scholarly journals four-jointed interacts with dachs, abelson and enabled and feeds back onto the Notch pathway to affect growth and segmentation in the Drosophila leg

Development ◽  
2001 ◽  
Vol 128 (18) ◽  
pp. 3533-3542
Author(s):  
Gerri R. Buckles ◽  
Cordelia Rauskolb ◽  
John Lee Villano ◽  
Flora N. Katz
Keyword(s):  
Notch Signaling ◽  
Molecular Basis ◽  
Feedback Loop ◽  
Regional Growth ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Normal Pattern ◽  
Notch Ligands ◽  
Notch Activation

The molecular basis of segmentation and regional growth during morphogenesis of Drosophila legs is poorly understood. We show that four-jointed is not only required for these processes, but also can direct ectopic growth and joint initiation when its normal pattern of expression is disturbed. These effects are non-autonomous, consistent with our demonstration of both transmembrane and secreted forms of the protein in vivo. The similarities between four-jointed and Notch phenotypes led us to further investigate the relationships between these pathways. Surprisingly, we find that although four-jointed expression is regulated downstream of Notch activation, four-jointed can induce expression of the Notch ligands, Serrate and Delta, and may thereby participate in a feedback loop with the Notch signaling pathway. We also show that four-jointed interacts with abelson, enabled and dachs, which leads us to suggest that one target of four-jointed signaling is the actin cytoskeleton. Thus, four-jointed may bridge the gap between the signals that direct morphogenesis and those that carry it out.

scholarly journals Notch pathway activation targets AML-initiating cell homeostasis and differentiation

2013 ◽  
Vol 210 (2) ◽  
pp. 301-319 ◽  
Author(s):  
Camille Lobry ◽  
Panagiotis Ntziachristos ◽  
Delphine Ndiaye-Lobry ◽  
Philmo Oh ◽  
Luisa Cimmino ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Notch Signaling ◽  
Myeloproliferative Neoplasms ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Notch Receptor ◽  
Pathway Activation ◽  
Function Models

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.

scholarly journals Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of Notch signaling

2020 ◽  
Author(s):  
Wahafu Alafate ◽  
Dongze Xu ◽  
Wei Wu ◽  
Jianyang Xiang ◽  
Xudong Ma ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Acquired Resistance ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Gene Expression Omnibus ◽  
Primary Brain Tumor ◽  
Biological Behavior ◽  
Clinical Samples

Abstract BackgroundGlioblastoma (GBM) is a lethal type of primary brain tumor with a median survival less than 15 months. Despite the recent improvements of comprehensive strategies, the outcomes for GBM patients remain dismal. Accumulating evidence indicates that rapid acquired chemoresistance is the major cause of GBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. MethodsTranscriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. ResultsIn this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1.ConclusionLoss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

scholarly journals Multifaceted regulation of Notch signaling by glycosylation

Glycobiology ◽  
2020 ◽  
Author(s):  
Ashutosh Pandey ◽  
Nima Niknejad ◽  
Hamed Jafar-Nejad
Keyword(s):  
Notch Signaling ◽  
Cell Biology ◽  
Normal Development ◽  
Notch Pathway ◽  
Cell Types ◽  
Notch Signaling Pathway ◽  
Protein Glycosylation ◽  
Notch Receptors ◽  
Current Review ◽  
Notch Activation

Abstract To build a complex body composed of various cell types and tissues and to maintain tissue homeostasis in the postembryonic period, animals use a small number of highly conserved intercellular communication pathways. Among these is the Notch signaling pathway, which is mediated via the interaction of transmembrane Notch receptors and ligands usually expressed by neighboring cells. Maintaining optimal Notch pathway activity is essential for normal development, as evidenced by various human diseases caused by decreased and increased Notch signaling. It is therefore not surprising that multiple mechanisms are used to control the activation of this pathway in time and space. Over the last 20 years, protein glycosylation has been recognized as a major regulatory mechanism for Notch signaling. In this review, we will provide a summary of the various types of glycan that have been shown to modulate Notch signaling. Building on recent advances in the biochemistry, structural biology, cell biology and genetics of Notch receptors and the glycosyltransferases that modify them, we will provide a detailed discussion on how various steps during Notch activation are regulated by glycans. Our hope is that the current review article will stimulate additional research in the field of Notch glycobiology and will potentially be of benefit to investigators examining the contribution of glycosylation to other developmental processes.

