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gamma secretase

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https://www.readbyqxmd.com/read/28922471/a-phenotype-combining-hidradenitis-suppurativa-with-dowling-degos-disease-caused-by-a-founder-mutation-in-psenen
#1
M Pavlovsky, O Sarig, M Eskin-Schwartz, N Malchin, R Bochner, J Mohamad, A Gat, A Peled, A Hafner, E Sprecher
Dowling-Degos disease, featuring reticulate pigmentation, and familial hidradenitis suppurativa share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The co-existence of the two disorders was recently found to result from mutations in PSENEN, encoding protein presenilin enhancer gamma-secretase subunit. Here we report 4 additional families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c...
September 18, 2017: British Journal of Dermatology
https://www.readbyqxmd.com/read/28920078/notch1-activation-depletes-the-pool-of-side-population-stem-cells-in-atl
#2
Xue Tao Bai, Chien-Hung Yeh, Christophe Nicot
BACKGROUND: HTLV-I infection is associated with the development of adult T-cell leukemia (ATL), a malignancy characterized by a high rate of disease relapse and poor survival. Previous studies reported the existence of side population (SP) cells in HTLV-I Tax transgenic mouse models. These studies showed that these ATL-like derived SP cells have both self-renewal and leukemia renewal capacity and represent Cancer Stem Cells (CSC)/Leukemia-Initiating Cells (LIC). Since CSC/LIC are resistant to conventional therapies, a better characterization is needed...
June 2017: Journal of Cancer Sciences
https://www.readbyqxmd.com/read/28919280/soluble-gamma-secretase-modulators-attenuate-alzheimer-s-%C3%AE-amyloid-pathology-and-induce-conformational-changes-in-presenilin-1
#3
Frank Raven, Joseph F Ward, Katarzyna M Zoltowska, Yu Wan, Enjana Bylykbashi, Sean J Miller, Xunuo Shen, Se Hoon Choi, Kevin D Rynearson, Oksana Berezovska, Steven L Wagner, Rudolph E Tanzi, Can Zhang
A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations...
September 4, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28904208/genome-wide-screen-of-gamma-secretase-mediated-intramembrane-cleavage-of-receptor-tyrosine-kinases
#4
Johannes A M Merilahti, Veera K Ojala, Anna M Knittle, Arto T Pulliainen, Klaus Elenius
Receptor tyrosine kinases (RTK) have been demonstrated to signal via regulated intramembrane proteolysis (RIP), in which ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular receptor fragment with functional activity. For most RTKs, however, it is not known whether they can exploit this new signaling mechanism or not. Here we used a system-wide screen to address the frequency of susceptibility to gamma-secretase cleavage among human RTKs. The screen covering 45 of the 55 human RTKs identified 12 new as well as all 9 previously published gamma-secretase substrates...
September 13, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28887726/long-term-follow-up-of-desmoid-fibromatosis-treated-with-pf-03084014-an-oral-gamma-secretase-inhibitor
#5
Victor Manuel Villalobos, Francis Hall, Antonio Jimeno, Lia Gore, Kenneth Kern, Rossano Cesari, Bo Huang, Jeffrey T Schowinsky, Patrick Judson Blatchford, Brianna Hoffner, Anthony Elias, Wells Messersmith
BACKGROUND: Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in β-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral gamma secretase inhibitor, PF-03084014. METHODS: PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9...
September 8, 2017: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/28842505/the-glycosyltransferase-gnt-iii-activates-notch-signaling-and-drives-stem-cell-expansion-to-promote-the-growth-and-invasion-of-ovarian-cancer
#6
Heba Allam, Blake P Johnson, Mao Zhang, Zhongpeng Lu, Martin J Cannon, Karen L Abbott
Glycosylation changes associated with cellular transformation can facilitate the growth and progression of tumors. Previously we discovered that the gene Mgat3 encoding the glycosyltransferase GnT-III is elevated in epithelial ovarian carcinomas (EOC) and leads to the production of abnormal truncated N-linked glycan structures. In this study we are interested in discovering how these abnormal glycans impact the growth and progression of ovarian cancer. We have discovered using stable shRNA gene suppression that GnT-III expression controls the expansion of side-population cells or cancer stem cells...
August 23, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28829038/dual-control-of-pcdh8l-pcns-expression-and-function-in-xenopus-laevis-neural-crest-cells-by-adam13-33-via-the-transcription-factors-tfap2%C3%AE-and-arid3a
#7
Vikram Khedgikar, Genevieve Abbruzzese, Ketan Mathavan, Hannah Szydlo, Helene Cousin, Dominique Alfandari
Adam13/33 is a cell surface metalloprotease critical for cranial neural crest (CNC) cell migration. It can cleave multiple substrates including itself, fibronectin, ephrinB, cadherin-11, pdh8 and pcdh8l (this work). Cleavage of cadherin-11 produces an extracellular fragment that promotes CNC migration. In addition the adam13 cytoplasmic domain is cleaved by gamma secretase, translocates into the nucleus and regulates multiple genes. Here we show that adam13 interacts with the arid3a/dril1/Bright transcription factor...
