1 and KDR/VEGFR2) and is transmitted via the phosphatidylinositol 3-kinase/Akt pathway. Constitutive activation of NOTCH1 signaling stabilizes network formation of endothelial cells on Matrigel and enhances formation of vessel-like structures in a three-dimensional angiogenesis model. Blocking Notch signaling can inhibit network formation.
  • Regulating cell communication events between endocardium and myocardium during ventricular chamber formation: Ventricular chamber morphogenesis is critical for proper cardiac function and embryonic viability and depends on cellular interactions between the endocardium and myocardium. Ventricular Notch1 activity is highest at presumptive trabecular endocardium. RBPJk and Notch1 mutants show impaired trabeculation and marker expression, weakened EphrinB2, NRG1, and BMP10 expression and signaling, and decreased myocardial proliferation. Functional and molecular analyses have shown that Notch1 inhibition prevents EphrinB2 expression, and that EphrinB2 is a direct Notch1 target acting upstream of NRG1 in the ventricles.
  • Cell lineage specification of both endocrine and exocrine pancreas: Multiple cell types of the pancreas appear asynchronously during embryogenesis, which requires that pancreatic progenitor cell potential changes over time. Loss-of-function studies have shown that NOTCH1 signaling modulates the differentiation of these progenitors. It has been demonstrated that misexpression of activated NOTCH1 in Pdx1-expressing progenitor cells prevents differentiation of both exocrine and endocrine lineages. Progenitors remained trapped in an undifferentiated state even if notch1 activation occurred long after the pancreas was specified. Endocrine differentiation is associated with escape from this activity, as Ngn3-expressing endocrine precursors were susceptible to notch1 inhibition, whereas fully differentiated endocrine cells were resistant.
  • Notch1-dependent bone morphogenic protein (BMP) signaling: NOTCH1 enhances BMP2-induced commitment to the osteoblastic lineage during bone development.
  • Regulation of cell-fate decision in the mammary gland: It has been suggested that Notch1 signaling plays a critical role in normal human mammary development by acting on both stem cells and progenitor cells, affecting self-renewal and lineage-specific differentiation. Notch signaling can act on mammary stem cells to promote self renewal and on early progenitor cells to promote their proliferation, as demonstrated in one study by a 10-fold increase in secondary mammosphere formation upon addition of a Notch activating DSL peptide. The same study showed that in addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. Notch1 signaling has no such effect on fully committed, differentiated, mammary epithelial cells.
  • Cytoskeletal component formation: It has been suggested that NOTCH1 signaling, via some non-nuclear mechanisms, controls the actin cytoskeleton through the tyrosine kinase Abl.
  • Normal lymphocyte function: NOTCH1 signaling is involved in the maturation of both CD4+ and CD8+ cells in the thymus. In altered form, NOTCH1 may contribute to transformation or progression in some T-cell neoplasms. NOTCH1 may be important for follicular differentiation and possibly cell fate selection within the follicle.
  • Regulation of fate choices in the inner ear.
  • Induction of left-right asymmetry.
  • Regulation of limb bud development.
  • Regulation of kidney development.
  • Mutations

    Note Notch1 mutant mice display defects in somite morphology.
    Mutations in the NOTCH1 ligand affect the development of many organs, including that of the liver, skeleton, heart and eye.
    Mutations in the NOTCH1 ligand DLL3 result in rib fusions and trunk dwarfism.
    Notch1 mutations play a dual role in carcinogenesis as either a tumor suppressor or an oncogene. The role of NOTCH1 within and between cells depends on signal strength, timing, cell type, and context.
    Notch1 mutant cells infected with a retrovirus transducing the ras oncogene and injected subcutaneously into nude mice form aggressive squamous cell carcinoma (SCC), whereas wild-type cells do not. Loss of notch1 activity may thus cooperate with ras oncogene transformation in keratinocyte tumor development.
    In humans, aberrant NOTCH1 expression has been identified as a causative factor in the development of T-cell acute lymphoblastic leukemia and lymphoma (T-ALL). Recurrent t(7;9) translocation that involves the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1 is associated with T-ALL. The t (7; 9) translocation in T-ALL patients is characterized by juxtaposition of the 3' portion of the human notch1 gene with the T cell receptor beta (TCRB) locus. This leads to expression of truncated NOTCH1 transcripts and consequent production of dominant active, ligand-independent forms of the NOTCH1 receptor, causing T-ALL. Less than 1% of human T-ALLs exhibit the t(7;9) translocation, however, activating mutations in notch1 independent of t(7;9) have been identified in more than 50% of human T-ALL.
    Cells that are mutant for notch1 form skin and corneal tumors in mice, indicating that Notch1 signaling suppresses tumorigenesis in these instances.
    Notch1 mutations cause an early developmental defect in the aortic valve and a later derepression of calcium deposition that causes progressive aortic valve disease.
    Many other human and murine cancers, including certain neuroblastomas, mammary, skin, cervical and prostate cancers are correlated with alterations in expression of Notch proteins and/or ligands. These cases await better characterization, but these observations suggest broad roles for Notch dysfunction in a wide range of neoplasms.
    Based on analysis of neuroendocrine tumors and cell lines, NOTCH1 appears to be absent in this type of cancer. Expression of ectopic NOTCH1 in human medullary thyroid carcinoma and carcinoid tumor cell lines resulted in suppression of cancer cell growth. These data suggest that in neuroendocrine malignancies notch1 may act as a tumor suppressor.

    Implicated in

    Entity Medullary Thyroid Cancer (MTC)
    Disease A neuroendocrine tumor (NET) derived from parafollicular C cells of the thyroid, MTC is the third most common form of thyroid cancer accounting for 3-5% of all thyroid cancers. Symptoms include airway obstruction and diarrhea. MTC typically secretes the bioactive hormone calcitonin. Currently, surgery is the only curative therapy for these patients, consisting of total thyroidectomy with lymph node dissection. 50% of these patients suffer persistent disease.
    Oncogenesis 20% of patients with MTC have an autosomal dominant inherited form of the disease, which has been shown to be the result of well-characterized point mutations in the RET-protooncogene. The results of human MTC tissue sample analysis revealed an absence of active NOTCH1 protein in all tumors tested whereas NET markers such as chromogranin A (CgA) and ASCL1 were highly expressed. Activation of doxycycline-inducible notch1 in MTC cells by varying concentrations of doxycycline led to a dose-dependent increase in NOTCH1 protein and HES-1 protein expression. The level of ASCL1 was reduced with increase in NOTCH1. Further, it was observed that activation of notch1 significantly reduced the growth of MTC cells and the reduction in growth was dependent on the level of active NOTCH1 protein. NOTCH1 also down-regulates aberrant calcitonin secretion in a dose-dependent manner.
      