scholarly journals Structural and functional analysis of the repressor complex in the Notch signaling pathway ofDrosophila melanogaster

2011 ◽  
Vol 22 (17) ◽  
pp. 3242-3252 ◽  
Author(s):  
Dieter Maier ◽  
Patricia Kurth ◽  
Adriana Schulz ◽  
Andrew Russell ◽  
Zhenyu Yuan ◽  
...  
Keyword(s):  
Cell Culture ◽  
Notch Signaling ◽  
Target Genes ◽  
Notch Pathway ◽  
Structural Similarity ◽  
Receptor Activation ◽  
Notch Signaling Pathway ◽  
Repressor Complex

In metazoans, the highly conserved Notch pathway drives cellular specification. On receptor activation, the intracellular domain of Notch assembles a transcriptional activator complex that includes the DNA-binding protein CSL, a composite of human C-promoter binding factor 1, Suppressor of Hairless of Drosophila melanogaster [Su(H)], and lin-12 and Glp-1 phenotype of Caenorhabditis elegans. In the absence of ligand, CSL represses Notch target genes. However, despite the structural similarity of CSL orthologues, repression appears largely diverse between organisms. Here we analyze the Notch repressor complex in Drosophila, consisting of the fly CSL protein, Su(H), and the corepressor Hairless, which recruits general repressor proteins. We show that the C-terminal domain of Su(H) is necessary and sufficient for forming a high-affinity complex with Hairless. Mutations in Su(H) that affect interactions with Notch and Mastermind have no effect on Hairless binding. Nonetheless, we demonstrate that Notch and Hairless compete for CSL in vitro and in cell culture. In addition, we identify a site in Hairless that is crucial for binding Su(H) and subsequently show that this Hairless mutant is strongly impaired, failing to properly assemble the repressor complex in vivo. Finally, we demonstrate Hairless-mediated inhibition of Notch signaling in a cell culture assay, which hints at a potentially similar repression mechanism in mammals that might be exploited for therapeutic purposes.

Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats

Development ◽  
1995 ◽  
Vol 121 (8) ◽  
pp. 2633-2644 ◽  
Author(s):  
K. Matsuno ◽  
R.J. Diederich ◽  
M.J. Go ◽  
C.M. Blaumueller ◽  
S. Artavanis-Tsakonas
Keyword(s):  
Notch Signaling ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Ankyrin Repeats ◽  
Suppressor Of Hairless ◽  
Expression Studies ◽  
Heterotypic Interactions ◽  
Interaction Domains ◽  
Physical Interactions

We present a molecular and genetic analysis which elucidates the role of deltex in the Notch signaling pathway. Using the yeast ‘interaction trap’ assay, we define the protein regions responsible for heterotypic interactions between Deltex and the intracellular domain of Notch as well as uncover homotypic interaction among Deltex molecules. The function of the Deltex-Notch interaction domains is examined by in vivo expression studies. Taken together, data from overexpression of Deltex fragments and from studies of physical interactions between Deltex and Notch, suggest that Deltex positively regulates the Notch pathway through interactions with the Notch ankyrin repeats. Experiments involving cell cultures indicate that the Deltex-Notch interaction prevents the cytoplasmic retention of the Suppressor of Hairless protein, which otherwise is sequestered in the cytoplasm via association with the Notch ankyrin repeats and translocates to the nucleus when Notch binds to its ligand Delta. On the basis of these findings, we propose a model wherein Deltex regulates Notch activity by antagonizing the interaction between Notch and Suppressor of Hairless.

