scholarly journals Inhibition of Notch Signaling Promotes the Adipogenic Differentiation of Mesenchymal Stem Cells Through Autophagy Activation and PTEN-PI3K/AKT/mTOR Pathway

2015 ◽  
Vol 36 (5) ◽  
pp. 1991-2002 ◽  
Author(s):  
Bao-quan Song ◽  
Ying Chi ◽  
Xue Li ◽  
Wen-jing Du ◽  
Zhi-Bo Han ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Adipogenic Differentiation ◽  
Notch Signaling Pathway ◽  
Mtor Pathway ◽  
Cell Fate Decisions ◽  
Autophagy Inhibitor ◽  
Secretase Inhibitor ◽  
Novel Target

Background: The Notch signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. This study was designed to determine the role of Notch signaling in adipogenic differentiation of human bone marrow derived MSCs (BM-MSCs). Methods: The Notch signaling was inhibited by the γ-secretase inhibitor N-[N-(3,5-difluor- ophenacetyl-L-alanyl)]-S-phenylglycine t-butylester (DAPT). The markers involving adipogenic differentiation of MSCs, the relative pathway PTEN-PI3K/Akt/mTOR and autophagy activation were then analyzed. Furthermore, the autophagy inhibitor chloroquine (CQ) and 3-methyladenine (3-MA) were used to study the role of autophagy in the DAPT-induced the adipogenic differentiation of MSCs. Results: We first confirmed the down -regulation of Notch gene expression during MSCs adipocyte differentiation, and showed that the inhibition of Notch signaling significantly enhanced adipogenic differentiation of MSCs. Furthermore, Notch inhibitor DAPT induced early autophagy by acting on PTEN-PI3K/Akt/mTOR pathway. The autophagy inhibitor CQ and 3-MA dramatically abolished the effects of DAPT-induced autophagy and adipogenic differentiation of MSCs. Conclusion: Our results indicate that inhibition of Notch signaling could promote MSCs adipogenesis mediated by autophagy involving PTEN-PI3K/Akt/mTOR pathway. Notch signaling could be a novel target for regulating the adipogenic differentiation of MSCs.

scholarly journals Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1879 ◽  
Author(s):  
Christian T. Meisel ◽  
Cristina Porcheri ◽  
Thimios A. Mitsiadis
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Adult Life ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Fine Tuning ◽  
Cell Fate Decisions

The Notch signaling pathway regulates cell proliferation, cytodifferentiation and cell fate decisions in both embryonic and adult life. Several aspects of stem cell maintenance are dependent from the functionality and fine tuning of the Notch pathway. In cancer, Notch is specifically involved in preserving self-renewal and amplification of cancer stem cells, supporting the formation, spread and recurrence of the tumor. As the function of Notch signaling is context dependent, we here provide an overview of its activity in a variety of tumors, focusing mostly on its role in the maintenance of the undifferentiated subset of cancer cells. Finally, we analyze the potential of molecules of the Notch pathway as diagnostic and therapeutic tools against the various cancers.

scholarly journals An updated evolutionary study of the Notch family reveals a new ancient origin and novel invariable motifs as potential pharmacological targets

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10334
Author(s):  
Dimitrios Vlachakis ◽  
Louis Papageorgiou ◽  
Ariadne Papadaki ◽  
Maria Georga ◽  
Sofia Kossida ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Notch Signaling Pathway ◽  
Evolutionary Analysis ◽  
Cell Fate Decisions ◽  
Pharmacological Targets ◽  
Organ Systems

Notch family proteins play a key role in a variety of developmental processes by controlling cell fate decisions and operating in a great number of biological processes in several organ systems, such as hematopoiesis, somatogenesis, vasculogenesis, neurogenesis and homeostasis. The Notch signaling pathway is crucial for the majority of developmental programs and regulates multiple pathogenic processes. Notch family receptors’ activation has been largely related to its multiple effects in sustaining oncogenesis. The Notch signaling pathway constitutes an ancient and conserved mechanism for cell to cell communication. Much of what is known about Notch family proteins function comes from studies done in Caenorhabditis Elegans and Drosophila Melanogaster. Although, human Notch homologs had also been identified, the molecular mechanisms which modulate the Notch signaling pathway remained substantially unknown. In this study, an updated evolutionary analysis of the Notch family members among 603 different organisms of all kingdoms, from bacteria to humans, was performed in order to discover key regions that have been conserved throughout evolution and play a major role in the Notch signaling pathway. The major goal of this study is the presentation of a novel updated phylogenetic tree for the Notch family as a reliable phylogeny “map”, in order to correlate information of the closely related members and identify new possible pharmacological targets that can be used in pathogenic cases, including cancer.

