scholarly journals Mechanisms of ligand-mediated inhibition in Notch signaling activity inDrosophila

2010 ◽  
Vol 239 (3) ◽  
pp. 798-805 ◽  
Author(s):  
Ulla-Maj Fiuza ◽  
Thomas Klein ◽  
Alfonso Martinez Arias ◽  
Penelope Hayward
Keyword(s):  
Notch Signaling ◽  
Signaling Activity

scholarly journals MiR-129 blocks estrogen induction of NOTCH signaling activity in breast cancer stem-like cells

Oncotarget ◽  
2017 ◽  
Vol 8 (61) ◽  
pp. 103261-103273 ◽  
Author(s):  
Guodong Xiao ◽  
Xiang Li ◽  
Gang Li ◽  
Boxiang Zhang ◽  
Chongwen Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Notch Signaling ◽  
Signaling Activity ◽  
Estrogen Induction

scholarly journals An RBPJ-Drosophila Model Reveals Dependence of RBPJ Protein Stability on the Formation of Transcription–Regulator Complexes

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1252 ◽  
Author(s):  
Gahr ◽  
Brändle ◽  
Zimmermann ◽  
Nagel
Keyword(s):  
Protein Stability ◽  
Notch Signaling ◽  
Genome Engineering ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Model Systems ◽  
Congenital Diseases ◽  
Murine Homologue ◽  
Pathway Regulation ◽  
Signaling Activity

Notch signaling activity governs widespread cellular differentiation in higher animals, including humans, and is involved in several congenital diseases and different forms of cancer. Notch signals are mediated by the transcriptional regulator RBPJ in a complex with activated Notch (NICD). Analysis of Notch pathway regulation in humans is hampered by a partial redundancy of the four Notch receptor copies, yet RBPJ is solitary, allowing its study in model systems. In Drosophila melanogaster, the RBPJ orthologue is encoded by Suppressor of Hairless [Su(H)]. Using genome engineering, we replaced Su(H) by murine RBPJ in order to study its function in the fly. In fact, RBPJ largely substitutes for Su(H)’s function, yet subtle phenotypes reflect increased Notch signaling activity. Accordingly, the binding of RBPJ to Hairless (H) protein, the general Notch antagonist in Drosophila, was considerably reduced compared to that of Su(H). An H-binding defective RBPJLLL mutant matched the respective Su(H)LLL allele: homozygotes were lethal due to extensive Notch hyperactivity. Moreover, RBPJLLL protein accumulated at lower levels than wild type RBPJ, except in the presence of NICD. Apparently, RBPJ protein stability depends on protein complex formation with either H or NICD, similar to Su(H), demonstrating that the murine homologue underlies the same regulatory mechanisms as Su(H) in Drosophila. These results underscore the importance of regulating the availability of RBPJ protein to correctly mediate Notch signaling activity in the fly.

Identification of Domains for Efficient Notch Signaling Activity in Immobilized Notch Ligand Proteins

2016 ◽  
Vol 118 (4) ◽  
pp. 785-796 ◽  
Author(s):  
Ledi Liu ◽  
Hiroe Wada ◽  
Natsuki Matsubara ◽  
Katsuto Hozumi ◽  
Motoyuki Itoh
Keyword(s):  
Notch Signaling ◽  
Notch Ligand ◽  
Signaling Activity

scholarly journals TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma

2020 ◽  
Vol 11 ◽  
Author(s):  
Jingwei Wan ◽  
Alyssa Aihui Guo ◽  
Pendelton King ◽  
Shanchun Guo ◽  
Talib Saafir ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Notch Signaling ◽  
Glioma Cell ◽  
Kinase Domain ◽  
Normal Brain ◽  
Diffuse Astrocytoma ◽  
Notch1 Signaling ◽  
Aldh1 Expression ◽  
Signaling Activity