A New Target in Multiple Myeloma: Inhibition of Notch Pathway Induces Apoptosis and Enhances Drug Sensitivity of Myeloma Cells In Vitro and In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 841-841
Author(s):  
Yulia Nefedova ◽  
Krista Verali ◽  
Daniel M. Sullivan ◽  
William S. Dalton ◽  
Dmitry I. Gabrilovich
Keyword(s):  
Multiple Myeloma ◽  
Notch Signaling ◽  
Stromal Cells ◽  
Tumor Size ◽  
Critical Role ◽  
Notch Pathway ◽  
Control Group ◽  
Induced Apoptosis ◽  
Notch Ligands

Abstract Bone marrow (BM) microenvironment and particularly BM stromal cells play a critical role in de novo drug resistance of multiple myeloma (MM) cells. BM stromal cells express Notch ligands and activate Notch signaling in MM cells. We have previously demonstrated that Notch signaling is one of the major mechanisms of BM stroma mediated MM cell protection from chemotherapeutic drugs. Here we investigated whether the pharmacological inhibition of Notch signaling with γ-secretase inhibitor (GSI) could affect viability of MM cells and overcome BM stroma mediated resistance of MM cells to chemotherapy. GSI (6–8 μM) induced apoptosis of MM cells cultured in suspension or on monolayer of BM stroma via specific inhibition of Notch signaling. The effect of GSI was evaluated in four different MM cell lines and primary MM cells isolated from BM of four patients with MM. Treatment with GSI alone significantly reduced the viability of MM cells with IC50 almost 5-fold lower than that for peripheral blood mononuclear cells or BM cells from healthy donors. In addition, treatment of MM cells with GSI reversed BM stroma mediated protection of MM cells from drug-induced apoptosis. This effect of GSI was associated by dramatic up-regulation of pro-apoptotic protein NOXA and down-regulation of anti-apoptotic proteins bcl-xL, bcl-2, and Akt. Inhibition of NOXA with siRNA canceled the cytotoxic effect of GSI on MM cells indicating that NOXA could mediate the direct effect of GSI on MM cells. To test the effect of GSI on MM cells in vivo we used SCID/NOD mouse model. Mice were injected s.c. with human MM RPMI-8226 cells. These cells express both Notch ligands and Notch receptors so Notch signaling is activated by interaction between MM cells themselves. Tumor became visible in ~3 weeks after inoculation and grew as a solid tumor which allowed easily monitoring tumor size. Mice were treated with doxorubicin (1.5 mg/kg, i.p., once a 4 days, 3 times), GSI (5mg/kg/day i.p. for 14 days), combinations of doxorubicin and GSI, or vehicle control (PBS). Tumor size was constantly monitored during treatment and 3 weeks after the treatment. Treatment with doxorubicin and GSI alone resulted in moderate decreased in tumor burden as compared with control group. In contrast, combination of GSI and doxorubicin induced dramatic antitumor effect. Thus, our study, for the first time, demonstrates that inhibition of Notch signaling with GSI can be a new promising approach for therapeutic intervention in MM.

scholarly journals Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of notch signaling

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Wahafu Alafate ◽  
Dongze Xu ◽  
Wei Wu ◽  
Jianyang Xiang ◽  
Xudong Ma ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Acquired Resistance ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Gene Expression Omnibus ◽  
Primary Brain Tumor ◽  
Biological Behavior ◽  
Clinical Samples

Abstract Background Glioblastoma (GBM) is a lethal type of primary brain tumor with a median survival less than 15 months. Despite the recent improvements of comprehensive strategies, the outcomes for GBM patients remain dismal. Accumulating evidence indicates that rapid acquired chemoresistance is the major cause of GBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. Methods Transcriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. Results In this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1. Conclusion Loss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

scholarly journals Fetal Dermal Mesenchymal Stem Cell-Derived Exosomes Accelerate Cutaneous Wound Healing by Activating Notch Signaling

