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https://www.readbyqxmd.com/read/28492364/na-influx-via-orai1-inhibits-intracellular-atp-induced-mtorc2-signaling-to-disrupt-cd4-t-cell-gene-expression-and-differentiation
#1
Yong Miao, Jaya Bhushan, Adish Dani, Monika Vig
T cell effector functions require sustained calcium influx. However, the signaling and phenotypic consequences of non-specific sodium permeation via calcium channels remain unknown. α-SNAP is a crucial component of Orai1 channels, and its depletion disrupts the functional assembly of Orai1 multimers. Here we show that α-SNAP hypomorph, hydrocephalos with hopping gait, Napa(hyh/hyh) mice harbor significant defects in CD4 T cell gene expression and Foxp3 regulatory T cell (Treg) differentiation. Mechanistically, TCR stimulation induced rapid sodium influx in Napa(hyh/hyh) CD4 T cells, which reduced intracellular ATP, [ATP]i...
May 11, 2017: ELife
https://www.readbyqxmd.com/read/28489822/traf2-and-otud7b-govern-a-ubiquitin-dependent-switch-that-regulates-mtorc2-signalling
#2
Bin Wang, Zuliang Jie, Donghyun Joo, Alban Ordureau, Pengda Liu, Wenjian Gan, Jianping Guo, Jinfang Zhang, Brian J North, Xiangpeng Dai, Xuhong Cheng, Xiuwu Bian, Lingqiang Zhang, J Wade Harper, Shao-Cong Sun, Wenyi Wei
The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways. mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer. Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells...
May 10, 2017: Nature
https://www.readbyqxmd.com/read/28475179/mtorc1-independent-autophagy-regulates-receptor-tyrosine-kinase-phosphorylation-in-colorectal-cancer-cells-via-an-mtorc2-mediated-mechanism
#3
Aikaterini Lampada, James O'Prey, Gyorgy Szabadkai, Kevin M Ryan, Daniel Hochhauser, Paolo Salomoni
The intracellular autophagic degradative pathway can have a tumour suppressive or tumour-promoting role depending on the stage of tumour development. Upon starvation or targeting of oncogenic receptor tyrosine kinases (RTKs), autophagy is activated owing to the inhibition of PI3K/AKT/mTORC1 signalling pathway and promotes survival, suggesting that autophagy is a relevant therapeutic target in these settings. However, the role of autophagy in cancer cells where the PI3K/AKT/mTORC1 pathway is constitutively active remains partially understood...
June 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28468668/proteomic-anaysis-of-aged-microglia-shifts-in-transcription-bioenergetics-and-nutrient-response
#4
Antwoine Flowers, Harris Bell-Temin, Ahmad Jalloh, Stanley M Stevens, Paula C Bickford
BACKGROUND: Age is the primary risk factor for many diseases. As such, age is a critical co-factor for examination in order to understand the progression and potential intervention in disease progression. Studies examining both the phenotype and transcriptome of aged microglia demonstrated a propensity for the development of a pro-inflammatory phenotype. Less well studied is the concomitant blunting of anti-inflammatory aspects of microglial function with age which also impact plasticity and repair in the CNS...
May 3, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28467426/pkb%C3%AE-akt3-loss-of-function-causes-learning-and-memory-deficits-and-deregulation-of-akt-mtorc2-signaling-relevance-for-schizophrenia
#5
Kristy R Howell, Kirsten Floyd, Amanda J Law
Psychiatric genetic studies have identified genome-wide significant loci for schizophrenia. The AKT3/1q44 locus is a principal risk region and gene-network analyses identify AKT3 polymorphisms as a constituent of several neurobiological pathways relevant to psychiatric risk; the neurobiological mechanisms remain unknown. AKT3 shows prenatal enrichment during human neocortical development and recurrent copy number variations involving the 1q43-44 locus are associated with cortical malformations and intellectual disability, implicating an essential role in early brain development...
2017: PloS One
https://www.readbyqxmd.com/read/28464351/mtorc2-regulates-muscle-glucose-uptake-during-exercise-in-mice
#6
Maximilian Kleinert, Benjamin L Parker, Andreas M Fritzen, Jonas R Knudsen, Thomas E Jensen, Rasmus Kjøbsted, Lykke Sylow, Markus Ruegg, David E James, Erik A Richter
Exercise increases glucose uptake into insulin-resistant muscle. Thus, elucidating the exercise signalling network in muscle may uncover new therapeutic targets. mTORC2, a regulator of insulin-controlled glucose uptake, has been reported to interact with Rac1, which plays a role in exercise-induced glucose uptake in muscle. Therefore, we tested the hypothesis that mTORC2 activity is necessary for muscle glucose uptake during treadmill exercise. We used mice that specifically lack mTORC2 signalling in muscle, by deletion of the obligatory mTORC2 component, Rictor (Ric mKO)...
