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gamma secretase

Michael Rehman, Sreeharsha Gurrapu, Gabriella Cagnoni, Lorena Capparuccia, Luca Tamagnone
The secreted semaphorin Sema3E controls cell migration and invasiveness in cancer cells. Sema3E-receptor, PlexinD1, is frequently upregulated in melanoma, breast, colon, ovarian and prostate cancers; however, the mechanisms underlying PlexinD1 upregulation and the downstream events elicited in tumor cells are still unclear. Here we show that the canonical RBPjk-dependent Notch signaling cascade controls PlexinD1 expression in primary endothelial and cancer cells. Transcriptional activation was studied by quantitative PCR and promoter activity reporter assays...
2016: PloS One
Mark Y Chiang, Qing Wang, Anna C Gormley, Sarah J Stein, Lanwei Xu, Olga Shestova, Jon C Aster, Warren S Pear
Activating NOTCH1 mutations are frequent in human T-cell acute lymphoblastic leukemia (T-ALL) and Notch inhibitors (gamma-secretase inhibitors or GSI) have produced responses in patients with relapsed, refractory disease. However, sustained responses, while reported, are uncommon, suggesting other pathways can substitute for Notch in T-ALL. To address this possibility, we first generated Kras(G12D) transgenic mice with T-cell specific expression of the pan-Notch inhibitor, DNMAML. These mice developed leukemia, but instead of accessing alternative oncogenic pathways, the tumor cells acquired Notch1 mutations and subsequently deleted DNMAML, reinforcing the notion that activated Notch1 is particularly transforming within the context of T-cell progenitors...
September 26, 2016: Blood
Viola Lanier, Corey Gillespie, Merle Leffers, Danielle Daley-Brown, Joy Milner, Crystal Lipsey, Nia Webb, Leonard M Anderson, Gale Newman, Johannes Waltenberger, Ruben Rene Gonzalez-Perez
Leptin increases vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and Notch expression in cancer cells, and transphosphorylates VEGFR-2 in endothelial cells. However, the mechanisms involved in leptin's actions in endothelial cells are not completely known. Here we investigated whether a leptin-VEGFR-Notch axis is involved in these leptin's actions. To this end, human umbilical vein and porcine aortic endothelial cells (wild type and genetically modified to overexpress VEGFR-1 or -2) were cultured in the absence of VEGF and treated with leptin and inhibitors of Notch (gamma-secretase inhibitors: DAPT and S2188, and silencing RNA), VEGFR (kinase inhibitor: SU5416, and silencing RNA) and leptin receptor, OB-R (pegylated leptin peptide receptor antagonist 2: PEG-LPrA2)...
October 2016: International Journal of Biochemistry & Cell Biology
Rui D Mendes, Kirsten Canté-Barrett, Rob Pieters, Jules P P Meijerink
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT...
September 2016: Haematologica
Jiunn-Ren Wu, Jwu-Lai Yeh, Shu-Fen Liou, Zen-Kong Dai, Bin-Nan Wu, Jong-Hau Hsu
Patent ductus arteriosus (PDA) can cause morbidity and mortality in neonates. Vascular remodeling, characterized by proliferation and migration of smooth muscle cells (SMCs), is an essential process for postnatal DA closure. Notch signaling is an important mediator of vascular remodelling but its role in DA is unkonwn. We investigated the effects and underlying mechanisms of γ-secretase inhibitor DAPT, a Notch signaling inhibitor on angiotensin II (Ang II)-induced proliferation and migration of DASMCs. Proliferation and migration of DASMCs cultured from neonatal Wistar rats were induced by Ang II, with or without DAPT pre-treatment...
2016: International Journal of Biological Sciences
Paul B Rosenberg, Krista L Lanctôt, Nathan Herrmann, Jacobo E Mintzer, Anton P Porsteinsson, Xiaoying Sun, Rema Raman
BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD). OBJECTIVE: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). METHODS: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains)...
August 10, 2016: Journal of Alzheimer's Disease: JAD
Yasuyuki Ikezawa, Jun Sakakibara-Konishi, Hidenori Mizugaki, Satoshi Oizumi, Masaharu Nishimura
BACKGROUND: The Notch receptor plays an important role in various cell fate decisions during development and in cancer. We have previously reported that Notch3 is upregulated by radiation in non-small cell lung cancer (NSCLC) cell lines and that the Notch pathway inhibitor γ secretase inhibitor GSI (gamma-secretase inhibitor), when combined with radiation therapy, significantly suppressed the growth of lung cancer cells. However, little is known about the mechanism of Notch upregulation induced by radiation...