    Entity Gastrointestinal (GI) Carcinoid Tumors
    Disease GI carcinoids are rare tumors that arise from the diffuse neuroendocrine tissue of the gut with a reported incidence of 1-8 per 100,000. They frequently metastasize to the liver and are the second most common source of isolated liver metastases. GI carcinoids secrete various bioactive hormones such as 5-HT (serotonin) and CgA. Patients with hepatic metastases suffer debilitating symptoms such as abdominal pain, flushing, bronchoconstriction, and diarrhea. Standard palliative treatment for these hormone-induced symptoms includes somatostatin analogs (such as octeotride).
    Oncogenesis RT-PCR reactions for various Notch receptors and ligands showed the presence of transcripts for notch1, notch2, notch3 and DLL1 in all carcinoid tumors tested. The human pancreatic carcinoid BON cell line also showed detectable amounts all three NOTCH receptors (1-3). An absence of active NOTCH1 intracellular domain (NICD) protein in BON cells was noted, suggesting that the NOTCH1 signaling pathway is inactive in carcinoids. Transient expression of active NOTCH1 via adenoviral vector in BON cells resulted in growth suppression and significant reduction in NET markers such as 5-HT, CgA, synaptophysin, neuron specific enolase (NSE), and ASCL1, confirming the tumor suppressor role of Notch1 signaling in carcinoid tumors. Further, it was shown that the reduction in serotonin is at the level of transcription of tryptophan hydroxylase 1 mRNA suggesting that NOTCH1 signaling regulates tryptophan hydroxylase 1, a rate-limiting enzyme in 5-HT biosynthesis. In addition, stable expression of a NOTCH1 fusion protein in BON cells also resulted in high levels of functional NOTCH1 that led to an increase in the level of HES-1, an immediate downstream NOTCH1 effector. Increases in the level of HES-1 significantly reduced the level of ASCL1 protein. Similar to transient adenoviral NOTCH1 activation, the stable expression of NOTCH1 in BON cells also caused reductions in the levels of serotonin, CgA, NSE, and synaptophysin.
    Treatment of human carcinoid cancer cells with histone deacetylase (HDAC) inhibitors resulted in activation of NOTCH1 signaling and inhibition of carcinoid cell growth in vitro and in vivo. These findings suggest that NOTCH1 activation with HDAC inhibitors may be an attractive approach for the treatment of these tumors.
      
    Entity Small-Cell Lung Cancer (SCLC)
    Disease SCLC tends to present with metastatic and regional spread. SCLC is extremely aggressive and is characterized by rapid growth and early metastases. SCLC arises from major bronchi, and expresses NSE, CgA, and synaptophysin.
    Oncogenesis Similar to the observations in other neuroendocrine tumors such as carcinoids and MTC, neither the Notch1 nor the raf-1 pathway is active in SCLC cells. In addition, these tumors express high levels of ASCL1. Inhibition of ASCL1 expression by anti sense or RNA interference has been shown to suppress the growth of SCLC cells and reduce expression of NET markers, furthering the idea that ASCL1 plays a critical role in SCLC development.
    RNA interference against ASCL1 significantly inhibited growth both in vitro and in vivo xenograft model. It was also demonstrated that the growth inhibition by suppression of ASCL1 is mediated by cell cycle arrest and apoptotic cell death. It is also known that NOTCH1 is a negative regulator of ASCL1 and it is inactive in various SCLC cell lines tested. Adenoviral mediated expression of active NOTCH1 in these cell lines resulted in both NET marker reduction and growth suppression. Furthermore, the reduction in ASCL1 by Notch1 is achieved both at the level of transcription and post-translational degradation of the ASCL1 protein. These results further confirm that the Notch1 pathway is not active in SCLC at baseline. Activation of NOTCH1 signaling in SCLC led to growth inhibition and NET marker reduction, suggesting a tumor suppressor role for notch1 in SCLC.
      
    Entity T Cell Malignancies.
    Disease Human acute T cell acute lymphoblastic leukemia/lymphoma (T-ALL) is the prototypical notch1-associated cancer. The disease constitutes approximately 15 or 20% of ALL in children and adults.
    Oncogenesis Oncogenesis is attributed to constitutively active notch1 due to t(7;9) (q34:q34.3) activating mutations. This leads to expression of NICD in a T cell receptor-beta-regulated manner. Although the t(7; 9) mutation is rare (less that 1% of T-ALL), the majority of human T-ALL have gain-of-function mutations in notch1, leading to aberrant increases in downstream signaling.
      
    Entity B-Cell Malignancies
    Disease Several mature B-cell and therapy-resistant B-cell malignancies have been shown to be susceptible to NOTCH1-mediated growth inhibition/apoptosis including Hodgkin, myeloma, and mixed-lineage leukemia (MLL)-translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies.
    In direct contrast to the previously mentioned studies, several groups have reported NOTCH1-mediated growth proliferation in such B cell malignancies as multiple myeloma and Hodgkin and anaplastic large cell lymphoma.
    Oncogenesis Several studies support the existence of a dual-role for NOTCH1 signaling as either a tumor suppressor or oncogene in malignant B cells. These studies conflict, indicating that more definitive research is needed. A reasonably comprehensive study targeted the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. They found that expression of constitutively active, truncated forms of several mammalian Notch receptors (including NOTCH1) inhibited growth and induced apoptosis in both murine and human B-cell lines. Similar results were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by coculture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. Truncated NOTCH1 receptors, as well as the Jagged ligands, induced HES-1 transcription. Retroviral expression of Hairy/Enhancer of Split-1 (HES-1) recapitulated the NOTCH1 effects, suggesting that HES-1 is an important mediator of NOTCH1-induced growth arrest and apoptosis in B cells.
      
