scholarly journals Activation of Notch Signaling by Oocytes and Jag1 in Mouse Ovarian Granulosa Cells

Endocrinology ◽  
2019 ◽  
Vol 160 (12) ◽  
pp. 2863-2876 ◽  
Author(s):  
Nisan Hubbard ◽  
Rexxi D Prasasya ◽  
Kelly E Mayo
Keyword(s):  
Notch Signaling ◽  
Germ Cells ◽  
Granulosa Cells ◽  
Target Gene ◽  
Notch Pathway ◽  
Ovarian Granulosa Cells ◽  
Pathway Activation ◽  
Proliferation And Differentiation ◽  
Initial Activation ◽  
Notch Activation

Abstract The Notch pathway plays diverse and complex roles in cell signaling during development. In the mammalian ovary, Notch is important for the initial formation and growth of follicles, and for regulating the proliferation and differentiation of follicular granulosa cells during the periovulatory period. This study seeks to determine the contribution of female germ cells toward the initial activation and subsequent maintenance of Notch signaling within somatic granulosa cells of the ovary. To address this issue, transgenic Notch reporter (TNR) mice were crossed with Sohlh1-mCherry (S1CF) transgenic mice to visualize Notch-active cells (EGFP) and germ cells (mCherry) simultaneously in the neonatal ovary. To test the involvement of oocytes in activation of Notch signaling in ovarian somatic cells, we ablated germ cells using busulfan, a chemotherapeutic alkylating agent, or investigated KitWv/Wv (viable dominant white-spotting) mice that lack most germ cells. The data reveal that Notch pathway activation in granulosa cells is significantly suppressed when germ cells are reduced. We further demonstrate that disruption of the gene for the Notch ligand Jag1 in oocytes similarly impacts Notch activation and that recombinant JAG1 enhances Notch target gene expression in granulosa cells. These data are consistent with the hypothesis that germ cells provide a ligand, such as Jag1, that is necessary for activation of Notch signaling in the developing ovary.

Clinical disease course and survival outcomes following disease recurrence in adenoid cystic carcinoma (ACC) with NOTCH signaling pathway activation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6072-6072
Author(s):  
Brindley Sonal Hapuarachi ◽  
Laura Feeney ◽  
Sam Rack ◽  
Helen Adderley ◽  
David Morgan ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Notch Signaling ◽  
Clinical Review ◽  
Notch Pathway ◽  
Disease Recurrence ◽  
Primary Site ◽  
Major Salivary Gland ◽  
Disease Course ◽  
Pathway Activation ◽  
Notch Activation

6072 Background: ACC is a rare salivary cancer for which effective drug therapies remain lacking. The highest rates of disease recurrence are in patients with NOTCH pathway activation, which is reported in 10-20% of ACC tumors. Novel drugs targeting NOTCH signaling are under investigation in the recurrent and metastatic setting. To understand their clinical utility, there is an urgent need to better characterize the disease course and outcomes following current standard of care treatment from diagnosis and following recurrence. Methods: 120 patients with ACC underwent clinical review at a single UK Cancer Centre from 2017-19. Patients were retrospectively assessed for tumor NOTCH pathway activation using next generation sequencing (NGS) targeting NOTCH1/2/3 genes (n = 98) and/or by immunohistochemistry (IHC) for the NOTCH1 intra-cellular domain (NICD1) (n = 87). To understand the disease course with NOTCH pathway activation, treatment data including surgery, radiotherapy and systemic therapies were extracted and presented as swimmer plots. Kaplan-Meier survival analysis was performed and a difference in survival with/without NOTCH activation was calculated with log rank test. Overall survival (OS) was calculated both from diagnosis and from first confirmed disease recurrence or metastasis, and recurrence free survival (RFS) calculated from diagnosis. Results: Of 120 patients, median age was 46 years (22-74 years). 114/120 patients (95%) had confirmed disease recurrence at clinical review. The primary site was major salivary gland in 58/120 (48%), the others were minor salivary. NOTCH1/3 activating somatic mutations were identified in 11% by NGS (11/98) and NICD1 diffuse nuclear staining was seen in 6% by IHC (5/87) for overall NOTCH activation in 11% (13/120). In NOTCH activated ACC, primary site was major salivary gland in 7/13 (54%), and non-pulmonary visceral/bone metastases were present in 6/13 (46%). Consistent with other reports, patients with NOTCH activation (n = 13) had shorter RFS (0.9 vs 3.6 years, p = 0.11) and significantly reduced OS from diagnosis (4.0 vs 16.3 years, p < 0.0001). Critically, as therapies targeting NOTCH signaling are being evaluated in recurrent/metastatic ACC, there was significantly reduced OS from time of first confirmed disease recurrence or metastasis (1.5 vs 9.6 years, p < 0.0001). This reduction in OS for NOTCH activation following recurrence was seen consistently whether patients were classified using NGS (1.9 vs 9.6 years, p = 0.0009) or NICD1 IHC (0.8 vs 8.5 years, p < 0.0001). Conclusions: This is the first study to report clinical outcomes for patients with NOTCH pathway activated ACC following disease recurrence. Although ACC is frequently considered an indolent disease, the short survival in this sub-group of ACC patients demonstrates the urgent need to develop effective drug therapies in this setting.