August 22, 2017: ELife
https://www.readbyqxmd.com/read/28790170/dimerization-of-the-transmembrane-domain-of-amyloid-precursor-protein-is-determined-by-residues-around-the-gamma-secretase-cleavage-sites
#8
Yan Yan, Ting-Hai Xu, Kaleeckal G Harikumar, Laurence J Miller, Karsten Melcher, H Eric Xu
One of the hallmarks of Alzheimer's disease (AD) is the formation of extracellular amyloid plaques that consist mainly of abnormally aggregated forms of amyloid β (Aβ) peptides. These peptides are generated by γ-secretase-catalyzed cleavage of a dimeric membrane-bound C-terminal fragment (C99) of the amyloid precursor protein (APP). While C99 homodimerization has been linked to Aβ; production and changes in the aggregation-determining Aβ42/Aβ40 ratio, the motif through which C99 dimerizes has remained controversial...
August 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28769027/synergistic-effect-of-notch-3-specific-inhibition-and-paclitaxel-in-non-small-cell-lung-cancer-nsclc-cells-via-activation-of-the-intrinsic-apoptosis-pathway
#9
Fenglian He, Ting Du, Qian Jiang, Yanbei Zhang
BACKGROUND Lung cancers are resistant to conventional chemotherapeutic interventions such as paclitaxel. Notch signaling is crucial in the chemoresistance of lung cancer cells. The Notch inhibitor gamma-secretase inhibitor (GSI) inhibits the Notch signaling pathway. MATERIAL AND METHODS Here, we evaluated how Notch-3 inhibition by GSI can enhance the sensitivity of lung cancer cells to paclitaxel. To study how Notch-3-specific inhibition affects non-small cell lung cancer (NSCLC), we compared the cell viability, apoptosis, and colony formation of A549 and H1299 cells treated with Notch-3 siRNA and GSI...
August 3, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28762604/tmeff2-shedding-is-regulated-by-oxidative-stress-and-mediated-by-adams-and-transmembrane-serine-proteases-implicated-in-prostate-cancer
#10
Katarzyna Gaweł-Bęben, Nazim Ali, Vincent Ellis, Gloria Velasco, Zaruhi Poghosyan, Ann Ager, Vera Knäuper
TMEFF2 is a type I transmembrane protein with two follistatin (FS) and one EGF-like domain over-expressed in prostate cancer; however its biological role in prostate cancer development and progression remains unclear, which may, at least in part, be explained by its proteolytic processing. The extracellular part of TMEFF2 (TMEFF2-ECD) is cleaved by ADAM17 and the membrane-retained fragment is further processed by the gamma-secretase complex. TMEFF2 shedding is increased with cell crowding, a condition associated with the tumour microenvironment, which was mediated by oxidative stress signalling, requiring jun-kinase (JNK) activation...
August 1, 2017: Cell Biology International
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
#11
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/28735867/cleavage-of-the-interleukin-11-receptor-induces-processing-of-its-c-terminal-fragments-by-the-gamma-secretase-and-the-proteasome
#12
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...
September 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28630497/chronic-treatment-with-a-smart-antioxidative-nanoparticle-for-inhibition-of-amyloid-plaque-propagation-in-tg2576-mouse-model-of-alzheimer-s-disease
#13
Phetcharat Boonruamkaew, Pennapa Chonpathompikunlert, Long Binh Vong, Sho Sakaue, Yasushi Tomidokoro, Kazuhiro Ishii, Akira Tamaoka, Yukio Nagasaki
The present study aimed to assess whether our newly developed redox nanoparticle (RNP(N)) that has antioxidant potential decreases Aβ levels or prevents Aβ aggregation associated with oxidative stress. The transgenic Tg2576 Alzheimer's disease (AD) mice were used to investigate the effect of chronic ad libitum drinking of RNP(N) solution for 6 months, including memory and learning functions, antioxidant activity, and amyloid plaque aggregation. The results showed that RNP(N)-treated mice had significantly attenuated cognitive deficits of both spatial and non-spatial memories, reduced oxidative stress of lipid peroxide, and DNA oxidation...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28607007/synergistic-activity-with-notch-inhibition-and-androgen-ablation-in-erg-positive-prostate-cancer-cells
#14
Ahmed A Mohamed, Shyh-Han Tan, Charles P Xavier, Shilpa Katta, Wei Huang, Lakshmi Ravindranath, Muhammad Jamal, Hua Li, Meera Srivastava, Eri S Srivatsan, Taduru L Sreenath, David G McLeod, Alagarsamy Srinivasan, Gyorgy Petrovics, Albert Dobi, Shiv Srivastava
The oncogenic activation of the ETS-related gene (ERG) due to gene fusions is present in over half of prostate cancers in Western countries. Because of its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for prostate cancer. Utilizing gene expression datasets, from matched normal and prostate tumor epithelial cells, an association of NOTCH transcription factors with ERG expression status was identified, confirming that NOTCH factors are direct transcriptional targets of ERG...