    Entity Breast Cancer
    Disease Breast cancer is the most commonly diagnosed malignancy in women after skin cancer, and is a leading cause of cancer death in women from western countries.
    Oncogenesis NOTCH1 is over-expressed in solid tumors of the breast in the human model. Moreover, NOTCH1 expression isincreased in poorly differentiated tumors. A separate study found that elevated coexpression of the NOTCH1 ligand Jagged1 and NOTCH1 is characteristic of a subclass of breast cancer with a very poor outcome. Patients with tumors expressing high levels of JAG1 or NOTCH1 had a significantly poorer overall survival compared with patients expressing low levels of these genes (5-year survival rate of 42% versus 65% and median survival of 50 versus 83 months, respectively, for JAG1(High vs. Low) (P = 0.01); 49% versus 64% and 53 versus 91 months, respectively, for NOTCH1(High vs. Low) (P = 0.02)). Moreover, a synergistic effect of high-level JAG1 and high-level NOTCH1 coexpression on overall survival was observed (5-year survival rate of 32% and median survival of 40 months; P = 0.003).
      
    Entity Skin Cancer
    Disease In basal cell carcinoma (BCC), the most common non-melanocytic human skin cancer, hyperplasic cell division may lead to invasion of the dermis by epidermal tissues. NOTCH1 signaling has been linked to BCC. NOTCH1 signaling has also been linked to primary melanoma. Melanomas originate from pigment-producing melanocytes. In human skin, melanocytes are positioned at the epidermal-dermal junction and are interspersed every 5 to 10 basal keratinocytes.
    Oncogenesis Notch1 is implicated differentially as an oncogene in melanocyte-derived carcinoma and as a tumor suppressor gene in keratinocyte-derived carcinoma.
    Notch1 may act as a tumor suppressor gene in basal cell carcinoma (BCC). This conclusion was drawn from the observation that when keratinocytes were hyperproliferating, as in BCC, notch1 expression was essentially absent.
    A study showed that blocking NOTCH1 signaling suppressed, whereas constitutive activation of the NOTCH1 pathway enhanced, primary melanoma cell growth both in vitro and in vivo yet had little effect on metastatic melanoma cells. Activation of NOTCH1 signaling enabled primary melanoma cells to gain metastatic capability. Furthermore, the oncogenic effect of notch1 on primary melanoma cells was mediated by beta-catenin, which was upregulated following notch1 activation. Inhibiting beta-catenin expression reversed notch1-enhanced tumor growth and metastasis. Another study continued, finding that NOTCH1 signaling drives the vertical growth phase (VGP) of primary melanoma toward a more aggressive phenotype. Constitutive activation of NOTCH1 by ectopic expression of the NICD enables VGP primary melanoma cell lines to proliferate in a serum-independent and growth factor-independent manner in vitro and to grow more aggressively with metastatic activity in vivo. They show that notch1 activation also enhances tumor cell survival when cultured as three-dimensional spheroids. Such effects of NOTCH1 signaling are mediated by activation of the mitogen-activated protein kinase (MAPK) and Akt pathways. Both pathways are activated in melanoma cells following Notch1 pathway activation. Inhibition of either the MAPK or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway reverses the NOTCH1 signaling-induced tumor cell growth.
      
    Entity Cervical Cancer
    Disease Cervical carcinomas are a major type of epithelial keratinocyte-derived tumors. Infection with human papillomaviruses (HPVs), more specifically the high-risk HPV16 and HPV18, is associated with most cervical cancer and is thought to have a causal link with the disease.
    Oncogenesis NOTCH1 signaling is believed to play an oncogenic role in early disease stages and a tumor suppressive role in late disease stages.
    Immunohistochemical data have indicated that notch1 expression is elevated in squamous metaplasia of the columnar epithelium, and in early HPV-induced lesions (CINI-III) and well-differentiated superficial carcinomas of the cervix. A study shows that in invasive cervical cancers, notch1 expression is substantially reduced. This dual-role pattern of notch1 expression suggests that the protein may play an oncogenic function in the early stages of cervical carcinogenesis, and a tumor suppressive function in the later stages.
      
    Entity Epithelial-mesenchymal transition (EMT)
    Disease EMT occurs during tumor progression when cells from a primary epithelial tumor change phenotype, become mesenchymal, and disseminate as single carcinoma cells, invading other organs as metastases. EMT may also be involved in the dedifferentiation program that leads to malignant carcinoma.
    Oncogenesis Jagged1 activation of endogenous Notch receptors in human endothelial cells promotes EMT in endothelial cells. NICD induction in the human adenocarcinoma cell line MCF7 promotes migratory behavior associated with E-CADHERIN loss.
    TGFb is another well-known inducer of EMT during embryonic development and the later stages of tumor progression. One possible mechanism of Notch-induced tumor development and progression may involve modulation of the TGFb signaling pathway, as it has been suggested that TGFb may be Notch-dependent.
      

    Other Leukemias implicated (Data extracted from papers in the Atlas)

    Leukemias 11q23ChildAMLID1615 11q23ID1030 11q23secondLeukID1131 t1119ELLID1029

    Other Solid tumors implicated (Data extracted from papers in the Atlas)