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Xiao Wang ◽  
Ya Jiao ◽  
Yi Pan ◽  
Longxiao Zhang ◽  
Hongmin Gong ◽  
...  
Keyword(s):  
Wound Healing ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cellular Therapy ◽  
Therapeutic Potential ◽  
Dermal Fibroblast ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Skin Wound

Fetal dermal mesenchymal stem cells (FDMSCs), isolated from fetal skin, are serving as a novel MSC candidate with great potential in regenerative medicine. More recently, the paracrine actions, especially MSC-derived exosomes, are being focused on the vital role in MSC-based cellular therapy. This study was to evaluate the therapeutic potential of exosomes secreted by FDMSCs in normal wound healing. First, the in vivo study indicated that FDMSC exosomes could accelerate wound closure in a mouse full-thickness skin wound model. Then, we investigated the role of FDMSC-derived exosomes on adult dermal fibroblast (ADFs). The results demonstrated that FDMSC exosomes could induce the proliferation, migration, and secretion of ADFs. We discovered that after treatment of exosomes, the Notch signaling pathway was activated. Then, we found that in FDMSC exosomes, the ligands of the Notch pathway were undetectable expect for Jagged 1, and the results of Jagged 1 mimic by peptide and knockdown by siRNA suggested that Jagged 1 may lead the activation of the Notch signal in ADFs. Collectively, our findings indicated that the FDMSC exosomes may promote wound healing by activating the ADF cell motility and secretion ability via the Notch signaling pathway, providing new aspects for the therapeutic strategy of FDMSC-derived exosomes for the treatment of skin wounds.

scholarly journals GOLM1 restricts colitis and colon tumorigenesis by ensuring Notch signaling equilibrium in intestinal homeostasis

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yang Pu ◽  
Ya Song ◽  
Mengdi Zhang ◽  
Caifeng Long ◽  
Jie Li ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Mucosal Inflammation ◽  
Intestinal Epithelial ◽  
Colorectal Tumorigenesis ◽  
Colon Tumorigenesis ◽  
Epithelial Lesions ◽  
Deficient Mice ◽  
Notch Activation

AbstractIntestinal epithelium serves as the first barrier against the infections and injuries that mediate colonic inflammation. Colorectal cancer is often accompanied with chronic inflammation. Differed from its well-known oncogenic role in many malignancies, we present here that Golgi membrane protein 1 (GOLM1, also referred to as GP73) suppresses colorectal tumorigenesis via maintenance of intestinal epithelial barrier. GOLM1 deficiency in mice conferred susceptibility to mucosal inflammation and colitis-induced epithelial damage, which consequently promoted colon cancer. Mechanistically, depletion of GOLM1 in intestinal epithelial cells (IECs) led to aberrant Notch activation that interfered with IEC differentiation, maturation, and lineage commitment in mice. Pharmacological inhibition of Notch pathway alleviated epithelial lesions and restrained pro-tumorigenic inflammation in GOLM1-deficient mice. Therefore, GOLM1 maintains IEC homeostasis and protects against colitis and colon tumorigenesis by modulating the equilibrium of Notch signaling pathway.

scholarly journals Loss of PLK2 Induces Acquired Resistance to Temozolomide in GBM via Activation of Notch Signaling

2020 ◽  
Author(s):  
Wahafu Alafate ◽  
Dongze Xu ◽  
Wei Wu ◽  
Jianyang Xiang ◽  
Xudong Ma ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Acquired Resistance ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Gene Expression Omnibus ◽  
Primary Brain Tumor ◽  
Biological Behavior ◽  
Clinical Samples

Abstract BackgroundGlioblastoma (GBM) isa lethal type of primary brain tumor with a median survival less than 15 months.Despiting the recent improvements of comprehensive strategies,the outcomes for GBM patients remain dismal.Accumulating evidence indicates that rapid acquired chemoresistance is the major cause ofGBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. MethodsTranscriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. ResultsIn this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, immigration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1.ConclusionLoss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

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