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https://www.readbyqxmd.com/read/28334865/structure-of-human-pofut1-its-requirement-in-ligand-independent-oncogenic-notch-signaling-and-functional-effects-of-dowling-degos-mutations
#1
Brian J McMillan, Brandon Zimmerman, Emily D Egan, Michael Lofgren, Xiang Xu, Anthony Hesser, Stephen C Blacklow
Protein O-fucosyltransferase-1 (POFUT1), which transfers fucose residues to acceptor sites on serine and threonine residues of epidermal growth factor-like repeats of recipient proteins, is essential for Notch signal transduction in mammals. Here, we examine the consequences of POFUT1 loss on the oncogenic signaling associated with certain leukemia-associated mutations of human Notch1, report the structures of human POFUT1 in free and GDP-fucose bound states, and assess the effects of Dowling-Degos mutations on human POFUT1 function...
March 17, 2017: Glycobiology
https://www.readbyqxmd.com/read/28330128/over-expression-of-notch1-as-a-biomarker-for-invasive-breast-ductal-carcinoma
#2
Mahdi Paryan, Rezvan Tavakoli, Seyed Mohammad Ali Hosseini Rad, Neda Feizi, Fereshteh Kamani, Ehsan Mostafavi, Samira Mohammadi-Yeganeh
Breast cancer is the leading cause of cancer-related death in women worldwide. Invasive ductal carcinoma (IDC) is the most frequent invasive form of breast cancer followed by metastasis. There is no accepted marker for distinguishing this form from other less aggressive forms of breast cancer. Therefore, finding new markers especially molecularly detectable ones are noteworthy. It has been shown that NOTCH1 has been overexpressed in the patients with breast cancer, but no study has investigated the expression of NOTCH1 and its correlation with other molecular and hormonal markers of breast cancer so far...
June 2016: 3 Biotech
https://www.readbyqxmd.com/read/28325276/limiting-thymic-precursor-supply-increases-the-risk-of-lymphoid-malignancy-in-murine-x-linked-severe-combined-immunodeficiency
#3
Samantha L Ginn, Claus V Hallwirth, Sophia H Y Liao, Erdahl T Teber, Jonathan W Arthur, Jianmin Wu, Hong Ching Lee, Szun S Tay, Min Hu, Roger R Reddel, Matthew P McCormack, Adrian J Thrasher, Marina Cavazzana, Stephen I Alexander, Ian E Alexander
In early gene therapy trials for SCID-X1, using γ-retroviral vectors, T cell leukemias developed in a subset of patients secondary to insertional proto-oncogene activation. In contrast, we have reported development of T cell leukemias in SCID-X1 mice following lentivirus-mediated gene therapy independent of insertional mutagenesis. A distinguishing feature in our study was that only a proportion of transplanted γc-deficient progenitors were transduced and therefore competent for reconstitution. We hypothesized that reconstitution of SCID-X1 mice with limiting numbers of hematopoietic progenitors might be a risk factor for lymphoid malignancy...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28321121/dnmt3a-regulates-t-cell-development-and-suppresses-t-all-transformation
#4
A C Kramer, A Kothari, W C Wilson, H Celik, J Nikitas, C Mallaney, E L Ostrander, E Eultgen, A Martens, M C Valentine, A L Young, T E Druley, M E Figueroa, B Zhang, G A Challen
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises approximately 15 and 25% of pediatric and adult ALL cases respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects...
March 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28321119/notch1-mutated-chronic-lymphocytic-leukemia-cells-are-characterized-by-a-myc-related-overexpression-of-nucleophosmin-1-and-ribosome-associated-components
#5
F Pozzo, T Bittolo, E Vendramini, R Bomben, P Bulian, F M Rossi, A Zucchetto, E Tissino, M Degan, G D'Arena, F Di Raimondo, F Zaja, G Pozzato, D Rossi, G Gaidano, G Del Poeta, V Gattei, M Dal Bo
In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in presence of NOTCH1 mutations remain largely unexplored. By performing a gene expression profile of NOTCH1 mutated (NOTCH1-mut) versus NOTCH1 wild type CLL, we identified a gene signature of NOTCH1-mut CLL characterized by upregulation of genes related to ribosome biogenesis, such as nucleophosmin1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by EDTA or by co-culture with JAGGED1-expressing stromal cells increased NPM1 expression, and inhibition of NOTCH1 signaling by either NOTCH1-specific small interfering RNA (siRNA) or γ-secretase inhibitor reduced NPM1 expression...