scholarly journals Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling

2015 ◽  
Vol 210 (2) ◽  
pp. 303-318 ◽  
Author(s):  
Maria J. Gomez-Lamarca ◽  
Laura A. Snowdon ◽  
Ekatarina Seib ◽  
Thomas Klein ◽  
Sarah J. Bray
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Critical Role ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Dnaj Protein ◽  
Pathway Activation ◽  
Proliferation And Differentiation ◽  
Signal Activation

Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur.

scholarly journals Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 521
Author(s):  
Catia Giovannini ◽  
Francesca Fornari ◽  
Fabio Piscaglia ◽  
Laura Gramantieri
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Hepatitis Virus ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Gamma Secretase ◽  
Stem Cell Maintenance ◽  
Pathway Activation ◽  
Promising Therapeutic Approach ◽  
Conserved Genes

The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy.

scholarly journals Suppression of Notch Signaling Stimulates Progesterone Synthesis by Enhancing the Expression of NR5A2 and NR2F2 in Porcine Granulosa Cells

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 120
Author(s):  
Rihong Guo ◽  
Fang Chen ◽  
Zhendan Shi
Keyword(s):  
Notch Signaling ◽  
Granulosa Cells ◽  
Butyl Ester ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Progesterone Secretion ◽  
Expression Of Genes ◽  
Porcine Granulosa Cells ◽  
Progesterone Synthesis ◽  
Progesterone Biosynthesis

The conserved Notch pathway is reported to be involved in progesterone synthesis and secretion; however, the exact effects remain controversial. To determine the role and potential mechanisms of the Notch signaling pathway in progesterone biosynthesis in porcine granulosa cells (pGCs), we first used a pharmacological γ-secretase inhibitor, N-(N-(3,5-difluorophenacetyl-l-alanyl))-S-phenylglycine t-butyl ester (DAPT), to block the Notch pathway in cultured pGCs and then evaluated the expression of genes in the progesterone biosynthesis pathway and key transcription factors (TFs) regulating steroidogenesis. We found that DAPT dose- and time-dependently increased progesterone secretion. The expression of steroidogenic proteins NPC1 and StAR and two TFs, NR5A2 and NR2F2, was significantly upregulated, while the expression of HSD3B was significantly downregulated. Furthermore, knockdown of both NR5A2 and NR2F2 with specific siRNAs blocked the upregulatory effects of DAPT on progesterone secretion and reversed the effects of DAPT on the expression of NPC1, StAR, and HSD3B. Moreover, knockdown of NR5A2 and NR2F2 stimulated the expression of Notch3. In conclusion, the inhibition of Notch signaling stimulated progesterone secretion by enhancing the expression of NPC1 and StAR, and the two TFs NR5A2 and NR2F2 acted as downstream TFs of Notch signaling in regulating progesterone synthesis.

scholarly journals Notch Signaling Mediates TNF-α-Induced IL-6 Production in Cultured Fibroblast-Like Synoviocytes from Rheumatoid Arthritis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Zhijun Jiao ◽  
Wenhong Wang ◽  
Jie Ma ◽  
Shengjun Wang ◽  
Zhaoliang Su ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Notch Signaling ◽  
Target Gene ◽  
Cytokine Production ◽  
Notch Pathway ◽  
Mrna Levels ◽  
Secretase Inhibitor ◽  
Tnf Α ◽  
Functional Involvement ◽  
Fibroblast Like Synoviocytes

