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Notch signaling

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https://www.readbyqxmd.com/read/28738360/targeting-developmental-pathways-the-achilles-heel-of-cancer
#1
Wolfram C M Dempke, Klaus Fenchel, Peter Uciechowski, Timothy Chevassut
Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development...
July 22, 2017: Oncology
https://www.readbyqxmd.com/read/28737769/local-lung-hypoxia-determines-epithelial-fate-decisions-during-alveolar-regeneration
#2
Ying Xi, Thomas Kim, Alexis N Brumwell, Ian H Driver, Ying Wei, Victor Tan, Julia R Jackson, Jianming Xu, Dong-Kee Lee, Jeffrey E Gotts, Michael A Matthay, John M Shannon, Harold A Chapman, Andrew E Vaughan
After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5(pos) basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5(pos) basal-like state...
July 24, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28736522/gliotoxin-targets-nuclear-notch2-in-human-solid-tumor-derived-cell-lines-in-vitro-and-inhibits-melanoma-growth-in-xenograft-mouse-model
#3
Rainer Hubmann, Wolfgang Sieghart, Susanne Schnabl, Mohammad Araghi, Martin Hilgarth, Marlies Reiter, Dita Demirtas, Peter Valent, Christoph Zielinski, Ulrich Jäger, Medhat Shehata
Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28736165/intra-lineage-fate-decisions-involve-activation-of-notch-receptors-basal-to-the-midbody-in-drosophila-sensory-organ-precursor-cells
#4
Mateusz Trylinski, Khalil Mazouni, François Schweisguth
Notch receptors regulate cell fate decisions during embryogenesis and throughout adult life. In many cell lineages, binary fate decisions are mediated by directional Notch signaling between the two sister cells produced by cell division. How Notch signaling is restricted to sister cells after division to regulate intra-lineage decision is poorly understood. More generally, where ligand-dependent activation of Notch occurs at the cell surface is not known, as methods to detect receptor activation in vivo are lacking...
July 11, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28735867/cleavage-of-the-interleukin-11-receptor-induces-processing-of-its-c-terminal-fragments-by-the-gamma-secretase-and-the-proteasome
#5
Juliane Lokau, Charlotte M Flynn, Christoph Garbers
The cytokine Interleukin-11 (IL-11) signals through the membrane-bound IL-11 receptor (IL-11R), which is expressed in a cell-type specific manner. We have recently shown that the metalloprotease ADAM10 can cleave the IL-11R. The liberated soluble IL-11R (sIL-11R) ectodomain can bind its ligand, and the resulting IL-11/sIL-11R complex can activate cells that do not express the IL-11R (trans-signaling). In this study, we show that the remaining C-terminal fragment (CTF1) after ADAM10-mediated cleavage is subsequently cleaved within the membrane by the gamma-secretase complex, and that the resulting shorter CTF2 is further degraded by the proteasome...
July 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28734841/potential-involvement-of-mi-rna-574-3p-in-progression-of-prostate-cancer-a-bioinformatic-study
#6
Naeem M Ashraf, Komal Imran, David W Kastner, Khadija Ikram, Ayesha Mushtaq, Aadil Hussain, Nadia Zeeshan
Aberrant gene expression is a hallmark of prostate cancer (PCa), the second deadliest disease affecting males worldwide. Dysregulation of miRNA has been associated with the progression of PCa, and in recent studies, miRNA 574-3p was found to be upregulated in cancerous prostate tissue. In this study, we characterize the effects of up-regulated miRNA 574-3p on gene expression in the tumor microenvironment through different bioinformatic tools such as Diana-Tools, KEGG Pathway database, and the Reactome Database...
July 19, 2017: Molecular and Cellular Probes
https://www.readbyqxmd.com/read/28732358/lenalidomide-restores-the-osteogenic-differentiation-of-bone-marrow-mesenchymal-stem-cells-from-multiple-myeloma-patients-via-deactivating-notch-signaling-pathway
#7
Juan Guo, Chengming Fei, Youshan Zhao, Sida Zhao, Qingqing Zheng, Jiying Su, Dong Wu, Xiao Li, Chunkang Chang
Multiple myeloma (MM) always presents osteolytic bone lesions, resulting from the abnormal osteoblastic and osteoclastic function in patients. MM patients exhibit the impairment of osteogenic differentiation of BMMSCs (bone marrow mesenchymal stem cells) and osteoblast deficiency. Effects of the drug, lenalidomide on the osteoblastic functions and the involved mechanisms remain unexplored. In the present study, it is observed that the osteogenic differentiation of BMMSCs from MM patients (MM-MSCs) is impaired and activation of Notch signaling pathway in MM-MSCs is abnormal...
July 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28732189/erratum-to-blos2-maintains-hematopoietic-stem-cells-in-the-fetal-liver-via-repressing-notch-signaling
#8
Qiuping He, Suwei Gao, Junhua Lv, Wei Li, Feng Liu
No abstract text is available yet for this article.
