scholarly journals Pleiotropic Role of Notch Signaling in Human Skin Diseases

2020 ◽  
Vol 21 (12) ◽  
pp. 4214 ◽  
Author(s):  
Rossella Gratton ◽  
Paola Maura Tricarico ◽  
Chiara Moltrasio ◽  
Ana Sofia Lima Estevão de Oliveira ◽  
Lucas Brandão ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Human Skin ◽  
Hidradenitis Suppurativa ◽  
Target Genes ◽  
Skin Diseases ◽  
Current Knowledge ◽  
Cellular Mechanisms ◽  
Degos Disease ◽  
Cellular Pathways

Notch signaling orchestrates the regulation of cell proliferation, differentiation, migration and apoptosis of epidermal cells by strictly interacting with other cellular pathways. Any disruption of Notch signaling, either due to direct mutations or to an aberrant regulation of genes involved in the signaling route, might lead to both hyper- or hypo-activation of Notch signaling molecules and of target genes, ultimately inducing the onset of skin diseases. The mechanisms through which Notch contributes to the pathogenesis of skin diseases are multiple and still not fully understood. So far, Notch signaling alterations have been reported for five human skin diseases, suggesting the involvement of Notch in their pathogenesis: Hidradenitis Suppurativa, Dowling Degos Disease, Adams–Oliver Syndrome, Psoriasis and Atopic Dermatitis. In this review, we aim at describing the role of Notch signaling in the skin, particularly focusing on the principal consequences associated with its alterations in these five human skin diseases, in order to reorganize the current knowledge and to identify potential cellular mechanisms in common between these pathologies.

Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1154-1162 ◽  
Author(s):  
Wei Zheng ◽  
Tuomas Tammela ◽  
Masahiro Yamamoto ◽  
Andrey Anisimov ◽  
Tanja Holopainen ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Notch Pathway ◽  
Lymphatic Vessels ◽  
Soluble Form ◽  
Fibrin Gel ◽  
3 Dimensional ◽  
Endothelial Growth Factor

Abstract Notch signaling plays a central role in cell-fate determination, and its role in lateral inhibition in angiogenic sprouting is well established. However, the role of Notch signaling in lymphangiogenesis, the growth of lymphatic vessels, is poorly understood. Here we demonstrate Notch pathway activity in lymphatic endothelial cells (LECs), as well as induction of delta-like ligand 4 (Dll4) and Notch target genes on stimulation with VEGF or VEGF-C. Suppression of Notch signaling by a soluble form of Dll4 (Dll4-Fc) synergized with VEGF in inducing LEC sprouting in 3-dimensional (3D) fibrin gel assays. Expression of Dll4-Fc in adult mouse ears promoted lymphangiogenesis, which was augmented by coexpressing VEGF. Lymphangiogenesis triggered by Notch inhibition was suppressed by a monoclonal VEGFR-2 Ab as well as soluble VEGF and VEGF-C/VEGF-D ligand traps. LECs transduced with Dll4 preferentially adopted the tip cell position over nontransduced cells in 3D sprouting assays, suggesting an analogous role for Dll4/Notch in lymphatic and blood vessel sprouting. These results indicate that the Notch pathway controls lymphatic endothelial quiescence, and explain why LECs are poorly responsive to VEGF compared with VEGF-C. Understanding the role of the Notch pathway in lymphangiogenesis provides further insight for the therapeutic manipulation of the lymphatic vessels.

scholarly journals Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

2015 ◽  
Vol 112 (5) ◽  
pp. E402-E409 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Mingyang Lu ◽  
José N. Onuchic ◽  
Cecilia Clementi ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Tumor Stroma ◽  
Notch Receptor ◽  
Toggle Switch ◽  
Cell Fate Determination ◽  
Asymmetric Effect ◽  
Fate Determination

Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

scholarly journals Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells

Oncogene ◽  
2019 ◽  
Vol 39 (6) ◽  
pp. 1185-1197 ◽  
Author(s):  
Mónica López-Guerra ◽  
Sílvia Xargay-Torrent ◽  
Patricia Fuentes ◽  
Jocabed Roldán ◽  
Blanca González-Farré ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Notch Signaling ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Target Genes ◽  
Notch Signaling Pathway ◽  
Lymphocytic Leukemia ◽  
Therapeutic Targeting ◽  
Notch Ligand

Abstract Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.

scholarly journals Phagocytosis: A Fundamental Process in Immunity

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Carlos Rosales ◽  
Eileen Uribe-Querol
Keyword(s):  
Immune Responses ◽  
Host Response ◽  
Current Knowledge ◽  
General View ◽  
Cellular Mechanisms ◽  
Complex Process ◽  
Fundamental Process ◽  
Target Particle ◽  
Acquired Immune Responses