May 2, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28462079/loss-of-hepatic-deptor-alters-the-metabolic-transition-to-fasting
#7
Alexandre Caron, Mathilde Mouchiroud, Nicolas Gautier, Sébastien M Labbé, Romain Villot, Laurie Turcotte, Blandine Secco, Guillaume Lamoureux, Michael Shum, Yves Gélinas, André Marette, Denis Richard, David M Sabatini, Mathieu Laplante
OBJECTIVE: The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulates growth and metabolism. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to reduce their activity. Whether DEPTOR loss affects metabolism and organismal growth in vivo has never been tested. METHODS: We have generated a conditional transgenic mouse allowing the tissue-specific deletion of DEPTOR...
May 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28462076/acid-sphingomyelinase-deficiency-in-western-diet-fed-mice-protects-against-adipocyte-hypertrophy-and-diet-induced-liver-steatosis
#8
Svenja Sydor, Jan-Peter Sowa, Dominik A Megger, Martin Schlattjan, Sami Jafoui, Lena Wingerter, Alexander Carpinteiro, Hideo A Baba, Lars P Bechmann, Barbara Sitek, Guido Gerken, Erich Gulbins, Ali Canbay
OBJECTIVE: Alterations in sphingolipid and ceramide metabolism have been associated with various diseases, including nonalcoholic fatty liver disease (NAFLD). Acid sphingomyelinase (ASM) converts the membrane lipid sphingomyelin to ceramide, thereby affecting membrane composition and domain formation. We investigated the ways in which the Asm knockout (Smpd1(-/-)) genotype affects diet-induced NAFLD. METHODS: Smpd1(-/-) mice and wild type controls were fed either a standard or Western diet (WD) for 6 weeks...
May 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28461391/host-serine-threonine-kinases-mtor-and-protein-kinase-c-%C3%AE-promote-inlb-mediated-entry-of-listeria-monocytogenes
#9
Manmeet Bhalla, Daria Law, Georgina C Dowd, Keith Ireton
The bacterial pathogen Listeria monocytogenes causes food-borne illnesses resulting in gastroenteritis, meningitis, or abortion. Listeria induces its internalization into some human cells through interaction of the bacterial surface protein InlB with the host receptor tyrosine kinase Met. InlB-dependent entry requires localized polymerization of the host actin cytoskeleton. Signal transduction pathways that act downstream of Met to regulate actin filament assembly or other processes during Listeria uptake remain incompletely characterized...
May 1, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28453552/specific-blockade-of-rictor-mtor-association-inhibits-mtorc2-activity-and-is-cytotoxic-in-glioblastoma
#10
Angelica Benavides-Serrato, Jihye Lee, Brent Holmes, Kenna A Landon, Tariq Bashir, Michael E Jung, Alan Lichtenstein, Joseph Gera
A small molecule which specifically blocks the interaction of Rictor and mTOR was identified utilizing a high-throughput yeast two-hybrid screen and evaluated as a potential inhibitor of mTORC2 activity in glioblastoma multiforme (GBM). In vitro, CID613034 inhibited mTORC2 kinase activity at submicromolar concentrations and in cellular assays specifically inhibited phosphorylation of mTORC2 substrates, including AKT (Ser-473), NDRG1 (Thr-346) and PKCα (Ser-657), while having no appreciable effects on the phosphorylation status of the mTORC1 substrate S6K (Thr-389) or mTORC1-dependent negative feedback loops...
