A Notch updated

Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 04/2009; 184(5):621-9. DOI: 10.1083/jcb.200811141
Source: PubMed


Cell-cell signaling mediated by the Notch receptor is iteratively involved in numerous developmental contexts, and its dysregulation has been associated with inherited genetic disorders and cancers. The core components of the signaling pathway have been identified for some time, but the study of the modulation of the pathway in different cellular contexts has revealed many layers of regulation. These include complex sugar modifications in the extracellular domain as well as transit of Notch through defined cellular compartments, including specific endosomes.

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Available from: An-Chi Tien, Jun 10, 2015
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    • "Cleavage at the S2 site by ADAMs activates the receptor, which is still anchored to the plasma membrane . The γ-secretase enzyme complex (Presenilin 1 and 2, Nicastrin, APH1 and PEN2) cleaves the NOTCH receptor at S3 and S4 sites and subsequently releases the active NOTCH- ICD (De Strooper et al. 1999; Tien et al. 2009). The two nuclear localization signals on the NOTCH-ICD direct its translocation to the nucleus. "
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    ABSTRACT: The NOTCH pathway is an evolutionarily conserved signalling network, which is fundamental in regulating developmental processes in invertebrates and vertebrates (Gazave et al. in BMC Evol Biol 9:249, 2009). It regulates self-renewal (Butler et al. in Cell Stem Cell 6:251-264, 2010), differentiation (Auderset et al. in Curr Top Microbiol Immunol 360:115-134, 2012), proliferation (VanDussen et al. in Development 139:488-497, 2012) and apoptosis (Cao et al. in APMIS 120:441-450, 2012) of diverse cell types at various stages of their development. NOTCH signalling governs cell-cell interactions and the outcome of such responses is highly context specific. This makes it impossible to generalize about NOTCH functions as it stimulates survival and differentiation of certain cell types, whereas inhibiting these processes in others (Meier-Stiegen et al. in PLoS One 5:e11481, 2010). NOTCH was first identified in 1914 in Drosophila and was named after the indentations (notches) present in the wings of the mutant flies (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010). Homologs of NOTCH in vertebrates were initially identified in Xenopus (Coffman et al. in Science 249:1438-1441, 1990) and in humans NOTCH was first identified in T-Acute Lymphoblastic Leukaemia (T-ALL) (Ellisen et al. in Cell 66:649-61, 1991). NOTCH signalling is integral in neurogenesis (Mead and Yutzey in Dev Dyn 241:376-389, 2012), myogenesis (Schuster-Gossler et al. in Proc Natl Acad Sci U S A 104:537-542, 2007), haematopoiesis (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010), oogenesis (Xu and Gridley in Genet Res Int 2012:648207, 2012), differentiation of intestinal cells (Okamoto et al. in Am J Physiol Gastrointest Liver Physiol 296:G23-35, 2009) and pancreatic cells (Apelqvist et al. in Nature 400:877-881, 1999). The current review will focus on NOTCH signalling in normal and malignant blood cell production or haematopoiesis.
    Journal of Cell Communication and Signaling 02/2015; 9(1). DOI:10.1007/s12079-015-0271-0
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    • "Both canonical Notch signaling in the nucleus and the non-canonical Notch signaling are up-regulated in heph03429 embryos [22], [30]. The canonical Notch signaling involves ligand-dependent processing, release, and translocation into the nucleus of the Notch intracellular domain (Nintra/NICD) to activate target genes [31]–[33]. Up-regulation of canonical Notch signaling is associated with the development of the anti-neurogenic phenotype [34]–[36]. The heph embryos manifest the anti-neurogenic phenotype due to increased canonical Notch signaling [22]. "
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    ABSTRACT: The Drosophila polypyrimidine tract-binding protein (dmPTB or hephaestus) plays an important role during embryogenesis. A loss of function mutation, heph03429, results in varied defects in embryonic developmental processes, leading to embryonic lethality. However, the suite of molecular functions that are disrupted in the mutant remains unknown. We have used an unbiased high throughput sequencing approach to identify transcripts that are misregulated in this mutant. Misregulated transcripts show evidence of significantly altered patterns of splicing (exon skipping, 5' and 3' splice site switching), alternative 5' ends, and mRNA level changes (up and down regulation). These findings are independently supported by reverse-transcription-polymerase chain reaction (RT-PCR) analysis and in situ hybridization. We show that a group of genes, such as Zerknüllt, z600 and screw are among the most upregulated in the mutant and have been functionally linked to dorso-ventral patterning and/or dorsal closure processes. Thus, loss of dmPTB function results in specific misregulated transcripts, including those that provide the missing link between the loss of dmPTB function and observed developmental defects in embryogenesis. This study provides the first comprehensive repertoire of genes affected in vivo in the heph mutant in Drosophila and offers insight into the role of dmPTB during embryonic development.
    PLoS ONE 07/2014; 9(7):e98585. DOI:10.1371/journal.pone.0098585 · 3.23 Impact Factor
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    • "Mammals express four neurogenic locus notch homolog (Notch) family proteins during tumorigenesis and embryogenesis [15], [16]. Unlike many other signaling molecules, activation of the Notch pathway does not require secondary messengers for amplification [17]. Upon ligand binding to the N-terminal EGF-repeat region, the Notch transmembrane receptor undergoes a series of proteolytic cleavages by tumor necrosis factor-α-converting enzyme, metalloprotease, and γ-secretase [18]. "
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    ABSTRACT: Ovarian cancer, the deadliest of gynecologic cancers, is usually not diagnosed until advanced stages. Although carboplatin has been popular for treating ovarian cancer for decades, patients eventually develop resistance to this platinum-containing drug. Expression of neurogenic locus notch homolog 3 (Notch3) is associated with chemoresistance and poor overall survival in ovarian cancer patients. Overexpression of NICD3 (the constitutively active form of Notch3) in OVCA429 ovarian cancer cells (OVCA429/NICD3) renders them resistance to carboplatin treatment compared to OVCA429/pCEG cells expressing an empty vector. We have previously shown that methylseleninic acid (MSeA) induces oxidative stress and activates ataxia-telangiectasia mutated and DNA-dependent protein kinase in cancer cells. Here we tested the hypothesis that MSeA and carboplatin exerted a synthetic lethal effect on OVCA429/NICD3 cells. Co-treatment with MSeA synergistically sensitized OVCA429/NICD3 but not OVCA429/pCEG cells to the killing by carboplatin. This synergism was associated with a cell cycle exit at the G2/M phase and the induction of NICD3 target gene HES1. Treatment of N-acetyl cysteine or inhibitors of the above two kinases did not directly impact on the synergism in OVCA429/NICD3 cells. Taken together, these results suggest that the efficacy of carboplatin in the treatment of high grade ovarian carcinoma can be enhanced by a combinational therapy with MSeA.
    PLoS ONE 07/2014; 9(7):e101664. DOI:10.1371/journal.pone.0101664 · 3.23 Impact Factor
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