Notch Receptors, Partners and Regulators: From Conserved Domains to Powerful Functions

Egan, Sean E.; St-Pierre, Benoît; Leow, Ching Ching

doi:10.1007/978-3-642-80481-6_11

Cited by 85 publications

(99 citation statements)

References 268 publications

(276 reference statements)

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“…To assess the effects of LLNle and DAPT on the NOTCH pathway in GBM TICs, we examined the expression of NICD transcriptional target genes JAG1, HES1, HEY1, and HEY2 (32)(33)(34) as evaluated by the GeneChip microarray studies. The values of mRNA expression for these genes showed that the effects of the two drugs were not homogeneous across the three patients (see Supplementary Data S5).…”

Section: Llnle and Dapt Effects On Notch Target Genesmentioning

confidence: 99%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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γ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor-initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G 2 -M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models.

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Section: Llnle and Dapt Effects On Notch Target Genesmentioning

confidence: 99%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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“…The main targets of Notch signalling are HES genes in mammals and enhancer of split E(spl) genes in Drosophila, often indicated as HES/E(spl) gene family (Egan et al, 1998;Artavanis-Tsakonas et al, 1999;Iso et al, 2001Iso et al, , 2002. These genes code for transcriptional repressors of the ''basic helix-loop-helix'' (bHLH) type acting as Notch effectors, downregulating expression of other target genes, such as specific tissue transcription factors.…”

Section: Target Genes Of Notch Signallingmentioning

confidence: 99%

Physiology and pathology of notch signalling system

Bianchi

Dotti

Federico

2005

Journal Cellular Physiology

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Notch proteins encode a family of transmembrane receptors that are part of a signalling transduction system known as Notch signalling, an extremely conserved and widely used mechanism regulating programs governing growth, apoptosis and differentiation in metazoans. Notch signalling begins when the Notch receptor binds ligands and ends when the Notch intracellular domain enters the nucleus and activates transcription of target genes. This core pathway is subjected to a wide array of regulatory influences and protein-protein interactions and is correlated with other signalling pathway. This review will sumarize recent findings concerning the physiology and pathology of Notch signalling in vascular development and homeostasis. Moreover, the clinical phenotypes of Notch3 signalling system pathology will be described, with particular regard to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) for which the most recent pathogenetic hypotheses are reported.

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“…They have been implicated in neurogenesis (Artavanis-Tsakonas et al, 1999;Sestan et al, 1999), hematopoiesis (Milner and Bigas, 1999), vasculogenesis (Uyttendale et al, 2001), and cortical neurite growth (Sestan et al, 1999). When Notch interacts with one of its ligands on the surface of an adjacent cell, the receptor is proteolytically processed, and nuclear translocation of the receptor's intracellular domain results in transcriptional regulation of lineage-specific genes (Egan et al, 1998;ArtavanisTsakonas et al, 1999;Weinmaster, 2000).…”

Section: Introductionmentioning

confidence: 99%

Characterization of tissue specific expression of Notch-1 in human tissues

Baldi

Falco

Luca

et al. 2004

Biology of the Cell

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Signaling through the Notch cell surface receptors is a highly conserved mechanism of cell fate specification. Notch signaling regulates proliferation, differentiation and cell death. In vertebrates, putative gene duplication has originated four Notch genes, Notch-1, -2, -3 and -4. They have been implicated in neurogenesis, hematopoiesis, T-cell development, vasculogenesis and brain cortical growth. We have investigated Notch-1 distribution in normal human tissues by immunohistochemistry and immunoblot. We detected widespread expression of Notch-1 cytoplasmatic staining, with different tissue distributions in the different organs examined. In particular, high expression of Notch-1 was detected in the intermediate suprabasal layers, but not in the dead cells at the extreme periphery of stratified epithelia. Moreover, a low/intermediate level of Notch-1 was observed in lymphocytes in several peripheral lymphoid tissues; in particular the germinal centers of lymph nodes showed the most abundant number of positive cells, which appeared to be centroblasts/immunoblasts based on nuclear morphology. Notch-1 participates in keratinocytes differentiation. We showed by Western blot analysis that Notch-1 level was clearly increased in HaCaT cells after Ca ++ addition and remained substantially elevated until late differentiation stages. These results suggest that Notch-1 may function in numerous cell types in processes beyond cell fate determination, such as neuronal plasticity, muscle hypertrophy, liver regeneration, and germinal center lymphopoiesis during the immune response.

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Notch Receptors, Partners and Regulators: From Conserved Domains to Powerful Functions

Cited by 85 publications

References 268 publications

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Physiology and pathology of notch signalling system

Characterization of tissue specific expression of Notch-1 in human tissues

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