July 18, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28730338/jagged1-promotes-aromatase-inhibitor-resistance-by-modulating-tumor-associated-macrophage-differentiation-in-breast-cancer-patients
#9
Hang Liu, Jingxuan Wang, Minghui Zhang, Qijia Xuan, Zhipeng Wang, Xin Lian, Qingyuan Zhang
PURPOSE: Endocrine resistance limits the efficacy of anti-estrogen therapies. Notch signaling is involved in modulating tumor-associated macrophage (TAM) differentiation and is upregulated in endocrine-resistant breast cancer cells. Here, we analyzed the role of Jagged1 in the regulation of TAM polarization to investigate whether the Jagged1-Notch pathway promotes the acquisition of aromatase inhibitor (AI) resistance by upregulating TAM infiltration. METHODS: The Jagged1 expression levels and M2 TAM infiltration density, in 203 tumor samples from ER-positive postmenopausal patients, who received AI treatment, were evaluated by immunohistochemical staining and the results were compared with clincopathological parameters and survival...
July 20, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28729299/notch2-blockade-enhances-hematopoietic-stem-cell-mobilization-and-homing
#10
Weihuan Wang, Shuiliang Yu, Jay Myers, Yiwei Wang, William W Xin, Marwah Alkabri, Alison W Xin, Ming Li, Alex Y Huang, Wei Xin, Christian W Siebel, Hillard M Lazarus, Lan Zhou
Despite use of newer approaches, some patients being considered for autologous hematopoietic cell transplantation may mobilize limited numbers of hematopoietic progenitor cells into blood, precluding use of the procedure, or being placed at increased risk for complications due to slow hematopoietic reconstitution. Developing more efficacious hematopoietic progenitor cell mobilization regimens and strategies may enhance the mobilization process and improve patient outcome. Although Notch signaling is dispensable for homeostasis of adult hematopoietic stem cells, Notch-ligand adhesive interaction maintains hematopoietic stem cell quiescence and niche retention...
July 20, 2017: Haematologica
https://www.readbyqxmd.com/read/28729032/a-novel-model-of-autosomal-recessive-polycystic-kidney-questions-the-role-of-the-fibrocystin-c-terminus-in-disease-mechanism
#11
Patricia Outeda, Luis Menezes, Erum A Hartung, Stacey Bridges, Fang Zhou, Xianjun Zhu, Hangxue Xu, Qiong Huang, Qin Yao, Feng Qian, Gregory G Germino, Terry Watnick
Autosomal recessive polycystic kidney disease (OMIM 263200) is a serious condition of the kidney and liver caused by mutations in a single gene, PKHD1. This gene encodes fibrocystin/polyductin (FPC, PD1), a large protein shown by in vitro studies to undergo Notch-like processing. Its cytoplasmic tail, reported to include a ciliary targeting sequence, a nuclear localization signal, and a polycystin-2 binding domain, is thought to traffic to the nucleus after cleavage. We now report a novel mouse line with a triple HA-epitope "knocked-in" to the C-terminus along with lox P sites flanking exon 67, which encodes most of the C-terminus (Pkhd1(Flox67HA))...
July 17, 2017: Kidney International
https://www.readbyqxmd.com/read/28724574/the-microvascular-niche-instructs-t-cells-in-large-vessel-vasculitis-via-the-vegf-jagged1-notch-pathway
#12
Zhenke Wen, Yi Shen, Gerald Berry, Farhad Shahram, Yinyin Li, Ryu Watanabe, Yaping Joyce Liao, Jörg J Goronzy, Cornelia M Weyand
Microvascular networks in the adventitia of large arteries control access of inflammatory cells to the inner wall layers (media and intima) and thus protect the immune privilege of the aorta and its major branches. In autoimmune vasculitis giant cell arteritis (GCA), CD4 T helper 1 (TH1) and TH17 cells invade into the wall of the aorta and large elastic arteries to form tissue-destructive granulomas. Whether the disease microenvironment provides instructive cues for vasculitogenic T cells is unknown. We report that adventitial microvascular endothelial cells (mvECs) perform immunoregulatory functions by up-regulating the expression of the Notch ligand Jagged1...
July 19, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28723653/inhibition-of-notch-1-pathway-is-involved-in-rottlerin-induced-tumor-suppressive-function-in-nasopharyngeal-carcinoma-cells
#13
Yingying Hou, Shaoyan Feng, Lixia Wang, Zhe Zhao, Jingna Su, Xuyuan Yin, Nana Zheng, Xiuxia Zhou, Jun Xia, Zhiwei Wang
Recent studies have revealed that rottlerin is a natural chemical drug to exert its anti-cancer activity. However, the molecular mechanisms of rottlerin-induced tumor suppressive function have not been fully elucidated. Notch signaling pathway has been characterized to play a crucial role in tumorigenesis. Therefore, regulation of Notch pathway could be beneficial for the treatment of human cancer. The aims of our current study were to explore whether rottlerin could suppress Notch-1 expression, which leads to inhibition of cell proliferation, migration and invasion in nasopharyngeal carcinoma cells...
