Search results for NOTCH1

Showing 19 results out of 343

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Complex (3 results from a total of 106)

Identifier: R-HSA-157027
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-157091
Species: Homo sapiens
Compartment: Golgi membrane
Identifier: R-HSA-2672451
Species: Homo sapiens
Compartment: plasma membrane

Protein (3 results from a total of 67)

Identifier: R-HSA-2220929
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: NOTCH1: P46531
In a small percent of T-ALL patients, the translocation t(7;9)(q34;q34.3) fuses intron 24 of NOTCH1 gene with the promoter of T cell receptor beta gene. This results in deregulated expression of a truncated NOTCH1 protein, which lacks ligand binding activity and is constitutivelu processed into NICD1 (Ellisen et al. 1991).
Identifier: R-HSA-1467396
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane
Primary external reference: UniProt: NOTCH1: P46531
Identifier: R-HSA-1485602
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: P46531

RNA Sequence (1 results from a total of 1)

Identifier: R-HSA-1606559
Species: Homo sapiens
Compartment: cytosol
Primary external reference: ENSEMBL: NOTCH1 mRNA: ENST00000277541

DNA Sequence (1 results from a total of 1)

Identifier: R-HSA-1911481
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: ENSEMBL: NOTCH1 Gene: ENSG00000148400

Set (3 results from a total of 16)

Identifier: R-HSA-1911555
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-2220961
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-2220939
Species: Homo sapiens
Compartment: plasma membrane

Pathway (3 results from a total of 29)

Identifier: R-HSA-1980143
Species: Homo sapiens
Compartment: plasma membrane, cytosol, nucleoplasm
NOTCH1 functions as both a transmembrane receptor presented on the cell surface and as a transcriptional regulator in the nucleus.

NOTCH1 receptor presented on the plasma membrane is activated by a membrane bound ligand expressed in trans on the surface of a neighboring cell. In trans, ligand binding triggers proteolytic cleavage of NOTCH1 and results in release of the NOTCH1 intracellular domain, NICD1, into the cytosol.

NICD1 translocates to the nucleus where it associates with RBPJ (also known as CSL or CBF) and mastermind-like (MAML) proteins (MAML1, MAML2 or MAML3; possibly also MAMLD1) to form NOTCH1 coactivator complex. NOTCH1 coactivator complex activates transcription of genes that possess RBPJ binding sites in their promoters.

Identifier: R-HSA-2644603
Species: Homo sapiens
Human NOTCH1 was cloned as a chromosome 9 gene, translocated to the T-cell beta receptor (TCBR) promoter on chromosome 7 in T-cell acute lymphoblastic leukemia (T-ALL) (Ellisen et al. 1991). This translocation, present in only a small percentage of T-ALL patients, results in the overexpression of a truncated NOTCH1 receptor, which lacks almost the entire extracellular domain, in T lymphocytes. Oncogenic NOTCH1 mutations were subsequently found to be present in >50% of T-ALL patients, with hotspots in the heterodimerization domain (HD domain) and PEST domain of NOTCH1 (Weng et al. 2004).

Normal NOTCH1 becomes activated by binding DLL (DLL1 or DLL4) or JAG (JAG1 or JAG2) ligands expressed on the surface of a neighboring cell, which leads to proteolytic cleavage of NOTCH1 by ADAM10/17 and gamma-secretase, and release of the NOTCH1 intracellular domain (NICD1) which regulates expression of genes that play important roles in the development of T lymphocytes (Washburn et al. 1997. Radtke et al. 1999, Maillard et al. 2004, Sambandam et al. 2005, Tan et al. 2005). Mutations in the HD domain, responsible for association of NOTCH1 extracellular and transmembrane regions after furin-mediated cleavage of NOTCH1 precursor, as well as the truncation of the NOTCH1 extracellular domain by the rare T-ALL translocation, enable constitutive production of NICD1, in the absence of ligand binding (Malecki et al. 2006, Ellisen et al. 1991).

Mutations in the NOTCH1 PEST domain interfere with FBXW7 (FBW7)-mediated ubiquitination and degradation of NICD1, resulting in prolonged half-life and increased transcriptional activity of NICD1, which promotes growth and division of T-lymphocytes (Weng et al. 2004, Thompson et al. 2007, O'Neil et al. 2007).

Mutations in the HD domain and PEST domain of NOTCH1 are frequently found in cis in T-ALL. While HD mutations alone result in up to ~10-fold increase in NOTCH1 transcriptional activity and PEST domain mutations alone result in up to ~2-fold increase in NOTCH1 transcriptional activity, in cis mutations of HD and PEST domains act synergistically, increasing NOTCH1 transcriptional activity up to ~40-fold (Weng et al. 2004).

FBXW7 (FBW7), a component of the SCF (SKP1, CUL1, and F-box protein) ubiquitin ligase complex SCF-FBW7 involved in the degradation of NOTCH1 (Oberg et al. 2001, Wu et al. 2001, Fryer et al. 2004), is subject to loss of function mutations in T-ALL (Akhoondi et al. 2007, Thompson et al. 2007, O'Neil et al. 2007) which are mutually exclusive with NOTCH1 PEST domain mutations (Thompson et al. 2007, O'Neil et al. 2007).