scholarly journals Notch Signaling in B Cell Immune Responses

2021 ◽  
Vol 11 ◽  
Author(s):  
Matthew Garis ◽  
Lee Ann Garrett-Sinha
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
B Lymphocyte ◽  
Notch Signaling Pathway ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance

The Notch signaling pathway is highly evolutionarily conserved, dictating cell fate decisions and influencing the survival and growth of progenitor cells that give rise to the cells of the immune system. The roles of Notch signaling in hematopoietic stem cell maintenance and in specification of T lineage cells have been well-described. Notch signaling also plays important roles in B cells. In particular, it is required for specification of marginal zone type B cells, but Notch signaling is also important in other stages of B cell development and activation. This review will focus on established and new roles of Notch signaling during B lymphocyte lineage commitment and describe the function of Notch within mature B cells involved in immune responses.

scholarly journals Intriguing Roles for Endothelial ADAM10/Notch Signaling in the Development of Organ-Specific Vascular Beds

2018 ◽  
Vol 98 (4) ◽  
pp. 2025-2061 ◽  
Author(s):  
Rolake O. Alabi ◽  
Gregory Farber ◽  
Carl P. Blobel
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Waste Products ◽  
Cell Fate Decisions ◽  
Vital Functions ◽  
Organ Specific ◽  
Dependent Cell ◽  
Vascular Beds ◽  
Artery Disease

The vasculature is a remarkably interesting, complex, and interconnected organ. It provides a conduit for oxygen and nutrients, filtration of waste products, and rapid communication between organs. Much remains to be learned about the specialized vascular beds that fulfill these diverse, yet vital functions. This review was prompted by the discovery that Notch signaling in mouse endothelial cells is crucial for the development of specialized vascular beds found in the heart, kidneys, liver, intestines, and bone. We will address the intriguing questions raised by the role of Notch signaling and that of its regulator, the metalloprotease ADAM10, in the development of specialized vascular beds. We will cover fundamentals of ADAM10/Notch signaling, the concept of Notch-dependent cell fate decisions, and how these might govern the development of organ-specific vascular beds through angiogenesis or vasculogenesis. We will also consider common features of the affected vessels, including the presence of fenestra or sinusoids and their occurrence in portal systems with two consecutive capillary beds. We hope to stimulate further discussion and study of the role of ADAM10/Notch signaling in the development of specialized vascular structures, which might help uncover new targets for the repair of vascular beds damaged in conditions like coronary artery disease and glomerulonephritis.

scholarly journals Neoplastic Transformation by Notch Requires Nuclear Localization

2000 ◽  
Vol 20 (11) ◽  
pp. 3928-3941 ◽  
Author(s):  
Shawn Jeffries ◽  
Anthony J. Capobianco
Keyword(s):  
Plasma Membrane ◽  
Notch Signaling ◽  
Cell Fate ◽  
Mammalian Cells ◽  
Rat Kidney ◽  
Neoplastic Transformation ◽  
Notch Signaling Pathway ◽  
Proteolytic Processing ◽  
Cell Fate Decisions

ABSTRACT Notch proteins are plasma membrane-spanning receptors that mediate important cell fate decisions such as differentiation, proliferation, and apoptosis. The mechanism of Notch signaling remains poorly understood. However, it is clear that the Notch signaling pathway mediates its effects through intercellular contact between neighboring cells. The prevailing model for Notch signaling suggests that ligand, presented on a neighboring cell, triggers proteolytic processing of Notch. Following proteolysis, it is thought that the intracellular portion of Notch (Nic) translocates to the nucleus, where it is involved in regulating gene expression. There is considerable debate concerning where in the cell Notch functions and what proteins serve as effectors of the Notch signal. Several Notch genes have clearly been shown to be proto-oncogenes in mammalian cells. Activation of Notch proto-oncogenes has been associated with tumorigenesis in several human and other mammalian cancers. Transforming alleles of Notch direct the expression of truncated proteins that primarily consist of Nic and are not tethered to the plasma membrane. However, the mechanism by which Notch oncoproteins (generically termed here as Nic) induce neoplastic transformation is not known. Previously we demonstrated that N1ic and N2iccould transform E1A immortalized baby rat kidney cells (RKE) in vitro. We now report direct evidence that N1ic must accumulate in the nucleus to induce transformation of RKE cells. In addition, we define the minimal domain of N1ic required to induce transformation and present evidence that transformation of RKE cells by N1ic is likely to be through a CBF1-independent pathway.