July 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28719575/non-canonical-notch3-signalling-limits-tumour-angiogenesis
#14
Shuheng Lin, Ana Negulescu, Sirisha Bulusu, Benjamin Gibert, Jean-Guy Delcros, Benjamin Ducarouge, Nicolas Rama, Nicolas Gadot, Isabelle Treilleux, Pierre Saintigny, Olivier Meurette, Patrick Mehlen
Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature...
July 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28718798/co-expression-network-and-pathway-analyses-reveal-important-modules-of-mirnas-regulating-milk-yield-and-component-traits
#15
Duy N Do, Pier-Luc Dudemaine, Ran Li, Eveline M Ibeagha-Awemu
Co-expression network analyses provide insights into the molecular interactions underlying complex traits and diseases. In this study, co-expression network analysis was performed to detect expression patterns (modules or clusters) of microRNAs (miRNAs) during lactation, and to identify miRNA regulatory mechanisms for milk yield and component traits (fat, protein, somatic cell count (SCC), lactose, and milk urea nitrogen (MUN)) via miRNA target gene enrichment analysis. miRNA expression (713 miRNAs), and milk yield and components (Fat%, Protein%, lactose, SCC, MUN) data of nine cows at each of six different time points (day 30 (D30), D70, D130, D170, D230 and D290) of an entire lactation curve were used...
July 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28717251/transdifferentiated-human-vascular-smooth-muscle-cells-are-a-new-potential-cell-source-for-endothelial-regeneration
#16
Xuechong Hong, Andriana Margariti, Alexandra Le Bras, Laureen Jacquet, Wei Kong, Yanhua Hu, Qingbo Xu
Endothelial dysfunction is widely implicated in cardiovascular pathological changes and development of vascular disease. In view of the fact that the spontaneous endothelial cell (EC) regeneration is a slow and insufficient process, it is of great interest to explore alternative cell sources capable of generating functional ECs. Vascular smooth muscle cell (SMC) composes the majority of the vascular wall and retains phenotypic plasticity in response to various stimuli. The aim of this study is to test the feasibility of the conversion of SMC into functional EC through the use of reprogramming factors...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28717225/a-mammalian-mirtron-mir-1224-promotes-tube-formation-of-human-primary-endothelial-cells-by-targeting-anti-angiogenic-factor-epsin2
#17
Eiko Sakai, Yusuke Miura, Emi Suzuki-Kouyama, Kengo Oka, Masashi Tachibana, Kenji Kawabata, Fuminori Sakurai, Hiroyuki Mizuguchi
Angiogenesis, new vessel formation from pre-existing vessels, is a highly conserved event through vertebrates. However, the system for tuning angiogenesis by species-intrinsic factors is totally unknown. miR-1224 is a member of mammal-specific mirtrons, which were identified as non-canonical microRNAs. We found that the expression of miR-1224 was upregulated in capillary-like tube-forming human umbilical vein endothelial cells on Matrigel. Enforced expression of miR-1224 stimulated tube formation, whereas repression of endogenous miR-1224 inhibited formation...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716889/cytokines-transcription-factors-and-the-initiation-of-t-cell-development
#18
Hiroyuki Hosokawa, Ellen V Rothenberg
Multipotent blood progenitor cells migrate into the thymus and initiate the T-cell differentiation program. T-cell progenitor cells gradually acquire T-cell characteristics while shedding their multipotentiality for alternative fates. This process is supported by extracellular signaling molecules, including Notch ligands and cytokines, provided by the thymic microenvironment. T-cell development is associated with dynamic change of gene regulatory networks of transcription factors, which interact with these environmental signals...
July 17, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28714969/endothelial-notch-signalling-limits-angiogenesis-via-control-of-artery-formation
#19
Sana S Hasan, Roman Tsaryk, Martin Lange, Laura Wisniewski, John C Moore, Nathan D Lawson, Karolina Wojciechowska, Hans Schnittler, Arndt F Siekmann
Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial-venous blood flow patterns...
July 17, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28714968/dll4-and-notch-signalling-couples-sprouting-angiogenesis-and-artery-formation
#20
Mara E Pitulescu, Inga Schmidt, Benedetto Daniele Giaimo, Tobiah Antoine, Frank Berkenfeld, Francesca Ferrante, Hongryeol Park, Manuel Ehling, Daniel Biljes, Susana F Rocha, Urs H Langen, Martin Stehling, Takashi Nagasawa, Napoleone Ferrara, Tilman Borggrefe, Ralf H Adams
Endothelial sprouting and proliferation are tightly coordinated processes mediating the formation of new blood vessels during physiological and pathological angiogenesis. Endothelial tip cells lead sprouts and are thought to suppress tip-like behaviour in adjacent stalk endothelial cells by activating Notch. Here, we show with genetic experiments in postnatal mice that the level of active Notch signalling is more important than the direct Dll4-mediated cell-cell communication between endothelial cells. We identify endothelial expression of VEGF-A and of the chemokine receptor CXCR4 as key processes controlling Notch-dependent vessel growth...
July 17, 2017: Nature Cell Biology
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