Although gamma-secretase inhibitors (GSIs) are successfully used in vitro to inhibit NOTCH1 signaling in T-ALL cell lines, the gamma-secretase complex has many other substrates besides NOTCH. The specificity of GSIs is therefore limited and, as they are not considered to be particularly promising drugs for the clinical treatment of T-ALL (reviewed by Purow, 2012), they have not been annotated.

For a recent review of NOTCH1 signaling in cancer, please refer to Grabher et al. 2006.
Identifier: R-HSA-2644605
Species: Homo sapiens
FBXW7 (FBW7) is a component of the SCF (SKP1, CUL1, and F-box protein) ubiquitin ligase complex SCF-FBW7 which is involved in the degradation of NOTCH1 (Oberg et al. 2001, Wu et al. 2001, Fryer et al. 2004). Loss of function mutations in FBXW7 are frequently found in T-cell acute lymphoblastic leukemia (Akhoondi et al. 2007, Thompson et al. 2007, O'Neil et al. 2007) and are mutually exclusive with NOTCH1 PEST domain mutations (Thompson et al. 2007, O'Neil et al. 2007).

Interactor (1 results from a total of 1)

Identifier: Q6IAD4
Species: Homo sapiens
Primary external reference: UniProt: Q6IAD4

Reaction (3 results from a total of 121)

Identifier: R-HSA-1980044
Species: Homo sapiens
Compartment: plasma membrane
NOTCH1 is activated by JAG2 ligand expressed on a neighboring cell. When the mouse myoblast cell line C2C12 expressing exogenous human NOTCH1 is grown with NIH3T3 cells expressing exogenous human JAG2, myogenic differentiation is inhibited and a NOTCH1 polypeptide that corresponds to the NOTCH intracellular domain appears (Luo et al. 1997).
Identifier: R-HSA-1912416
Species: Homo sapiens
Compartment: nucleoplasm
NOTCH1 was cloned as a chromosome 9 gene involved in translocation t(7;9)(q34;q34.3) in several T-cell acute lymphoblastic leukemia (T-ALL) patients. The gene was found to be highly homologous to the Drosophila gene Notch and was initially named TAN-1 (translocation-associated Notch homolog). Transcripts of NOTCH1 were detected in many fetal and adult human and mouse tissues, with the highest abundance in lymphoid tissues. The translocation t(7;9)(q34;q34.3) found in a small fraction of T-ALL patients puts NOTCH1 transcription under the control of the T-cell receptor-beta (TCRB) locus, which results in expression of truncated peptides that lack the extracellular ligand binding domain and are constitutively active (reviewed by Grabher et al. 2006). Activating NOTCH1 point mutations, mainly affecting the extracellular heterodimerization domain and/or the C-terminal PEST domain, are found in more than 50% of human T-ALLs (Weng et al. 2004).

Studies of mouse Rbpj knockout embryos and zebrafish Mib (mindbomb) mutants indicate that the NOTCH1 coactivator complex positively regulates NOTCH1 transcription. The RBPJ-binding site(s) that the NOTCH1 coactivator complex normally binds have not been found in the NOTCH1 promoter, however, so this effect may be indirect and its mechanism is unknown (Del Monte et al. 2007).

CCND1 (cyclin D1) forms a complex with CREBBP and binds to the NOTCH1 promoter, stimulating NOTCH1 transcription. The involvement of CCND1 in transcriptional regulation of NOTCH1 was established in mouse retinas and the rat retinal precursor cell line R28 (Bienvenu et al. 2010).

E2F1 and E2F3 are able to bind to the NOTCH1 promoter and activate NOTCH1 transcription (Viatour et al. 2011).

NOTCH1 promoter possesses two putative p53-binding sites. Chromatin immunoprecipitation (ChIP) assays of human primary keratinocytes showed binding of endogenous p53 protein to both sites. Experiments in which p53 was downregulated or overexpressed implicate p53 as a positive regulator of NOTCH1 expression in primary human keratinocytes. It is likely that p53-mediated regulation of NOTCH1 expression involves interplay with other cell-type specific determinants of gene expression (Lefort et al. 2007). In lymphoid cells, NOTCH1 expression may be negatively regulated by p53 (Laws and Osborne 2004). Other proteins implicated in the negative regulation of NOTCH1 transcription are KLF9 (Ying et al. 2011), JARID2 (Mysliwiec et al. 2011, Mysliwiec et al. 2012), KLF4 and SP3 (Lambertini et al. 2010), and p63 (Yugawa et al. 2010).
Identifier: R-HSA-1980067
Species: Homo sapiens
Compartment: nucleoplasm
Binding of the NOTH1 Coactivator Complex to the MYC promoter stimulates MYC transcription (Palomero et al. 2006).

Icon (1 results from a total of 1)

Species: Homo sapiens
Neurogenic locus notch homolog protein 1
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