March 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28314854/common-nonmutational-notch1-activation-in-chronic-lymphocytic-leukemia
#6
Giulia Fabbri, Antony B Holmes, Mara Viganotti, Claudio Scuoppo, Laura Belver, Daniel Herranz, Xiao-Jie Yan, Yasmine Kieso, Davide Rossi, Gianluca Gaidano, Nicholas Chiorazzi, Adolfo A Ferrando, Riccardo Dalla-Favera
Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation...
March 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28302721/involvement-of-notch1-signaling-in-malignant-progression-of-a549-cells-subjected-to-prolonged-cadmium-exposure
#7
Kota Fujiki, Hisako Inamura, Takamitsu Miyayama, Masato Matsuoka
Cadmium exposure is known to increase lung cancer risk, but the underlying molecular mechanisms in cadmium-stimulated progression of malignancy are unclear. Here, we examined the effects of prolonged cadmium exposure on the malignant progression of A549 human lung adenocarcinoma cells and the roles of Notch1, hypoxia-inducible factor 1α (HIF-α), and insulin-like growth factor 1 receptor (IGF-1R)/Akt/extracellular signal-regulated kinase (ERK)/p70 S6 kinase 1 (S6K1) signaling pathways. Exposing A549 cells to 10 or 20 μM cadmium chloride (CdCl2) for 9-15 weeks induced a high proliferative potential, the epithelial-mesenchymal transition (EMT), stress fiber formation, high cell motility, and resistance to anti-tumor drugs...
March 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28298159/biological-behavior-of-human-nucleus-pulposus-mesenchymal-stem-cells-in-response-to-changes-in-the-acidic-environment-during-intervertebral-disc-degeneration
#8
Jianjun Liu, Hui Tao, Cailiang Shen, Xiaoying Liu, Hanbang Wang, Fulong Dong, Renjie Zhang, Jie Li, Peng Ge, Peiwen Song, Huaqing Zhang, Peng Xu
An acidic environment is vital for the maintenance of cellular activities but can be affected tremendously during intervertebral disc degeneration. The effect of changes in the acidity of the environment on human nucleus pulposus mesenchymal stem cells (NP-MSCs) is unknown, however. Thus, this study aimed to observe the biological effects of acidic conditions mimicking a degenerated intervertebral disc on NP-MSCs in vitro. NP-MSCs were isolated from patients with lumbar disc herniation and were further identified by their immunophenotypes and multilineage differentiation...
March 16, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28297578/%C3%AE-elemene-selectively-inhibits-the-proliferation-of-glioma-stem-like-cells-through-the-downregulation-of-notch1
#9
Hai-Bin Feng, Jing Wang, Hao-Ran Jiang, Xin Mei, Yi-Ying Zhao, Fu-Rong Chen, Yue Qu, Ke Sai, Cheng-Cheng Guo, Qun-Ying Yang, Zong-Ping Zhang, Zhong-Ping Chen
Glioma is the most frequent primary central nervous system tumor. Although the current first-line medicine, temozolomide (TMZ), promotes patient survival, drug resistance develops easily. Thus, it is important to investigate novel therapeutic reagents to solidify the treatment effect. β-Elemene (bELE) is a compound from a Chinese herb whose anticancer effect has been shown in various types of cancer. However, its role in the inhibition of glioma stem-like cells (GSLCs) has not yet been reported. We studied both the in vitro and the in vivo inhibitory effect of bELE and TMZ in GSLCs and parental cells and their combined effects...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28292960/degrons-in-cancer
#10
REVIEW
Bálint Mészáros, Manjeet Kumar, Toby J Gibson, Bora Uyar, Zsuzsanna Dosztányi
Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes ~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons...