    Solid Tumors AmeloblastomID5945

    External links

    Nomenclature
    HGNC (Hugo)NOTCH1   7881
    Cards
    AtlasNOTCH1ID30ch9q34
    Entrez_Gene (NCBI)NOTCH1  4851  notch 1
    GeneCards (Weizmann)NOTCH1
    Ensembl hg19 (Hinxton)ENSG00000148400 [Gene_View]  chr9:139388896-139440238 [Contig_View]  NOTCH1 [Vega]
    Ensembl hg38 (Hinxton)ENSG00000148400 [Gene_View]  chr9:139388896-139440238 [Contig_View]  NOTCH1 [Vega]
    ICGC DataPortalENSG00000148400
    cBioPortalNOTCH1
    AceView (NCBI)NOTCH1
    Genatlas (Paris)NOTCH1
    WikiGenes4851
    SOURCE (Princeton)NOTCH1
    Genomic and cartography
    GoldenPath hg19 (UCSC)NOTCH1  -     chr9:139388896-139440238 -  9q34.3   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)NOTCH1  -     9q34.3   [Description]    (hg38-Dec_2013)
    EnsemblNOTCH1 - 9q34.3 [CytoView hg19]  NOTCH1 - 9q34.3 [CytoView hg38]
    Mapping of homologs : NCBINOTCH1 [Mapview hg19]  NOTCH1 [Mapview hg38]
    OMIM109730   190198   
    Gene and transcription
    Genbank (Entrez)AB209873 AF308602 AK000012 BC013208 BC039147
    RefSeq transcript (Entrez)NM_017617
    RefSeq genomic (Entrez)AC_000141 NC_000009 NC_018920 NG_007458 NT_008470 NW_001839245 NW_004929369
    Consensus coding sequences : CCDS (NCBI)NOTCH1
    Cluster EST : UnigeneHs.495473 [ NCBI ]
    CGAP (NCI)Hs.495473
    Alternative Splicing : Fast-db (Paris)GSHG0031278
    Alternative Splicing GalleryENSG00000148400
    Gene ExpressionNOTCH1 [ NCBI-GEO ]     NOTCH1 [ SEEK ]   NOTCH1 [ MEM ]
    SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP46531 (Uniprot)
    NextProtP46531  [Medical]
    With graphics : InterProP46531
    Splice isoforms : SwissVarP46531 (Swissvar)
    Domaine pattern : Prosite (Expaxy)ANK_REP_REGION (PS50297)    ANK_REPEAT (PS50088)    ASX_HYDROXYL (PS00010)    EGF_1 (PS00022)    EGF_2 (PS01186)    EGF_3 (PS50026)    EGF_CA (PS01187)    LNR (PS50258)   
    Domains : Interpro (EBI)Ankyrin_rpt    Ankyrin_rpt-contain_dom    DUF3454_notch    EG-like_dom    EGF-like_Ca-bd_dom    EGF-like_CS    EGF-type_Asp/Asn_hydroxyl_site    EGF_Ca-bd_CS    Growth_fac_rcpt_N_dom    Notch    Notch_1    Notch_dom    Notch_NOD_dom    Notch_NODP_dom   
    Related proteins : CluSTrP46531
    Domain families : Pfam (Sanger)Ank (PF00023)    Ank_2 (PF12796)    DUF3454 (PF11936)    EGF (PF00008)    EGF_CA (PF07645)    hEGF (PF12661)    NOD (PF06816)    NODP (PF07684)    Notch (PF00066)   
    Domain families : Pfam (NCBI)pfam00023    pfam12796    pfam11936    pfam00008    pfam07645    pfam12661    pfam06816    pfam07684    pfam00066   
    Domain families : Smart (EMBL)ANK (SM00248)  EGF (SM00181)  EGF_CA (SM00179)  NL (SM00004)  
    DMDM Disease mutations4851
    Blocks (Seattle)P46531
    PDB (SRS)1PB5    1TOZ    1YYH    2F8X    2F8Y    2HE0    2VJ3    3ETO    3I08    3L95    3NBN    3V79   
    PDB (PDBSum)1PB5    1TOZ    1YYH    2F8X    2F8Y    2HE0    2VJ3    3ETO    3I08    3L95    3NBN    3V79   
    PDB (IMB)1PB5    1TOZ    1YYH    2F8X    2F8Y    2HE0    2VJ3    3ETO    3I08    3L95    3NBN    3V79   
    PDB (RSDB)1PB5    1TOZ    1YYH    2F8X    2F8Y    2HE0    2VJ3    3ETO    3I08    3L95    3NBN    3V79   
    Human Protein AtlasENSG00000148400
    Peptide AtlasP46531
    HPRD01827
    IPIIPI00386123   IPI00412982   
    Protein Interaction databases
    DIP (DOE-UCLA)P46531
    IntAct (EBI)P46531
    FunCoupENSG00000148400
    BioGRIDNOTCH1
    IntegromeDBNOTCH1
    STRING (EMBL)NOTCH1
    Ontologies - Pathways
    QuickGOP46531
    Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  Golgi membrane  core promoter binding  RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription  in utero embryonic development  cell fate specification  epithelial to mesenchymal transition  liver development  heart looping  sprouting angiogenesis  MAML1-RBP-Jkappa- ICN1 complex  inflammatory response to antigenic stimulus  endocardium development  endocardium morphogenesis  atrioventricular node development  coronary vein morphogenesis  aortic valve morphogenesis  atrioventricular valve morphogenesis  pulmonary valve morphogenesis  mitral valve formation  epithelial to mesenchymal transition involved in endocardial cushion formation  endocardial cushion morphogenesis  cardiac chamber formation  cardiac ventricle morphogenesis  cardiac atrium morphogenesis  cardiac right atrium morphogenesis  cardiac left ventricle morphogenesis  cardiac right ventricle formation  ventricular trabecula myocardium morphogenesis  growth involved in heart morphogenesis  regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation  Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation  cell migration involved in endocardial cushion formation  pericardium morphogenesis  sequence-specific DNA binding transcription factor activity  enzyme inhibitor activity  receptor activity  calcium ion binding  protein binding  extracellular region  nucleus  nucleus  nucleoplasm  endoplasmic reticulum membrane  cytosol  plasma membrane  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  immune response  humoral immune response  Notch signaling pathway  Notch signaling pathway  Notch receptor processing  positive regulation of transcription of Notch receptor target  determination of left/right symmetry  compartment pattern specification  axonogenesis  foregut morphogenesis  endoderm development  heart development  positive regulation of cell proliferation  positive regulation of cell proliferation  negative regulation of cell proliferation  auditory receptor cell fate commitment  cell surface  glial cell differentiation  gene expression  positive regulation of epithelial to mesenchymal transition  negative regulation of cell-substrate adhesion  negative regulation of myotube differentiation  mesenchymal cell development  regulation of somitogenesis  integral component of membrane  enzyme binding  neural tube development  keratinocyte differentiation  negative regulation of ossification  lung development  positive regulation of cell migration  positive regulation of BMP signaling pathway  negative regulation of BMP signaling pathway  forebrain development  hair follicle morphogenesis  chromatin DNA binding  response to muramyl dipeptide  embryonic hindlimb morphogenesis  tube formation  skeletal muscle cell differentiation  cellular response to vascular endothelial growth factor stimulus  anagen  positive regulation of apoptotic process  negative regulation of catalytic activity  receptor complex  sequence-specific DNA binding  positive regulation of keratinocyte differentiation  negative regulation of myoblast differentiation  negative regulation of osteoblast differentiation  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  negative regulation of calcium ion-dependent exocytosis  positive regulation of JAK-STAT cascade  negative regulation of photoreceptor cell differentiation  somatic stem cell division  positive regulation of astrocyte differentiation  negative regulation of oligodendrocyte differentiation  branching morphogenesis of an epithelial tube  positive regulation of epithelial cell proliferation  negative regulation of neurogenesis  cardiac muscle tissue morphogenesis  cardiac muscle cell proliferation  positive regulation of cardiac muscle cell proliferation  negative regulation of glial cell proliferation  cilium morphogenesis  cardiac epithelial to mesenchymal transition  cardiac septum morphogenesis  ventricular septum morphogenesis  secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development  prostate gland epithelium morphogenesis  regulation of epithelial cell proliferation involved in prostate gland development  arterial endothelial cell differentiation  venous endothelial cell differentiation  cardiac vascular smooth muscle cell development  endocardial cell differentiation  vasculogenesis involved in coronary vascular morphogenesis  coronary artery morphogenesis  Notch signaling involved in heart development  heart trabecula morphogenesis  positive regulation of transcription from RNA polymerase II promoter in response to hypoxia  left/right axis specification  cellular response to follicle-stimulating hormone stimulus  distal tubule development  collecting duct development  glomerular mesangial cell development  interleukin-4 secretion  negative regulation of cell migration involved in sprouting angiogenesis  negative regulation of canonical Wnt signaling pathway  neuronal stem cell maintenance  regulation of extracellular matrix assembly  apoptotic process involved in embryonic digit morphogenesis  negative regulation of stem cell differentiation  negative regulation of anoikis  negative regulation of pro-B cell differentiation  negative regulation of endothelial cell chemotaxis  
    Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  Golgi membrane  core promoter binding  RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription  in utero embryonic development  cell fate specification  epithelial to mesenchymal transition  liver development  heart looping  sprouting angiogenesis  MAML1-RBP-Jkappa- ICN1 complex  inflammatory response to antigenic stimulus  endocardium development  endocardium morphogenesis  atrioventricular node development  coronary vein morphogenesis  aortic valve morphogenesis  atrioventricular valve morphogenesis  pulmonary valve morphogenesis  mitral valve formation  epithelial to mesenchymal transition involved in endocardial cushion formation  endocardial cushion morphogenesis  cardiac chamber formation  cardiac ventricle morphogenesis  cardiac atrium morphogenesis  cardiac right atrium morphogenesis  cardiac left ventricle morphogenesis  cardiac right ventricle formation  ventricular trabecula myocardium morphogenesis  growth involved in heart morphogenesis  regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation  Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation  cell migration involved in endocardial cushion formation  pericardium morphogenesis  sequence-specific DNA binding transcription factor activity  enzyme inhibitor activity  receptor activity  calcium ion binding  protein binding  extracellular region  nucleus  nucleus  nucleoplasm  endoplasmic reticulum membrane  cytosol  plasma membrane  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  immune response  humoral immune response  Notch signaling pathway  Notch signaling pathway  Notch receptor processing  positive regulation of transcription of Notch receptor target  determination of left/right symmetry  compartment pattern specification  axonogenesis  foregut morphogenesis  endoderm development  heart development  positive regulation of cell proliferation  positive regulation of cell proliferation  negative regulation of cell proliferation  auditory receptor cell fate commitment  cell surface  glial cell differentiation  gene expression  positive regulation of epithelial to mesenchymal transition  negative regulation of cell-substrate adhesion  negative regulation of myotube differentiation  mesenchymal cell development  regulation of somitogenesis  integral component of membrane  enzyme binding  neural tube development  keratinocyte differentiation  negative regulation of ossification  lung development  positive regulation of cell migration  positive regulation of BMP signaling pathway  negative regulation of BMP signaling pathway  forebrain development  hair follicle morphogenesis  chromatin DNA binding  response to muramyl dipeptide  embryonic hindlimb morphogenesis  tube formation  skeletal muscle cell differentiation  cellular response to vascular endothelial growth factor stimulus  anagen  positive regulation of apoptotic process  negative regulation of catalytic activity  receptor complex  sequence-specific DNA binding  positive regulation of keratinocyte differentiation  negative regulation of myoblast differentiation  negative regulation of osteoblast differentiation  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  negative regulation of calcium ion-dependent exocytosis  positive regulation of JAK-STAT cascade  negative regulation of photoreceptor cell differentiation  somatic stem cell division  positive regulation of astrocyte differentiation  negative regulation of oligodendrocyte differentiation  branching morphogenesis of an epithelial tube  positive regulation of epithelial cell proliferation  negative regulation of neurogenesis  cardiac muscle tissue morphogenesis  cardiac muscle cell proliferation  positive regulation of cardiac muscle cell proliferation  negative regulation of glial cell proliferation  cilium morphogenesis  cardiac epithelial to mesenchymal transition  cardiac septum morphogenesis  ventricular septum morphogenesis  secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development  prostate gland epithelium morphogenesis  regulation of epithelial cell proliferation involved in prostate gland development  arterial endothelial cell differentiation  venous endothelial cell differentiation  cardiac vascular smooth muscle cell development  endocardial cell differentiation  vasculogenesis involved in coronary vascular morphogenesis  coronary artery morphogenesis  Notch signaling involved in heart development  heart trabecula morphogenesis  positive regulation of transcription from RNA polymerase II promoter in response to hypoxia  left/right axis specification  cellular response to follicle-stimulating hormone stimulus  distal tubule development  collecting duct development  glomerular mesangial cell development  interleukin-4 secretion  negative regulation of cell migration involved in sprouting angiogenesis  negative regulation of canonical Wnt signaling pathway  neuronal stem cell maintenance  regulation of extracellular matrix assembly  apoptotic process involved in embryonic digit morphogenesis  negative regulation of stem cell differentiation  negative regulation of anoikis  negative regulation of pro-B cell differentiation  negative regulation of endothelial cell chemotaxis  
    Pathways : BIOCARTASegmentation Clock [Genes]    Presenilin action in Notch and Wnt signaling [Genes]    Proteolysis and Signaling of Notch [Genes]   
    Pathways : KEGGDorso-ventral axis formation    Notch signaling pathway    Thyroid hormone signaling pathway    Prion diseases    MicroRNAs in cancer   
    REACTOMEP46531 [protein]
    REACTOME PathwaysREACT_691 A third proteolytic cleavage releases NICD [pathway]
    REACTOME PathwaysREACT_116125 Disease [pathway]
    REACTOME PathwaysREACT_71 Gene Expression [pathway]
    REACTOME PathwaysREACT_2155 NICD traffics to nucleus [pathway]
    REACTOME PathwaysREACT_2001 Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor [pathway]
    REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
    Protein Interaction DatabaseNOTCH1
    DoCM (Curated mutations)NOTCH1
    Wikipedia pathwaysNOTCH1
    Gene fusion - rearrangements
    Rearrangement : COSMICSEC16A [9q34.3]  -  NOTCH1 [9q34.3]
    Rearrangement : TICdbNOTCH1 [9q34.3]  -  - [3q29]
    Polymorphisms : SNP, variants
    NCBI Variation ViewerNOTCH1 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)NOTCH1
    dbVarNOTCH1
    ClinVarNOTCH1
    1000_GenomesNOTCH1 
    Exome Variant ServerNOTCH1
    SNP (GeneSNP Utah)NOTCH1
    SNP : HGBaseNOTCH1
    Genetic variants : HAPMAPNOTCH1
    Genomic VariantsNOTCH1  NOTCH1 [DGVbeta]
    Mutations
    ICGC Data PortalENSG00000148400 
    Cancer Gene: CensusNOTCH1 
    Somatic Mutations in Cancer : COSMICNOTCH1 
    CONAN: Copy Number AnalysisNOTCH1 
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
    Diseases
    DECIPHER (Syndromes)9:139388896-139440238
    Mutations and Diseases : HGMDNOTCH1
    OMIM109730    190198   
    MedgenNOTCH1
    NextProtP46531 [Medical]
    GENETestsNOTCH1
    Disease Genetic AssociationNOTCH1
    Huge Navigator NOTCH1 [HugePedia]  NOTCH1 [HugeCancerGEM]
    snp3D : Map Gene to Disease4851
    DGIdb (Drug Gene Interaction db)NOTCH1
    General knowledge
    Homologs : HomoloGeneNOTCH1
    Homology/Alignments : Family Browser (UCSC)NOTCH1
    Phylogenetic Trees/Animal Genes : TreeFamNOTCH1
    Chemical/Protein Interactions : CTD4851
    Chemical/Pharm GKB GenePA31683
    Drug Sensitivity NOTCH1
    Clinical trialNOTCH1
    Cancer Resource (Charite)ENSG00000148400
    Other databases
    Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=NOTCH1
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMineNOTCH1
    GoPubMedNOTCH1
    iHOPNOTCH1