June 12, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28574782/rna-based-ovarian-cancer-research-from-a-gene-to-systems-biomedicine-perspective
#15
Esra Gov, Medi Kori, Kazim Yalcin Arga
Ovarian cancer remains the leading cause of death from a gynecologic malignancy, and treatment of this disease is harder than any other type of female reproductive cancer. Improvements in the diagnosis and development of novel and effective treatment strategies for complex pathophysiologies, such as ovarian cancer, require a better understanding of disease emergence and mechanisms of progression through systems medicine approaches. RNA-level analyses generate new information that can help in understanding the mechanisms behind disease pathogenesis, to identify new biomarkers and therapeutic targets and in new drug discovery...
August 2017: Systems Biology in Reproductive Medicine
https://www.readbyqxmd.com/read/28460541/why-do-trials-for-alzheimer-s-disease-drugs-keep-failing-a-discontinued-drug-perspective-for-2010-2015
#16
Dev Mehta, Robert Jackson, Gaurav Paul, Jiong Shi, Marwan Sabbagh
There are dozens of drugs in development for AD with billions of dollars invested. Despite the massive investment in AD drugs and a burgeoning pipeline, there have been more setbacks and failures than treatment successes. Areas covered: The classes of drugs that have failed to date include the monoclonal antibodies, the gamma secretase inhibitors, dimebon, neurochemical enhancers, and one tau drug. Data for these compounds were sought through a PubMed search and a clinicaltrials.gov search. Expert opinion: The obvious question to be posed is: Why are they failing? Is the treatment of symptomatic dementia too late? Are the therapeutic targets incorrect? Are the clinical methodologies imprecise, misleading, or inaccurate? This review summarizes the drugs that have failed during 2010-2015 and offers possible theories as to why they have failed...
June 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28423318/oligodendrocyte-nf1-controls-aberrant-notch-activation-and-regulates-myelin-structure-and-behavior
#17
Alejandro López-Juárez, Haley E Titus, Sadiq H Silbak, Joshua W Pressler, Tilat A Rizvi, Madeleine Bogard, Michael R Bennett, Georgianne Ciraolo, Michael T Williams, Charles V Vorhees, Nancy Ratner
The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene (Nf1) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1 gene-dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen-activated protein kinase (MAPK), or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild-type (WT) mice...
April 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28416488/activation-of-notch-signaling-by-tenascin-c-promotes-growth-of-human-brain-tumor-initiating-cells
#18
Susobhan Sarkar, Reza Mirzaei, Franz J Zemp, Wu Wei, Donna L Senger, Stephen M Robbins, V Wee Yong
Oncogenic signaling by NOTCH is elevated in brain tumor-initiating cells (BTIC) in malignant glioma, but the mechanism of its activation is unknown. Here we provide evidence that tenascin-C (TNC), an extracellular matrix protein prominent in malignant glioma, increases NOTCH activity in BTIC to promote their growth. We demonstrate the proximal localization of TNC and BTIC in human glioblastoma specimens and in orthotopic murine xenografts of human BTIC implanted intracranially. In tissue culture, TNC was superior amongst several extracellular matrix proteins in enhancing the sphere-forming capacity of glioma patient-derived BTIC...
June 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28415816/targeting-the-pim-protein-kinases-for-the-treatment-of-a-t-cell-acute-lymphoblastic-leukemia-subset
#19
Sathish K R Padi, Libia A Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H Song, Jon C Aster, Xue-Zhong Yu, Shikhar Mehrotra, Andrew S Kraft
New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414207/defining-the-minimum-substrate-and-charge-recognition-model-of-gamma-secretase
#20
Yan Yan, Ting-Hai Xu, Karsten Melcher, H Eric Xu
γ-Secretase is an intramembrane aspartyl protease that cleaves the C99 fragment of amyloid precursor protein to generate extracellular Aβ peptides. These peptides can oligomerize and aggregate to form amyloid plaques, processes that are widely believed to be causal for Alzheimer's disease. In spite of this critical function, it remains unknown how γ-secretase recognizes C99 and its other substrates, including Notch. In this study we determined E22-K55 as the minimal C99 fragment that was sufficient and required for initial cleavage...
April 17, 2017: Acta Pharmacologica Sinica
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