Disease relevance of NOTCH1

• Recent work has shown that human T-ALL is frequently associated with C-terminal NOTCH1 truncations, which uniformly remove sequences lying between residues 2524 and 2556 [1].
• High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival [2].
• NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis [3].
• Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to gamma-secretase inhibitors treatment [4].
• Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSI) has emerged as a potential therapeutic strategy for the treatment of this disease [4].
• The ability of this model to detect a strong interaction between NOTCH1 and bcl2 suggests that genetic modifier screens have a high likelihood of revealing other genes that can cooperate with NOTCH1 to induce T-ALL [5].
• Cells inactivated for hCdc4 and T-ALL cells containing hCDC4 mutations exhibited an increased Notch1 protein half-life, consistent with the proposed role of hCdc4 in ubiquitin-dependent proteolysis of Notch1 [6].
• We conclude that NOTCH1 can be an early or initiating event in T-ALL arising prenatally, to be complemented by a postnatal SIL-TAL1 fusion [7].
• Notch1 facilitated melanoma development in a xenograft model by maintaining cell proliferation and by protecting cells from stress-induced cell death [8].

Psychiatry related information on NOTCH1

• Furthermore, the fact that inhibitors first target gamma-secretase in the plasma membrane for Notch processing, and not for APP, will have important implications for drug development to treat Alzheimer's disease and cancer [9].
• Against a background of consistent gene expression, several regulatory genes show marked differences between fetal and adult expression profiles, including those encoding two basic helix-loop-helix antagonist Id factors, the Ets family factor SpiB and the Notch target gene Deltex1 [10].
• Transient administration of Notch ligands to the brain of adult rats increases the numbers of newly generated precursor cells and improves motor skills after ischaemic injury [11].
• Human Genetics. Notch, stroke and dementia [12].
• Notch-1 immunoexpression is increased in Alzheimer's and Pick's disease [13].

High impact information on NOTCH1

• Commitment to the T cell lineage and subsequent stages of early thymopoiesis is critically regulated by Notch [14].
• Recent data indicate that Notch can also direct the differentiation and activity of peripheral T and B cells [14].
• The transmembrane receptor Notch participates in diverse cell fate decisions throughout embryonic development [15].
• Notch receptors and their ligands are expressed in the mammalian thymus, raising the possibility that Notch could regulate T cell fate decisions [15].
• Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes [16].

Chemical compound and disease context of NOTCH1

• BON carcinoid cells were further analyzed after Notch overexpression for neuroendocrine marker expression, serotonin production, and growth [17].
• Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells [18].
• These results suggest that the down-regulation of Notch signaling by curcumin may be a novel strategy for the treatment of patients with pancreatic cancer [19].
• The presence of NOTCH1 mutations was significantly correlated with a good prednisone response and favorable minimal residual disease (MRD) kinetics, which was independent from sex, age, white blood cell count, and T-cell immunophenotype at the time of diagnosis [20].
• The effect of all-trans retinoid acid (ATRA) on the expression of Notch1 gene by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in acute promyelocytic leukemia cells (APL), NB4, and HL-60 lacking t(15;17) was studied [21].

Biological context of NOTCH1

• In human acute lymphoblastic T-cell leukemia, a chromosomal translocation damages the NOTCH1 gene [22].
• These data are most consistent with NOTCH1 oncogenesis and transcriptional activation being independent of association with RBP-Jkappa at promoter sites [23].
• Oncogenic forms of NOTCH1 lacking either the primary binding site for RBP-Jkappa or nuclear localization sequences retain the ability to associate with RBP-Jkappa and activate transcription [23].
• Unlike full-sized NOTCH1, two such truncated forms of the protein either lacking a major portion of the extracellular domain (DeltaE) or consisting only of the intracellular domain (ICN) were found to activate transcription in cultured cells, presumably through RBP-Jkappa response elements within DNA [23].
• In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis [4].

Anatomical context of NOTCH1

• NOTCH1 is a large type I transmembrane receptor that regulates normal T-cell development via a signaling pathway that relies on regulated proteolysis [1].
• These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention [24].
• Consistent with these in vitro studies, mutation of the WSSSSP sequence converts nonleukemogenic weak gain-of-function NOTCH1 alleles into alleles that cause aggressive T-ALLs in a murine bone marrow transplant model [1].
• CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors [4].
• Mutations in NOTCH1 cause aortic valve disease [25].