One hundred years have passed since the death of Élie Metchnikoff (1845–1916). He was the first to observe the uptake of particles by cells and realized the importance of this process for the host response to injury and infection. He also was a strong advocate of the role of phagocytosis in cellular immunity, and with this he gave us the basis for our modern understanding of inflammation and the innate and acquired immune responses. Phagocytosis is an elegant but complex process for the ingestion and elimination of pathogens, but it is also important for the elimination of apoptotic cells and hence fundamental for tissue homeostasis. Phagocytosis can be divided into four main steps: (i) recognition of the target particle, (ii) signaling to activate the internalization machinery, (iii) phagosome formation, and (iv) phagolysosome maturation. In recent years, the use of new tools of molecular biology and microscopy has provided new insights into the cellular mechanisms of phagocytosis. In this review, we present a general view of our current knowledge on phagocytosis. We emphasize novel molecular findings, particularly on phagosome formation and maturation, and discuss aspects that remain incompletely understood.

Role of Extracellular Adenosine Triphosphate in Human Skin

2004 ◽  
Vol 8 (2) ◽  
pp. 90-96 ◽  
Author(s):  
Aton M. Holzer ◽  
Richard D. Granstein
Keyword(s):  
Human Skin ◽  
Adenosine Triphosphate ◽  
Current Knowledge ◽  
Extracellular Atp ◽  
Cell Type ◽  
Skin Injury ◽  
Direct Role ◽  
Extracellular Adenosine ◽  
Proliferation And Apoptosis

Background: The nucleotide adenosine triphosphate (ATP) has long been known to drive and participate in countless intracellular processes. Extracellular ATP and its metabolite adenosine have also been shown to exert a variety of effects on nearly every cell type in human skin. Knowledge of the sources and effects of extracellular ATP in human skin may help shape new therapies for skin injury, inflammation, and numerous other cutaneous disorders. Objective: The objective of this review is to introduce the reader to current knowledge regarding the sources and effects of extracellular ATP in human skin and to outline areas in which further research is necessary to clarify the nature and mechanism of these effects. Conclusion: Extracellular ATP seems to play a direct role in triggering skin inflammatory, regenerative, and fibrotic responses to mechanical injury, an indirect role in melanocyte proliferation and apoptosis, and a complex role in Langerhans cell-directed adaptive immunity.

scholarly journals Cutaneous Effects of Notch Inhibitor Therapy: A Report of Two Cases

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Claire J. Wiggins ◽  
Susan Y. Chon
Keyword(s):  
Side Effects ◽  
Notch Signaling ◽  
Hidradenitis Suppurativa ◽  
Disease Pathogenesis ◽  
Cutaneous Side Effects ◽  
Medication Side Effects ◽  
Medication Side ◽  
Notch Pathways ◽  
Inhibitor Treatment

As aberrant Notch signaling has been linked to cancerous growth, Notch inhibitors represent a novel category of targeted oncological therapy. Notch pathways in tumor cells may contribute to proliferation or limit apoptosis and differentiation. Healthy skin differentiation and homeostasis are reliant on normal Notch expression, and disruption of this signaling has been implicated in dermatological conditions such as hidradenitis suppurativa, psoriasis, atopic dermatitis, and lichen planus. Here, we describe two cases of patients with cutaneous side effects from Notch inhibitor treatment for adenoid cyst carcinoma (ACC) and review the role of Notch signaling in skin disease. By illuminating connections between medication side effects and disease pathogenesis, our goal is to increase awareness of the cutaneous side effects of Notch inhibitor treatment.

scholarly journals Applied bioinformatics tools for analysis of Microrna-214 expression and prediction of its potential targets genes in Nasopharyngeal carcinoma

2020 ◽  
Vol 9 (1) ◽  
pp. 3-13
Author(s):  
Nguyen Hoang Danh ◽  
Thieu Hong Hue ◽  
Quang Trong Minh ◽  
K' Trong Nghia ◽  
Nguyen Thanh Tung ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Experimental Validation ◽  
Target Genes ◽  
Human Cancer ◽  
Initial Study ◽  
Rna Molecules ◽  
Bioinformatics Tools ◽  
Different Types ◽  
Cellular Pathways

miRNA (microRNA) are short RNA molecules in length from 20 to 24 nucleotides that have been shown to play an important role in regulating gene expression in many different types of human cancer. Meanwhile, miRNA-214 is one of the known miRNAs involved in the formation of nasopharyngeal carcinoma (NPC) through overexpression that promotes proliferation and development of cancer cells. However, in Vietnam, the study of miR-214 related to NPC has not been conducted yet. With the aims to develop the further studies of miR-214 on NPC in Vietnamese patients, in this initial study, we conducted the analysis of miR-214 expression in previous publications, as well as the prediction of miR-214 potential target genes, which involved in many cellular pathways. Here we applied bioinformatics tools to predict miRNAs and their targets, and discuss the role of miR-214 in the context of human cancers. As the results, miR-214 acted as the oncogenic roles in NPC, relevanted to many pathways, such as cell proliferation, apoptosis, metastasis and invasion through the its target genes LTF, Bim, Bax, LINC0086, etc. In conclusion, the use of computional approaches facilitate the further experimental validation of miRNAs in general, particularly miR-214, in Vietnamese NPC patients.