March 14, 2017: Science Signaling
https://www.readbyqxmd.com/read/28287551/temporal-ordering-of-dynamic-expression-data-from-detailed-spatial-expression-maps
#11
Charlotte S L Bailey, Robert A Bone, Philip J Murray, J Kim Dale
During somitogenesis, pairs of epithelial somites form in a progressive manner, budding off from the anterior end of the pre-somitic mesoderm (PSM) with a strict species-specific periodicity. The periodicity of the process is regulated by a molecular oscillator, known as the "segmentation clock," acting in the PSM cells. This clock drives the oscillatory patterns of gene expression across the PSM in a posterior-anterior direction. These so-called clock genes are key components of three signaling pathways: Wnt, Notch, and fibroblast growth factor (FGF)...
February 9, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28286920/blockade-of-notch-signaling-promotes-acetaminophen-induced-liver-injury
#12
Longfeng Jiang, Michael Ke, Shi Yue, Wen Xiao, Youde Yan, Xiaozhao Deng, Qi-Long Ying, Jun Li, Bibo Ke
Liver injury after experimental acetaminophen treatment is mediated both by direct hepatocyte injury through a P450-generated toxic metabolite and indirectly by activated liver Kupffer cells and neutrophils. This study was designed to investigate the role of Notch signaling in the regulation of innate immune responses in acetaminophen (APAP)-induced liver injury. Using a mouse model of APAP-induced liver injury, wild-type (WT) and toll-like receptor 4 knockout (TLR4 KO) mice were injected intraperitoneally with APAP or PBS...
March 13, 2017: Immunologic Research
https://www.readbyqxmd.com/read/28281438/engineered-microvasculature-in-pdms-networks-using-endothelial-cells-derived-from-human-induced-pluripotent-stem-cells
#13
Amogh Sivarapatna, Mahboobe Ghaedi, Yang Xiao, Edward Han, Binod Aryal, Jing Zhou, Carlos Fernandez-Hernando, Yibing Qyang, Karen K Hirschi, Laura E Niklason
In this study, we used a PDMS-based platform for the generation of intact, perfusioncompetent microvessel networks <i>in vitro</i>. COMSOL Multiphysics, a finite element analysis and simulation software package, was used to obtain simulated velocity, pressure, and shear stress profiles. Transgene-free human iPSCs were differentiated into partially arterialized endothelial cells (hiPSC-ECs) in 5 days under completely chemically defined conditions, using the small molecule GSK3β inhibitor CHIR99021 and thoroughly characterized for functionality and arteriallike marker expression...
March 9, 2017: Cell Transplantation
https://www.readbyqxmd.com/read/28280605/next-generation-sequencing-identifies-interactome-signatures-in-relapsed-and-refractory-metastatic-colorectal-cancer
#14
Benny Johnson, Laurence Cooke, Daruka Mahadevan
BACKGROUND: In the management of metastatic colorectal cancer (mCRC), KRAS, NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making. METHODS: Relapsed and refractory mCRC pts (N=32) were molecularly profiled utilizing commercially available next generation sequencing (NGS) platforms...
February 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28279221/notch-signaling-plays-a-crucial-role-in-cancer-stem-like-cells-maintaining-stemness-and-mediating-chemotaxis-in-renal-cell-carcinoma
#15
Wei Xiao, Zhiyong Gao, Yixing Duan, Wuxiong Yuan, Yang Ke
BACKGROUND: Cancer stem cells (CSCs) are correlated with the initiation, chemoresistance and relapse of tumors. Notch pathway has been reported to function in CSCs maintenance, but whether it is involved in renal cell carcinoma (RCC) CSCs maintaining stemness remain unclear. This study aims to explore the effect of Notch pathway on stemness of CSCs in RCC and the underlying mechanisms. METHODS: The CD133(+)/CD24(+) cells were isolated from RCC ACHN and Caki-1 cell line using Magnetic-activated cell sorting and identified by Flow cytometry analysis...
March 9, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28273100/chronically-dysregulated-notch1-interactome-in-the-dentate-gyrus-after-traumatic-brain-injury
#16
Noora Puhakka, Anna Maria Bot, Niina Vuokila, Konrad Jozef Debski, Katarzyna Lukasiuk, Asla Pitkänen
Traumatic brain injury (TBI) can result in several dentate gyrus-regulated disabilities. Almost nothing is known about the chronic molecular changes after TBI, and their potential as treatment targets. We hypothesized that chronic transcriptional alterations after TBI are under microRNA (miRNA) control. Expression of miRNAs and their targets in the dentate gyrus was analyzed using microarrays at 3 months after experimental TBI. Of 305 miRNAs present on the miRNA-array, 12 were downregulated (p<0.05). In parallel, 75 of their target genes were upregulated (p<0...