August 23, 2016: International Journal of Clinical Oncology
Imma Raurell, Montserrat Codina, David Casagolda, Beatriz Del Valle, Josep Baulida, Antonio García de Herreros, Mireia Duñach
[This corrects the article DOI: 10.1371/journal.pone.0004080.].
2016: PloS One
Noémi Nagy, Melinda Hajdu, Ágnes Márk, Péter Attila Király, Mónika Tóth, Titanilla Dankó, Mónika Csóka, Anna Sebestyén
Growing evidence suggests that deregulation of signalling elements of Notch and mammalian target of rapamycin (mTOR) pathways contribute to tumorigenesis. These signals play important roles in cellular functions and malignancies. Their tumorigenic role in T-cell acute lymphoblastic leukaemia (T-ALL) is well known; however, their potential interactions and functions are poorly characterized in Hodgkin lymphoma (HL). The aim of our study was to characterize mTOR and Notch signalling elements in HL cell lines (DEV, L1236, KMH2) and human biopsies and to investigate their cross-talk in the tumorous process...
July 29, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Kaushik Ghosal, Qingyuan Fan, Hana N Dawson, Sanjay W Pimplikar
Amyloid precursor protein (APP) is cleaved by gamma-secretase to simultaneously generate amyloid beta (Aβ) and APP Intracellular Domain (AICD) peptides. Aβ plays a pivotal role in Alzheimer's disease (AD) pathogenesis but recent studies suggest that amyloid-independent mechanisms also contribute to the disease. We previously showed that AICD transgenic mice (AICD-Tg) exhibit AD-like features such as tau pathology, aberrant neuronal activity, memory deficits and neurodegeneration in an age-dependent manner...
2016: PloS One
Kevin D Rynearson, Ronald N Buckle, Keith D Barnes, R Jason Herr, Nicholas J Mayhew, William D Paquette, Samuel A Sakwa, Phuong D Nguyen, Graham Johnson, Rudolph E Tanzi, Steven L Wagner
The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aβ42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds...
August 15, 2016: Bioorganic & Medicinal Chemistry Letters
Pawan Upadhyay, Sudhir Nair, Ekjot Kaur, Jyotirmoi Aich, Prachi Dani, Vidyalakshmi Sethunath, Nilesh Gardi, Pratik Chandrani, Mukul Godbole, Kavita Sonawane, Ratnam Prasad, Sadhana Kannan, Beamon Agarwal, Shubhada Kane, Sudeep Gupta, Shilpee Dutt, Amit Dutt
BACKGROUND: Notch pathway plays a complex role depending on cellular contexts: promotes stem cell maintenance or induces terminal differentiation in potential cancer-initiating cells; acts as an oncogene in lymphocytes and mammary tissue or plays a growth-suppressive role in leukemia, liver, skin, and head and neck cancer. Here, we present a novel clinical and functional significance of NOTCH1 alterations in early stage tongue squamous cell carcinoma (TSCC). PATIENTS AND METHODS: We analyzed the Notch signaling pathway in 68 early stage TSCC primary tumor samples by whole exome and transcriptome sequencing, real-time PCR based copy number, expression, immuno-histochemical, followed by cell based biochemical and functional assays...
July 6, 2016: Oncotarget
Siladitta Biswas, Monica Adrian, Jochen Weber, Konstantin Evdokimov, Manuel Winkler, Cyrill Géraud
Leda-1/Pianp is a type I transmembrane protein expressed by CNS cells, murine melanoma cell line B16F10 and rat liver sinusoidal endothelial cells. The early steps of posttranslational modifications of Leda-1/Pianp have been described to include glycosylation and processing by proprotein convertases. Here, we comprehensively characterized the subsequent steps of proteolytic processing of Leda-1/Pianp. For this purpose specific protease inhibitors and cell lines deficient in PS1, PS2, PS1/PS2 and ADAM10/17 were deployed...