scholarly journals Microbiome of human skin - its immunohomeostatic role and the role in pathogenesis of skin diseases

2018 ◽  
Vol 15 (1) ◽  
pp. 63-81
Author(s):  
D D Petrunin
Keyword(s):  
Human Skin ◽  
Skin Diseases ◽  
Secondary Infection ◽  
Treatment Options ◽  
Infectious Complications ◽  
Special Importance ◽  
Skin Microbiome ◽  
Inflammatory Dermatoses ◽  
Pathogenic Microbes

In the last decade new methods of metagenomic analysis allowed to obtain important data regarding the microbiome of human skin. The problem of colonization and secondary infection by pathogenic microbes is of special importance for allergic dermatoses that require topical immunosuppressive therapy. One of treatment options in this case could be topical multicomponent drugs that allow successful treatment of infectious complications of inflammatory dermatoses. But there are still a lot of blanks regarding both fundamental questions regarding human skin microbiome and practice aspects of treatment of skin diseases where it plays a pathogenetic role. This literature review systematizes and structures the accumulated data regarding the composition and the role of human skin microbiome in normal conditions and in various skin diseases as well as summarizes clinical data of use of combinational topical glucocorticosteroid drugs. Furthermore, some algorithms concerning the choice and optimization of topical treatment of secondary infected dermatoses are outlined.

scholarly journals Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance

2019 ◽  
Vol 20 (12) ◽  
pp. 3076 ◽  
Author(s):  
Candice Chapouly ◽  
Sarah Guimbal ◽  
Pierre-Louis Hollier ◽  
Marie-Ange Renault
Keyword(s):  
Hedgehog Signaling ◽  
Current Knowledge ◽  
Vascular Biology ◽  
Cerebrovascular Diseases ◽  
Future Research ◽  
Cellular Mechanisms ◽  
Vascular Integrity ◽  
Hh Signaling ◽  
Vessel Integrity

The role of Hedgehog (Hh) signaling in vascular biology has first been highlighted in embryos by Pepicelli et al. in 1998 and Rowitch et al. in 1999. Since then, the proangiogenic role of the Hh ligands has been confirmed in adults, especially under pathologic conditions. More recently, the Hh signaling has been proposed to improve vascular integrity especially at the blood–brain barrier (BBB). However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood and conflicting results have been reported. As a matter of fact, in several settings, it is currently not clear whether Hh ligands promote vessel integrity and quiescence or destabilize vessels to promote angiogenesis. The present review relates the current knowledge regarding the role of the Hh signaling in vasculature development, maturation and maintenance, discusses the underlying proposed mechanisms and highlights controversial data which may serve as a guideline for future research. Most importantly, fully understanding such mechanisms is critical for the development of safe and efficient therapies to target the Hh signaling in both cancer and cardiovascular/cerebrovascular diseases.

Role of lncRNAs in prostate cancer development and progression

2014 ◽  
Vol 395 (11) ◽  
pp. 1275-1290 ◽  
Author(s):  
Melanie Weiss ◽  
Christoph Plass ◽  
Clarissa Gerhauser
Keyword(s):  
Prostate Cancer ◽  
Target Genes ◽  
Current Knowledge ◽  
Prostate Carcinogenesis ◽  
Prostate Cancer Development ◽  
Chromatin Remodeling Complexes ◽  
Regulation Mechanisms ◽  
Functional Analyses

Abstract Prostate cancer (PCa) is the second most common cause of cancer-related deaths in men. Despite advances in the characterization of genomic and epigenetic aberrations contributing to PCa, the etiology of PCa is still far from being understood. Research over the past decade demonstrated the role of long non-coding RNAs (lncRNAs) in deregulation of target genes mainly through epigenetic mechanisms. In PCa, evidence accumulated that hundreds of lncRNAs are dysregulated. Functional analyses revealed their contribution to prostate carcinogenesis by targeting relevant pathways and gene regulation mechanisms including PTEN/AKT and androgen receptor signaling as well as chromatin remodeling complexes. Here we summarize our current knowledge on the roles of lncRNAs in PCa and their potential use as biomarkers for aggressive PCa and as novel therapeutic targets.

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