2017: PloS One
https://www.readbyqxmd.com/read/28272325/c-myc-induced%C3%A2-survivin%C3%A2-is%C3%A2-essential%C3%A2-for%C3%A2-promoting%C3%A2-the%C3%A2-notch-dependent%C3%A2-t%C3%A2-cell%C3%A2-differentiation%C3%A2-from%C3%A2-hematopoietic%C3%A2-stem%C3%A2-cells
#17
Rizwanul Haque, Jianyong Song, Mohammad Haque, Fengyang Lei, Praneet Sandhu, Bing Ni, Songguo Zheng, Deyu Fang, Jin-Ming Yang, Jianxun Song
Notch is indispensable for T cell lineage commitment, and is needed for thymocyte differentiation at early phases. During early stages of T cell development, active Notch prevents other lineage potentials including B cell lineage and myeloid cell (e.g., dendritic cell) lineage. Nevertheless, the precise intracellular signaling pathways by which Notch promotes T cell differentiation remain unclear. Here we report that the transcription factor c-Myc is a key mediator of the Notch signaling-regulated T cell differentiation...
March 6, 2017: Genes
https://www.readbyqxmd.com/read/28266574/notch1-signaling-contributes-to-hypoxia-induced-high-expression-of-integrin-%C3%AE-1-in-keratinocyte-migration
#18
Di Tang, Tiantian Yan, Junhui Zhang, Xupin Jiang, Dongxia Zhang, Yuesheng Huang
Oxygen tension is an important micro-environmental factor that affects epidermal development and function. After injury, high oxygen consumption and vascular injury result in partial hypoxia. However, whether hypoxia benefits or hurts wound healing remains controversial. In this study, a tissue oxygen tension monitor was used to detect the spatial and temporal distribution of oxygen in burn wounds. In vitro, we demonstrate that hypoxia promoted the expression of integrin β1 and the migration of keratinocytes...
March 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28263185/laminar-flow-downregulates-notch-activity-to-promote-lymphatic-sprouting
#19
Dongwon Choi, Eunkyung Park, Eunson Jung, Young Jin Seong, Jaehyuk Yoo, Esak Lee, Mingu Hong, Sunju Lee, Hiroaki Ishida, James Burford, Janos Peti-Peterdi, Ralf H Adams, Sonal Srikanth, Yousang Gwack, Christopher S Chen, Hans J Vogel, Chester J Koh, Alex K Wong, Young-Kwon Hong
The major function of the lymphatic system is to drain interstitial fluid from tissue. Functional drainage causes increased fluid flow that triggers lymphatic expansion, which is conceptually similar to hypoxia-triggered angiogenesis. Here, we have identified a mechanotransduction pathway that translates laminar flow-induced shear stress to activation of lymphatic sprouting. While low-rate laminar flow commonly induces the classic shear stress responses in blood endothelial cells and lymphatic endothelial cells (LECs), only LECs display reduced Notch activity and increased sprouting capacity...
March 6, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28260032/slit2-suppresses-endothelial-cell-proliferation-and-migration-by-inhibiting-the-vegf-notch-signaling-pathway
#20
Guo-Jian Li, Yong Yang, Guo-Kai Yang, Jia Wan, Dao-Lei Cui, Zhen-Huan Ma, Ling-Juan Du, Gui-Min Zhang
Slit homolog 2 (Slit2) is distributed in various tissues and participates in numerous cellular processes; however, the role of Slit2 in the regulation of angiogenesis remains controversial, since it has previously been reported to exert proangiogenic and antiangiogenic activities. The present study aimed to investigate the effects of Slit2 on vascular endothelial cell proliferation and migration in vitro, and to reveal the possible underlying signaling pathway. Aortic endothelial cells were isolated from Sprague Dawley rats and cultured...
February 22, 2017: Molecular Medicine Reports
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