scholarly journals Notch in mechanotransduction – from molecular mechanosensitivity to tissue mechanostasis

2020 ◽  
Vol 133 (24) ◽  
pp. jcs250738
Author(s):  
Oscar M. J. A. Stassen ◽  
Tommaso Ristori ◽  
Cecilia M. Sahlgren
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Cellular Response ◽  
Computational Models ◽  
Notch Signaling Pathway ◽  
Tissue Mechanics ◽  
Mechanical Equilibrium ◽  
Molecular Signaling ◽  
Dynamic Relationship

ABSTRACTTissue development and homeostasis are controlled by mechanical cues. Perturbation of the mechanical equilibrium triggers restoration of mechanostasis through changes in cell behavior, while defects in these restorative mechanisms lead to mechanopathologies, for example, osteoporosis, myopathies, fibrosis or cardiovascular disease. Therefore, sensing mechanical cues and integrating them with the biomolecular cell fate machinery is essential for the maintenance of health. The Notch signaling pathway regulates cell and tissue fate in nearly all tissues. Notch activation is directly and indirectly mechanosensitive, and regulation of Notch signaling, and consequently cell fate, is integral to the cellular response to mechanical cues. Fully understanding the dynamic relationship between molecular signaling, tissue mechanics and tissue remodeling is challenging. To address this challenge, engineered microtissues and computational models play an increasingly large role. In this Review, we propose that Notch takes on the role of a ‘mechanostat’, maintaining the mechanical equilibrium of tissues. We discuss the reciprocal role of Notch in the regulation of tissue mechanics, with an emphasis on cardiovascular tissues, and the potential of computational and engineering approaches to unravel the complex dynamic relationship between mechanics and signaling in the maintenance of cell and tissue mechanostasis.

scholarly journals Inhibition of Notch Signaling Promotes the Differentiation of Epicardial Progenitor Cells into Adipocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Bin Liu ◽  
Dinghui Wang ◽  
Tianhua Xiong ◽  
Yajie Liu ◽  
Xiaodong Jing ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Progenitor Cells ◽  
Signaling Pathway ◽  
Adipogenic Differentiation ◽  
Notch Signaling Pathway ◽  
Lineage Tracing ◽  
Induction Medium ◽  
Genetic Lineage ◽  
Ppar Γ

Background. The role of Notch signaling pathway in the differentiation of epicardial progenitor cells (EPCs) into adipocytes is unclear. The objective is to investigate the effects of Notch signaling on the differentiation of EPCs into adipocytes. Methods. Frozen sections of C57BL/6J mouse hearts were used to observe epicardial adipose tissue (EAT), and genetic lineage methods were used to trace EPCs. EPCs were cultured in adipogenic induction medium with Notch ligand jagged-1 or γ-secretase inhibitor DAPT. The adipocyte markers, Notch signaling, and adipogenesis transcription factors were determined. Results. There was EAT located at the atrial–ventricular groove in mouse. By using genetic lineage tracing methods, we found that EPCs were a source of epicardial adipocytes. EPCs had lipid droplet accumulation, and the expression of adipocyte markers FABP-4 and perilipin-1 was upregulated under adipogenic induction. Activating the Notch signaling with jagged-1 attenuated the adipogenic differentiation of EPCs and downregulated the key adipogenesis transcription factor peroxisome proliferator activated receptor-γ (PPAR-γ), while inhibiting the signaling promoted adipogenic differentiation and upregulated PPAR-γ. When blocking PPAR-γ, the role of Notch signaling in promoting adipogenic differentiation was inhibited. Conclusions. EPCs are a source of epicardial adipocytes. Downregulation of the Notch signaling pathway promotes the differentiation of EPCs into adipocytes via PPAR-γ.