    Bibliography

    The theory of the gene.
    Morgan TH
    The American Naturalist. 1917.
     
    The theory of the gene, revised.
    Morgan TH
    Yale University Press. 1938.
     
    Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats.
    Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S
    Cell. 1985 ; 43 (3 Pt 2) : 567-581.
    PMID 3935325
     
    Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors.
    Kidd S, Kelley MR, Young MW
    Molecular and cellular biology. 1986 ; 6 (9) : 3094-3108.
    PMID 3097517
     
    Regulation of enzyme levels by proteolysis: the role of pest regions.
    Rechsteiner M
    Advances in enzyme regulation. 1988 ; 27 : 135-151.
    PMID 2907964
     
    TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.
    Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J
    Cell. 1991 ; 66 (4) : 649-661.
    PMID 1831692
     
    NF-kappa B and related proteins: Rel/dorsal homologies meet ankyrin-like repeats.
    Blank V, Kourilsky P, Isral A
    Trends in biochemical sciences. 1992 ; 17 (4) : 135-140.
    PMID 1533967
     
    Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H).
    Tamura K, Taniguchi Y, Minoguchi S, Sakai T, Tun T, Furukawa T, Honjo T
    Current biology : CB. 1995 ; 5 (12) : 1416-1423.
    PMID 8749394
     
    Alterations in Notch signaling in neoplastic lesions of the human cervix.
    Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S
    Proceedings of the National Academy of Sciences of the United States of America. 1995 ; 92 (14) : 6414-6418.
    PMID 7604005
     
    Tissue-specific expression of human achaete-scute homologue-1 in neuroendocrine tumors: transcriptional regulation by dual inhibitory regions.
    Chen H, Biel MA, Borges MW, Thiagalingam A, Nelkin BD, Baylin SB, Ball DW
    Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 1997 ; 8 (6) : 677-686.
    PMID 9186001
     
    Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression.
    Chen H, Thiagalingam A, Chopra H, Borges MW, Feder JN, Nelkin BD, Baylin SB, Ball DW
    Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (10) : 5355-5360.
    PMID 9144241
     
    Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors.
    Ball DW, Azzoli CG, Baylin SB, Chi D, Dou S, Donis-Keller H, Cumaraswamy A, Borges M, Nelkin BD
    Proceedings of the National Academy of Sciences of the United States of America. 1993 ; 90 (12) : 5648-5652.
    PMID 8390674
     
    The link between integration and expression of human papillomavirus type 16 genomes and cellular changes in the evolution of cervical intraepithelial neoplastic lesions.
    Daniel B, Rangarajan A, Mukherjee G, Vallikad E, Krishna S
    The Journal of general virology. 1997 ; 78 ( Pt 5) : 1095-1101.
    PMID 9152428
     
    Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.
    Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB
    Nature genetics. 1997 ; 16 (3) : 243-251.
    PMID 9207788
     
    Mutations in the human Jagged1 gene are responsible for Alagille syndrome.
    Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC
    Nature genetics. 1997 ; 16 (3) : 235-242.
    PMID 9207787
     
    A role for Abl in Notch signaling.
    Giniger E
    Neuron. 1998 ; 20 (4) : 667-681.
    PMID 9581760
     
    A histone deacetylase corepressor complex regulates the Notch signal transduction pathway.
    Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T
    Genes & development. 1998 ; 12 (15) : 2269-2277.
    PMID 9694793
     
    Human ligands of the Notch receptor.
    Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S
    The American journal of pathology. 1999 ; 154 (3) : 785-794.
    PMID 10079256
     
    Cytogenetics and molecular genetics of childhood leukemia.
    Ma SK, Wan TS, Chan LC
    Hematological oncology. 1999 ; 17 (3) : 91-105.
    PMID 10641030
     
    A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.
    Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Isral A
    Molecular cell. 2000 ; 5 (2) : 207-216.
    PMID 10882063
     
    Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.
    Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD
    Nature genetics. 2000 ; 24 (4) : 438-441.
    PMID 10742114
     
    Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5.
    Kurooka H, Honjo T
    The Journal of biological chemistry. 2000 ; 275 (22) : 17211-17220.
    PMID 10747963
     
    Cell cycle arrest and apoptosis induced by Notch1 in B cells.
    Morimura T, Goitsuka R, Zhang Y, Saito I, Reth M, Kitamura D
    The Journal of biological chemistry. 2000 ; 275 (47) : 36523-36531.
    PMID 10967117
     
    Notch signaling: from the outside in.
    Mumm JS, Kopan R
    Developmental biology. 2000 ; 228 (2) : 151-165.
    PMID 11112321
     
    MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.
    Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD
    Nature genetics. 2000 ; 26 (4) : 484-489.
    PMID 11101851
     
    Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.
    zur Hausen H
    Journal of the National Cancer Institute. 2000 ; 92 (9) : 690-698.
    PMID 10793105
     
    The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway.
    Krebs LT, Deftos ML, Bevan MJ, Gridley T
    Developmental biology. 2001 ; 238 (1) : 110-119.
    PMID 11783997
     
    Transcriptional repression by suppressor of hairless involves the binding of a hairless-dCtBP complex in Drosophila.
    Morel V, Lecourtois M, Massiani O, Maier D, Preiss A, Schweisguth F
    Current biology : CB. 2001 ; 11 (10) : 789-792.
    PMID 11378391
     
    Notch signaling induces cell cycle arrest in small cell lung cancer cells.
    Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, Ball DW
    Cancer research. 2001 ; 61 (7) : 3200-3205.
    PMID 11306509
     
    Asymmetric segregation of Numb: a mechanism for neural specification from Drosophila to mammals.
    Cayouette M, Raff M
    Nature neuroscience. 2002 ; 5 (12) : 1265-1269.
    PMID 12447381
     
    Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling.
    Fortini ME
    Nature reviews. Molecular cell biology. 2002 ; 3 (9) : 673-684.
    PMID 12209127
     
    Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma.
    Jundt F, Anagnostopoulos I, Frster R, Mathas S, Stein H, Drken B
    Blood. 2002 ; 99 (9) : 3398-3403.
    PMID 11964309
     
    Aph-2/Nicastrin: an essential component of gamma-secretase and regulator of Notch signaling and Presenilin localization.
    Kopan R, Goate A
    Neuron. 2002 ; 33 (3) : 321-324.
    PMID 11832221
     
    Notch signaling induces rapid degradation of achaete-scute homolog 1.
    Sriuranpong V, Borges MW, Strock CL, Nakakura EK, Watkins DN, Blaumueller CM, Nelkin BD, Ball DW
    Molecular and cellular biology. 2002 ; 22 (9) : 3129-3139.
    PMID 11940670
     
    Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation.
    Talora C, Sgroi DC, Crum CP, Dotto GP
    Genes & development. 2002 ; 16 (17) : 2252-2263.
    PMID 12208848
     
    Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing.
    Thlu J, Rossio P, Favier B
    BMC dermatology. 2002 ; 2 : page 7.
    PMID 11978185
     
    Epithelial-mesenchymal transitions in tumour progression.
    Thiery JP
    Nature reviews. Cancer. 2002 ; 2 (6) : 442-454.
    PMID 12189386
     
    p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro.
    Wallberg AE, Pedersen K, Lendahl U, Roeder RG
    Molecular and cellular biology. 2002 ; 22 (22) : 7812-7819.
    PMID 12391150
     
    An overview of the Notch signalling pathway.
    Baron M
    Seminars in cell & developmental biology. 2003 ; 14 (2) : 113-119.
    PMID 12651094
     
    Learning and memory deficits in Notch mutant mice.
    Costa RM, Honjo T, Silva AJ
    Current biology : CB. 2003 ; 13 (15) : 1348-1354.
    PMID 12906797
     
    HES and HERP families: multiple effectors of the Notch signaling pathway.
    Iso T, Kedes L, Hamamori Y
    Journal of cellular physiology. 2003 ; 194 (3) : 237-255.
    PMID 12548545
     
    The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments.
    LaVoie MJ, Selkoe DJ
    The Journal of biological chemistry. 2003 ; 278 (36) : 34427-34437.
    PMID 12826675
     
    Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis.
    Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M
    Molecular and cellular biology. 2003 ; 23 (1) : 14-25.
    PMID 12482957
     
    Notch signaling controls multiple steps of pancreatic differentiation.
    Murtaugh LC, Stanger BZ, Kwan KM, Melton DA
    Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (25) : 14920-14925.
    PMID 14657333
     
    Notch1 functions as a tumor suppressor in mouse skin.
    Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, Hui CC, Clevers H, Dotto GP, Radtke F
    Nature genetics. 2003 ; 33 (3) : 416-421.
    PMID 12590261
     