We have reported that transient receptor potential melastatin-related 7 (TRPM7) regulates glioma stem cells (GSC) growth and proliferation through Notch, STAT3-ALDH1, and CD133 signaling pathways. In this study, we determined the major contributor(s) to TRPM7 mediated glioma stemness by further deciphering each individual Notch signaling. We first determined whether TRPM7 is an oncotarget in glioblastoma multiforme (GBM) using the Oncomine database. Next, we determined whether TRPM7 silencing by siRNA TRPM7 (siTRPM7) induces cell growth arrest or apoptosis to reduce glioma cell proliferation using cell cycle analysis and annexin V staining assay. We then examined the correlations between the expression of TRPM7 and Notch signaling activity as well as the expression of GSC markers CD133 and ALDH1 in GBM by downregulating TRPM7 through siTRPM7 or upregulating TRPM7 through overexpression of human TRPM7 (M7-wt). To distinguish the different function of channel and kinase domain of TRPM7, we further determined how the α-kinase-dead mutants of TRPM7 (α-kinase domain deleted/M7-DK and K1648R point mutation/M7-KR) affect Notch activities and CD133 and ALDH1 expression. Lastly, we determined the changes in TRPM7-mediated regulation of glioma cell growth/proliferation, cell cycle, and apoptosis by targeting Notch1. The Oncomine data revealed a significant increase in TRPM7 mRNA expression in anaplastic astrocytoma, diffuse astrocytoma, and GBM patients compared to that in normal brain tissues. TRPM7 silencing reduced glioma cell growth by inhibiting cell entry into S and G2/M phases and promoting cell apoptosis. TRPM7 expression in GBM cells was found to be positively correlated with Notch1 signaling activity and CD133 and ALDH1 expression; briefly, downregulation of TRPM7 by siTRPM7 decreased Notch1 signaling whereas upregulation of TRPM7 increased Notch1 signaling. Interestingly, kinase-inactive mutants (M7-DK and M7-KR) resulted in reduced activation of Notch1 signaling and decreased expression of CD133 and ALDH1 compared to that of wtTRPM7. Finally, targeting Notch1 effectively suppressed TRPM7-induced growth and proliferation of glioma cells through cell G1/S arrest and apoptotic induction. TRPM7 is responsible for sustained Notch1 signaling activation, enhanced expression of GSC markers CD133 and ALDH1, and regulation of glioma stemness, which contributes to malignant glioma cell growth and invasion.

scholarly journals Notch signaling in mouse blastocyst development and hatching

2020 ◽  
Author(s):  
Mariana Batista ◽  
Patrícia Diniz ◽  
Ana Torres ◽  
Daniel Murta ◽  
Luís Lopes-da-Costa ◽  
...  
Keyword(s):  
Protein Expression ◽  
Notch Signaling ◽  
Gene Transcription ◽  
Embryo Culture ◽  
Expression Patterns ◽  
Mouse Blastocyst ◽  
Blastocyst Development ◽  
Gene Markers ◽  
Signaling Activity ◽  
Blastocyst Hatching

Abstract Background Mammalian early embryo development requires a well-orchestrated interplay of cell signaling pathways. Notch is a major regulatory pathway involved in cell-fate determination in embryonic and adult scenarios. However, the role of Notch in embryonic pre-implantation development is controversial. In particular, Notch role on blastocyst development and hatching remains elusive, and a complete picture of the transcription and expression patterns of Notch components during this time-period is not available.Results This study provided a comprehensive view on the dynamics of individual embryo gene transcription and protein expression patterns of Notch components (receptors Notch1-4; ligands Dll1 and Dll4, Jagged1-2; and effectors Hes1-2), and their relationship with transcription of gene markers of pluripotency and differentiation (Sox2, Oct4, Klf4, Cdx2) during mouse blastocyst development and hatching. Transcription of Notch1-2, Jagged1-2 and Hes1 was highly prevalent and dynamic along stages of development, whereas transcription of Notch3-4, Dll4 and Hes2 had a low prevalence among embryos. Transcription levels of Notch1, Notch2, Jagged2 and Hes1 correlated with each other and with those of pluripotency and differentiation genes. Gene transcription was associated to protein expression, except for Jagged2, where high transcription levels in all embryos were not translated into protein. Presence of Notch signaling activity was confirmed through nuclear NICD and Hes1 detection, and downregulation of Hes1 transcription following canonical signaling blockade with DAPT. In vitro embryo culture supplementation with Jagged1 had no effect on embryo developmental kinetics. In contrast, supplementation with Jagged2 abolished Jagged1 transcription, downregulated Cdx2 transcription and inhibited blastocyst hatching. Notch signaling blockade by DAPT downregulated transcription of Sox2, and retarded embryo hatching. Conclusion Transcription of Notch genes showed a dynamic pattern along blastocyst development and hatching. Data confirmed Notch signaling activity, and lead to the suggestion that Notch canonical signaling may be operating through Notch1, Notch3, Jagged1 and Hes1. Embryo culture supplementation with Jagged1 and Jagged2 unveiled a possible regulatory effect between Jagged1, Cdx2 and blastocyst hatching. Overall, results indicate that a deregulation in Notch signaling, either by its over or under-activation, affects blastocyst development and hatching.