Associations of NOTCH1 with chemical compounds

• The activating mutations cause soluble NOTCH1 heterodimers to dissociate more readily, either under native conditions (n = 3) or in the presence of urea (n = 11) [26].
• However, activation of only Notch-1, but not Notch-2, resulted in protection of tumor cells from melphalan- and mitoxantrone-induced apoptosis [27].
• Using a cell line deficient for the T cell-specific, Src family protein, the tyrosine kinase p56(lck) and by reconstitution approaches we demonstrate that p56(lck) is required for the Notch-1-mediated activation of Akt/PKB function [28].
• NOV associates with the epidermal growth factor-like repeats of Notch1 by the CT (C-terminal cysteine knot) domain [29].
• Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling [30].

Physical interactions of NOTCH1

• Furthermore we found that full-length expressed WWP1 could interact in vitro with the cytoplasmic domain of human Notch1 [31].
• JAG1 then binds to the Notch receptor on adjacent stem cells to induce Notch receptor proteolyses for the release of Notch intracellular domain (NICD) [32].
• The cleaved intracellular region (RAMIC) of Notch is translocated into the nucleus and interacts with a DNA-binding protein RBP-J to activate transcription of genes that regulate cell differentiation [33].
• Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated gamma-secretase activity [34].
• Consistent with these results, we found that the down-regulation of Notch-1 reduced NF-kappaB DNA-binding activity and VEGF expression [35].

Enzymatic interactions of NOTCH1

• Activation of Notch1 signaling in the RA synovium was identified using a specific antibody to the cleaved form of Notch1 [36].
• The NOTCH1 receptor is cleaved within its extracellular domain by furin during its maturation, yielding two subunits that are held together noncovalently by a juxtamembrane heterodimerization (HD) domain [26].
• Moreover, non-denaturing isolation of the intact enzyme complex revealed that cell surface gamma-secretase can specifically generate amyloid beta-protein from an APP substrate and similarly cleave a Notch substrate [37].
• After ligand binding, Notch is cleaved by the ADAM-17 metalloprotease followed by an intramembrane cleavage mediated by gamma-secretase [38].

Regulatory relationships of NOTCH1

• Strikingly, the PS1 L166P mutation not only induces an exceptionally high increase of Abeta(42) production but also impairs NICD production and Notch signaling, as well as AICD generation [39].
• Thus, Dl-1 behaves as a functional ligand for Notch-1 and has the same ability to suppress cell differentiation as the Jagged proteins do [40].
• Strikingly, blockade of Notch cleavage with a gamma secretase inhibitor failed to affect cytokine production in this system, implying that Delta1 can influence cytokine production via a Notch cleavage-independent mechanism [41].
• In this study, over-expression and depletion of Notch-1 intracellular domain (NICD) strategies were used to investigate whether expression of the GAA gene is under the control of Notch-1/Hes-1 signaling [42].
• We suggest that activation of Notch signaling may serve as an additional mechanism to inhibit wild-type p53 function in papillomavirus-associated neoplasia [43].
• We show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells [44].

Other interactions of NOTCH1

• Expression of constitutively active Notch1 or Notch2 does not upregulate MAG [45].
• F3/Notch signaling promotes oligodendrocyte precursor cell differentiation and upregulates the myelin-related protein MAG in OLN-93 cells [45].
• Alagille syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients [46].
• MRL631, a gamma-secretase inhibitor that is unable to penetrate the cell membrane, significantly blocks gamma-secretase-mediated Notch cleavage but has little effect on APP processing [9].
• Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis [47].
• Inhibition of the Akt/Hdm2 pathway by Notch1 signaling was responsible for the suppression of p53 proteasomal degradation, thus contributing to the Notch1 signaling-mediated up-regulation of p53 expression [48].

Analytical, diagnostic and therapeutic context of NOTCH1

• Interestingly, the statistically significant difference of survival according to NOTCH1 mutations was only observed in adult patients (>18 years) but not in pediatric patients (< or = 18 years), possibly due to the relatively good overall response of childhood T-ALL to the current chemotherapy [3].
• Immunoprecipitation analyses with antibodies to both the intracellular forms of NOTCH1 and to RBP-Jkappa demonstrated that little or no RBP-Jkappa is associated with NOTCH1 in B cell lines compared to the RBP-Jkappa associated with NOTCH1 in T cell lines and was further demonstrated in human primary lymphocytes [49].
• These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs [4].
• By using a two-cell coculture assay, we show here that vertebrate Dl-1 activates the Notch-1 cascade [40].
• The mRNA transcript levels of AAH, insulin receptor substrate (IRS), insulin and insulin-like growth factor (IGF) receptors and polypeptides, Notch, Jagged, and HES were measured in 15 paired samples of HCC and adjacent HCC-free human liver biopsy specimens using real-time quantitative RT-PCR and Western blot analysis [50].

References