September 2, 2016: Biochemical and Biophysical Research Communications
Lizandra G Magalhães, Enyara R Morais, Carla B Machado, Matheus S Gomes, Fernanda J Cabral, Julia M Souza, Cláudia S Soares, Renata G Sá, William Castro-Borges, Vanderlei Rodrigues
Several signaling molecules that govern development in higher animals have been identified in the parasite Schistosoma mansoni, including the transforming growth factor β, protein tyrosine kinases, nuclear hormone receptors, among others. The Notch pathway is a highly conserved signaling mechanism which is involved in a wide variety of developmental processes including embryogenesis and oogenesis in worms and flies. Here we aimed to provide the molecular reconstitution of the Notch pathway in S. mansoni using the available transcriptome and genome databases...
October 2016: Parasitology Research
Alejandro Villarreal, Gerardo Rosciszewski, Veronica Murta, Vanesa Cadena, Vanina Usach, Martin M Dodes-Traian, Patricia Setton-Avruj, Luis H Barbeito, Alberto J Ramos
UNLABELLED: Reactive gliosis involving activation and proliferation of astrocytes and microglia, is a widespread but largely complex and graded glial response to brain injury. Astroglial population has a previously underestimated high heterogeneity with cells differing in their morphology, gene expression profile, and response to injury. Here, we identified a subset of reactive astrocytes isolated from brain focal ischemic lesions that show several atypical characteristics. Ischemia-derived astrocytes (IDAs) were isolated from early ischemic penumbra and core...
2016: Frontiers in Cellular Neuroscience
Eugene Futai
No abstract text is available yet for this article.
April 2016: Seikagaku. the Journal of Japanese Biochemical Society
Holly D Soares, Maciej Gasior, Jeremy H Toyn, Jun-Sheng Wang, Quan Hong, Flora Berisha, Michael T Furlong, Joseph Raybon, Kimberley A Lentz, Francis Sweeney, Naiyu Zheng, Billy Akinsanya, Robert M Berman, Lorin A Thompson, Richard E Olson, John Morrison, Dieter M Drexler, John E Macor, Charlie F Albright, Michael K Ahlijanian, Malaz AbuTarif
The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a γ-secretase modulator (GSM), were tested in healthy young and elderly volunteers after single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality after a single dose administration, and had approximately 3-fold accumulation after multiple dosing. High-fat/caloric meals doubled the Cmax and area under the curve and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) Aβ39, Aβ40, and Aβ42 while increasing Aβ37 and Aβ38, thereby providing evidence of γ-secretase enzyme modulation rather than inhibition...
July 2016: Journal of Pharmacology and Experimental Therapeutics
Mark A Lovell, Bert C Lynn, Shuling Fister, Melissa Bradley-Whitman, M Paul Murphy, Tina L Beckett, Christopher M Norris
Because traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics...
May 4, 2016: Journal of Alzheimer's Disease: JAD
P Bernasconi-Elias, T Hu, D Jenkins, B Firestone, S Gans, E Kurth, P Capodieci, J Deplazes-Lauber, K Petropoulos, P Thiel, D Ponsel, S Hee Choi, P LeMotte, A London, M Goetcshkes, E Nolin, M D Jones, K Slocum, M J Kluk, D M Weinstock, A Christodoulou, O Weinberg, J Jaehrling, S A Ettenberg, A Buckler, S C Blacklow, J C Aster, C J Fryer
Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST (proline, glutamate, serine, threonine) domain coding regions of NOTCH3 in a panel of cell lines...
May 9, 2016: Oncogene
Ran Xu, Fumiko Shimizu, Koos Hovinga, Kathryn Beal, Sasan Karimi, Leif A Droms, Kyung K Peck, Philip Gutin, J Bryan Iorgulescu, Thomas J Kaley, Lisa M DeAngelis, Elena Pentsova, Craig Nolan, Christian Grommes, Timothy A Chan, Dylan Bobrow, Adilia Hormigo, Justin R Cross, Nian Wu, Naoko Takebe, Katherine Panageas, S Percy Ivy, Jeffrey G Supko, Viviane Tabar, Antonio M P Omuro
BACKGROUND: High grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO2929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed anti-angiogenic role. METHODS: In this phase 0/I trial, 21 patients with newly-diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the maximum tolerated dose, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuro-imaging parameters...
May 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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