It has been reported that Notch family proteins are expressed in synovium tissue and involved in the proliferation of synoviocyte from rheumatoid arthritis (RA). The aim of this paper was to investigate whether Notch signaling mediated TNF-α-induced cytokine production of cultured fibroblast-like synoviocytes (FLSs) from RA. Exposure of RA FLSs to TNF-α(10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels. Blockage of Notch signaling by aγ-secretase inhibitor (DAPT) inhibited IL-6 secretion of RA FLSs in response to TNF-αwhile treatment with recombinant fusion protein of Notch ligand Delta-like 1 promoted such response. TNF-αstimulation also induced IL-6 secretion in OA FLSs; however, the Hes-1 level remained unaffected. Our data confirm the functional involvement of Notch pathway in the pathophysiology of RA FLSs which may provide a new target for RA therapy.

Effects of Insulin-Like Growth Factor-ll on Proliferation and Differentiation of Ovarian Granulosa Cells

1992 ◽  
Vol 37 (4-5) ◽  
pp. 141-149 ◽  
Author(s):  
Shusaku Kamada ◽  
Toshiro Kubota ◽  
Makoto Taguchi ◽  
Ho Wen-Rong ◽  
Shuichi Sakamoto ◽  
...  
Keyword(s):  
Growth Factor ◽  
Granulosa Cells ◽  
Insulin Like Growth Factor ◽  
Ovarian Granulosa Cells ◽  
Proliferation And Differentiation

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 Notch Activation Is an Early and Critical Event during T-Cell Leukemogenesis in Ikaros-Deficient Mice

2006 ◽  
Vol 26 (1) ◽  
pp. 209-220 ◽  
Author(s):  
Alexis Dumortier ◽  
Robin Jeannet ◽  
Peggy Kirstetter ◽  
Eva Kleinmann ◽  
MacLean Sellars ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor ◽  
Target Gene ◽  
Critical Role ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Notch Target Gene ◽  
Target Gene Expression ◽  
T Cell Leukemogenesis ◽  
Notch Activation

ABSTRACT The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (IkL/L) in the Ikaros gene all develop thymic lymphomas. IkL/L tumors always exhibit strong activation of the Notch pathway, which is required for tumor cell proliferation in vitro. Notch activation occurs early in tumorigenesis and may precede transformation, as ectopic expression of the Notch targets Hes-1 and Deltex-1 is detected in thymocytes from young IkL/L mice with no overt signs of transformation. Notch activation is further amplified by secondary mutations that lead to C-terminal truncations of Notch 1. Strikingly, restoration of Ikaros activity in tumor cells leads to a rapid and specific downregulation of Notch target gene expression and proliferation arrest. Furthermore, Ikaros binds to the Notch-responsive element in the Hes-1 promoter and represses Notch-dependent transcription from this promoter. Thus, Ikaros-mediated repression of Notch target gene expression may play a critical role in defining the tumor suppressor function of this factor.

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 Endosomal entry regulates Notch receptor activation in Drosophila melanogaster

2008 ◽  
Vol 180 (4) ◽  
pp. 755-762 ◽  
Author(s):  
Thomas Vaccari ◽  
Han Lu ◽  
Ritu Kanwar ◽  
Mark E. Fortini ◽  
David Bilder
Keyword(s):  
Drosophila Melanogaster ◽  
Notch Pathway ◽  
Receptor Activation ◽  
Notch Receptor ◽  
Animal Development ◽  
Cell Proliferation And Differentiation ◽  
Pathway Activation ◽  
Proliferation And Differentiation ◽  
Low Efficiency ◽  
Endocytic Compartments

Signaling through the transmembrane receptor Notch is widely used throughout animal development and is a major regulator of cell proliferation and differentiation. During canonical Notch signaling, internalization and recycling of Notch ligands controls signaling activity, but the involvement of endocytosis in activation of Notch itself is not well understood. To address this question, we systematically assessed Notch localization, processing, and signaling in a comprehensive set of Drosophila melanogaster mutants that block access of cargo to different endocytic compartments. We find that γ-secretase cleavage and signaling of endogenous Notch is reduced in mutants that impair entry into the early endosome but is enhanced in mutants that increase endosomal retention. In mutants that block endosomal entry, we also uncover an alternative, low-efficiency Notch trafficking route that can contribute to signaling. Our data show that endosomal access of the Notch receptor is critical to achieve physiological levels of signaling and further suggest that altered residence in distinct endocytic compartments could underlie pathologies involving aberrant Notch pathway activation.

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