    Notch1 enhances B-cell receptor-induced apoptosis in mature activated B cells without affecting cell cycle progression and surface IgM expression.
    Romer S, Saunders U, Jck HM, Jehn BM
    Cell death and differentiation. 2003 ; 10 (7) : 833-844.
    PMID 12815466
     
    The role of human achaete-scute homolog-1 in medullary thyroid cancer cells.
    Sippel RS, Carpenter JE, Kunnimalaiyaan M, Chen H
    Surgery. 2003 ; 134 (6) : 866-871.
    PMID 14668716
     
    The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity.
    Takeyama K, Aguiar RC, Gu L, He C, Freeman GJ, Kutok JL, Aster JC, Shipp MA
    The Journal of biological chemistry. 2003 ; 278 (24) : 21930-21937.
    PMID 12670957
     
    Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells.
    Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS
    Breast cancer research : BCR. 2004 ; 6 (6) : R605-R615.
    PMID 15535842
     
    Drosophila deltex mediates suppressor of Hairless-independent and late-endosomal activation of Notch signaling.
    Hori K, Fostier M, Ito M, Fuwa TJ, Go MJ, Okano H, Baron M, Matsuno K
    Development (Cambridge, England). 2004 ; 131 (22) : 5527-5537.
    PMID 15496440
     
    Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells.
    Jundt F, Prbsting KS, Anagnostopoulos I, Muehlinghaus G, Chatterjee M, Mathas S, Bargou RC, Manz R, Stein H, Drken B
    Blood. 2004 ; 103 (9) : 3511-3515.
    PMID 14726396
     
    Notch signaling: control of cell communication and cell fate.
    Lai EC
    Development (Cambridge, England). 2004 ; 131 (5) : 965-973.
    PMID 14973298
     
    Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines.
    Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI
    Blood. 2004 ; 103 (9) : 3503-3510.
    PMID 14670925
     
    Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation.
    Noseda M, McLean G, Niessen K, Chang L, Pollet I, Montpetit R, Shahidi R, Dorovini-Zis K, Li L, Beckstead B, Durand RE, Hoodless PA, Karsan A
    Circulation research. 2004 ; 94 (7) : 910-917.
    PMID 14988227
     
    The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer.
    Parr C, Watkins G, Jiang WG
    International journal of molecular medicine. 2004 ; 14 (5) : 779-786.
    PMID 15492845
     
    Notch regulation of lymphocyte development and function.
    Radtke F, Wilson A, Mancini SJ, MacDonald HR
    Nature immunology. 2004 ; 5 (3) : 247-253.
    PMID 14985712
     
    Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.
    Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC
    Science (New York, N.Y.). 2004 ; 306 (5694) : 269-271.
    PMID 15472075
     
    Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression.
    Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I, Brown EJ, Capobianco AJ, Herlyn M, Liu ZJ
    The Journal of clinical investigation. 2005 ; 115 (11) : 3166-3176.
    PMID 16239965
     
    p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation.
    Devgan V, Mammucari C, Millar SE, Brisken C, Dotto GP
    Genes & development. 2005 ; 19 (12) : 1485-1495.
    PMID 15964998
     
    Conservation of the Notch1 signaling pathway in gastrointestinal carcinoid cells.
    Kunnimalaiyaan M, Traeger K, Chen H
    American journal of physiology. Gastrointestinal and liver physiology. 2005 ; 289 (4) : G636-G642.
    PMID 16160079
     
    Hairy Enhancer of Split-1 (HES-1), a Notch1 effector, inhibits the growth of carcinoid tumor cells.
    Kunnimalaiyaan M, Yan S, Wong F, Zhang YW, Chen H
    Surgery. 2005 ; 138 (6) : 1137-1142.
    PMID 16360401
     
    Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children.
    Lee SY, Kumano K, Masuda S, Hangaishi A, Takita J, Nakazaki K, Kurokawa M, Hayashi Y, Ogawa S, Chiba S
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    Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling.
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    Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling.
    Nobta M, Tsukazaki T, Shibata Y, Xin C, Moriishi T, Sakano S, Shindo H, Yamaguchi A
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    ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features.
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    Cancer research. 2005 ; 65 (23) : 10680-10685.
    PMID 16322211
     
    RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes.
    Oswald F, Winkler M, Cao Y, Astrahantseff K, Bourteele S, Knchel W, Borggrefe T
    Molecular and cellular biology. 2005 ; 25 (23) : 10379-10390.
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    High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival.
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    Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways.
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    Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies.
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    Notch signalling: a simple pathway becomes complex.
    Bray SJ
    Nature reviews. Molecular cell biology. 2006 ; 7 (9) : 678-689.
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    Overexpression of the NOTCH1 intracellular domain inhibits cell proliferation and alters the neuroendocrine phenotype of medullary thyroid cancer cells.
    Kunnimalaiyaan M, Vaccaro AM, Ndiaye MA, Chen H
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    PMID 17090547
     
    Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression.
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    Roles of O-fucose glycans in notch signaling revealed by mutant mice.
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    PMID 17132502
     
    Complex networks orchestrate epithelial-mesenchymal transitions.
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    Nature reviews. Molecular cell biology. 2006 ; 7 (2) : 131-142.
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    Notch signaling in development and cancer.
    Bols V, Grego-Bessa J, de la Pompa JL
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    Notch signaling is essential for ventricular chamber development.
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    Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors.
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    Suberoyl bishydroxamic acid inhibits cellular proliferation by inducing cell cycle arrest in carcinoid cancer cells.
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    Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors.
    Kunnimalaiyaan M, Chen H
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    PMID 17522241
     
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    Contributor(s)

    Written08-2007Max Cayo, David Yu Greenblatt, Muthusamy Kunnimalaiyaan, Herbert Chen
    Endocrine Cancer Disease Group, University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, H4/750 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA.

    Citation

    This paper should be referenced as such :
    Cayo, M ; Greenblatt, DY ; Kunnimalaiyaan, M ; Chen, H
    NOTCH1 (Notch homolog 1, translocation-associated (Drosophila))
    Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):111-119.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/NOTCH1ID30ch9q34.html

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