scholarly journals Regulation of Notch Signaling Activity

2004 ◽  
Vol 14 (3) ◽  
pp. R129-R138 ◽  
Author(s):  
François Schweisguth
Keyword(s):  
Notch Signaling ◽  
Signaling Activity

scholarly journals A computational guided, functional validation of a novel therapeutic antibody proposes Notch signaling as a clinical relevant and druggable target in glioma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Dayana Herrera-Rios ◽  
Guanzhang Li ◽  
Dilaware Khan ◽  
Julia Tsiampali ◽  
Ann-Christin Nickel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Signaling ◽  
Notch Signaling ◽  
Notch Pathway ◽  
Therapy Resistance ◽  
Drug Candidate ◽  
Severe Toxicity ◽  
Gamma Secretase ◽  
Signaling Activity ◽  
Notch1 Receptor

Abstract The Notch signaling network determines stemness in various tissues and targeting signaling activity in malignant brain cancers by gamma-secretase inhibitors (GSI) has shown promising preclinical success. However, the clinical translation remains challenging due to severe toxicity side effects and emergence of therapy resistance. Better anti-Notch directed therapies, specifically directed against the tumor promoting Notch receptor 1 signaling framework, and biomarkers predicting response to such therapy are of highest clinical need. We assessed multiple patient datasets to probe the clinical relevance Notch1 activation and possible differential distribution amongst molecular subtypes in brain cancers. We functionally assessed the biological effects of the first-in-human tested blocking antibody against Notch1 receptor (brontictuzumab, BRON) in a collection of glioma stem-like cell (GSC) models and compared its effects to genetic Notch1 inhibition as well as classical pharmacological Notch inhibitor treatment using gamma-secretase inhibitor MRK003. We also assess effects on Wingless (WNT) stem cell signaling activation, which includes the interrogation of genetic WNT inhibition models. Our computed transcriptional Notch pathway activation score is upregulated in neural stem cells, as compared to astrocytes; as well as in GSCs, as compared to differentiated glioblastoma cells. Moreover, the Notch signature is clinical predictive in our glioblastoma patient discovery and validation cohort. Notch signature is significantly increased in tumors with mutant IDH1 genome and tumors without 1p and 19q co-deletion. In GSCs with elevated Notch1 expression, BRON treatment blocks transcription of Notch pathway target genes Hes1/Hey1, significantly reduced the amount of cleaved Notch1 receptor protein and caused significantly impairment of cellular invasion. Benchmarking this phenotype to those observed with genetic Notch1 inhibition in corresponding cell models did result in higher reduction of cell invasion under chemotherapy. BRON treatment caused signs of upregulation of Wingless (WNT) stem cell signaling activity, and vice versa, blockage of WNT signaling caused induction of Notch target gene expression in our models. We extend the list of evidences that elevated Notch signal expression is a biomarker signature declaring stem cell prevalence and useful for predicting negative clinical course in glioblastoma. By using functional assays, we validated a first in man tested Notch1 receptor specific antibody as a promising drug candidate in the context of neuro oncology and propose biomarker panel to predict resistance and therapy success of this treatment option. We note that the observed phenotype seems only in part due to Notch1 blockage and the drug candidate leads to activation of off target signals. Further studies addressing a possible emergence of therapy resistance due to WNT activation need to be conducted. We further validated our 3D disease modeling technology to be of benefit for drug development projects.

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