scholarly journals Increasing Notch signaling antagonizes PRC2-mediated silencing to promote reprograming of germ cells into neurons

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Stefanie Seelk ◽  
Irene Adrian-Kalchhauser ◽  
Balázs Hargitai ◽  
Martina Hajduskova ◽  
Silvia Gutnik ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Germ Cells ◽  
Molecular Mechanisms ◽  
Notch Signaling Pathway ◽  
Germline Stem Cells ◽  
Polycomb Repressive Complex 2 ◽  
C Elegans ◽  
Functional Studies

Cell-fate reprograming is at the heart of development, yet very little is known about the molecular mechanisms promoting or inhibiting reprograming in intact organisms. In the C. elegans germline, reprograming germ cells into somatic cells requires chromatin perturbation. Here, we describe that such reprograming is facilitated by GLP-1/Notch signaling pathway. This is surprising, since this pathway is best known for maintaining undifferentiated germline stem cells/progenitors. Through a combination of genetics, tissue-specific transcriptome analysis, and functional studies of candidate genes, we uncovered a possible explanation for this unexpected role of GLP-1/Notch. We propose that GLP-1/Notch promotes reprograming by activating specific genes, silenced by the Polycomb repressive complex 2 (PRC2), and identify the conserved histone demethylase UTX-1 as a crucial GLP-1/Notch target facilitating reprograming. These findings have wide implications, ranging from development to diseases associated with abnormal Notch signaling.

scholarly journals Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Panagiotis F. Christopoulos ◽  
Torleif T. Gjølberg ◽  
Stig Krüger ◽  
Guttorm Haraldsen ◽  
Jan Terje Andersen ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Inflammatory Diseases ◽  
Notch Signaling Pathway ◽  
Therapeutic Strategies ◽  
Lessons Learned ◽  
Chronic Inflammatory Diseases ◽  
Cell Fate Decisions ◽  
The Impact

The Notch signaling pathway regulates developmental cell-fate decisions and has recently also been linked to inflammatory diseases. Although therapies targeting Notch signaling in inflammation in theory are attractive, their design and implementation have proven difficult, at least partly due to the broad involvement of Notch signaling in regenerative and homeostatic processes. In this review, we summarize the supporting role of Notch signaling in various inflammation-driven diseases, and highlight efforts to intervene with this pathway by targeting Notch ligands and/or receptors with distinct therapeutic strategies, including antibody designs. We discuss this in light of lessons learned from Notch targeting in cancer treatment. Finally, we elaborate on the impact of individual Notch members in inflammation, which may lay the foundation for development of therapeutic strategies in chronic inflammatory diseases.

scholarly journals Synergy between suppressor of Hairless and Notch in regulation of Enhancer of split m gamma and m delta expression.

1997 ◽  
Vol 17 (9) ◽  
pp. 5620-5628 ◽  
Author(s):  
D S Eastman ◽  
R Slee ◽  
E Skoufos ◽  
L Bangalore ◽  
S Bray ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Transcriptional Activation ◽  
Cultured Cells ◽  
Notch Signaling Pathway ◽  
Cell Fate Decisions ◽  
Suppressor Of Hairless ◽  
Enhancer Of Split

The Notch signaling pathway is known to regulate cell fate decisions in a variety of organisms from worms to humans. Although several components of the pathway have been characterized, the actual mechanism and molecular results of signaling remain elusive. We have examined the role of the Notch signaling pathway in the transcriptional regulation of two Drosophila Enhancer of split [E(spl)] genes, whose gene products have been shown to be downstream players in the pathway. Using a reporter assay system in Drosophila tissue culture cells, we have observed a significant induction of E(spl) m gamma and m delta expression after cotransfection with activated Notch. Characterization of the 5' regulatory regions of these two genes led to the identification of a number of target sites for the Suppressor of Hairless [Su(H)] protein, a transcription factor activated by Notch signaling. We show that Notch-inducible expression of E(spl) m gamma and m delta both in cultured cells and in vivo is dependent on functional Su(H). Although overexpression of Su(H) augments the level of induction of the reporter genes by activated Notch, Su(H) alone is insufficient to produce high levels of transcriptional activation. Despite the synergy observed between activated Notch and Su(H), the former affects neither the nuclear localization nor the DNA binding activity of the latter.

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