2017: PloS One
https://www.readbyqxmd.com/read/28445935/inhibition-of-mtorc2-component-rictor-impairs-tumor-growth-in-pancreatic-cancer-models
#11
Katharina M Schmidt, Claus Hellerbrand, Petra Ruemmele, Christoph W Michalski, Bo Kong, Alexander Kroemer, Christina Hackl, Hans J Schlitt, Edward K Geissler, Sven A Lang
Mammalian Target of Rapamycin complex 2 (mTORC2) and its regulatory component Rapamycin-insensitive companion of mTOR (RICTOR) are increasingly recognized as important players in human cancer development and progression. However, the role of RICTOR in human pancreatic ductal adenocarcinoma (PDAC) is unclear so far. Here, we sought to analyze the effects of RICTOR inhibition in human pancreatic cancer cell lines in vitro and in vivo. Furthermore, RICTOR expression was determined in human PDAC samples. Results demonstrate that depletion of RICTOR with siRNA (transient knock-down) or shRNA (stable knock-down) has an inhibitory effect on tumor growth in vitro...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28437526/prominin-1-is-a-novel-regulator-of-autophagy-in-the-human-retinal-pigment-epithelium
#12
Sujoy Bhattacharya, Jinggang Yin, Christina S Winborn, Qiuhua Zhang, Junming Yue, Edward Chaum
Purpose: Prominin-1 (Prom1) is a transmembrane glycoprotein, which is expressed in stem cell lineages, and has recently been implicated in cancer stem cell survival. Mutations in the Prom1 gene have been shown to disrupt photoreceptor disk morphogenesis and cause an autosomal dominant form of Stargardt-like macular dystrophy (STGD4). Despite the apparent structural role of Prom1 in photoreceptors, its role in other cells of the retina is unknown. The purpose of this study is to investigate the role of Prom1 in the highly metabolically active cells of the retinal pigment epithelium (RPE)...
April 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28435021/the-mtorc2-pkc-pathway-sustains-compensatory-insulin-secretion-of-pancreatic-%C3%AE-cells-in-response-to-metabolic-stress
#13
Yun Xie, Canqi Cui, Aifang Nie, Yan Wang, Qicheng Ni, Yun Liu, Qinglei Yin, Hongli Zhang, Yong Li, Qidi Wang, Yanyun Gu, Guang Ning
BACKGROUND: Compensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation. METHODS: We challenged four-week-old β-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4weeks and measured metabolic and pancreatic morphological parameters...
April 20, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28434143/the-mtor-signaling-pathway-in-myocardial-dysfunction-in-type-2-diabetes-mellitus
#14
REVIEW
Tomohiro Suhara, Yuichi Baba, Briana K Shimada, Jason K Higa, Takashi Matsui
PURPOSE OF REVIEW: T2DM (type 2 diabetes mellitus) is a risk factor for heart failure. The mTOR (mechanistic target of rapamycin) is a key mediator of the insulin signaling pathway. We will discuss the role of mTOR in myocardial dysfunction in T2DM. RECENT FINDINGS: In T2DM, chronically activated mTOR induces multiple pathological events, including a negative feedback loop that suppresses IRS (insulin receptor substrate)-1. While short-term treatment with rapamycin, an mTOR inhibitor, is a promising strategy for cardiac diseases such as acute myocardial infarction and cardiac hypertrophy in T2DM, there are many concerns about chronic usage of rapamycin...
June 2017: Current Diabetes Reports
https://www.readbyqxmd.com/read/28429706/direct-comparison-of-distinct-naive-pluripotent-states-in-human-embryonic-stem-cells
#15
S Warrier, M Van der Jeught, G Duggal, L Tilleman, E Sutherland, J Taelman, M Popovic, S Lierman, S Chuva De Sousa Lopes, A Van Soom, L Peelman, F Van Nieuwerburgh, D I M De Coninck, B Menten, P Mestdagh, J Van de Sompele, D Deforce, P De Sutter, B Heindryckx
Until recently, human embryonic stem cells (hESCs) were shown to exist in a state of primed pluripotency, while mouse embryonic stem cells (mESCs) display a naive or primed pluripotent state. Here we show the rapid conversion of in-house-derived primed hESCs on mouse embryonic feeder layer (MEF) to a naive state within 5-6 days in naive conversion media (NCM-MEF), 6-10 days in naive human stem cell media (NHSM-MEF) and 14-20 days using the reverse-toggle protocol (RT-MEF). We further observe enhanced unbiased lineage-specific differentiation potential of naive hESCs converted in NCM-MEF, however, all naive hESCs fail to differentiate towards functional cell types...
April 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28421341/insufficient-activation-of-akt-upon-reperfusion-because-of-its-novel-modification-by-reduced-pp2a-b55%C3%AE-contributes-to-enlargement-of-infarct-size-by-chronic-kidney-disease
#16
Toshiyuki Tobisawa, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Yukishige Kimura, Satoko Ishikawa, Hidemichi Kouzu, Keitaro Nishizawa, Hideaki Yoshida, Tetsuji Miura
Chronic kidney disease (CKD) increases myocardial infarct size by an unknown mechanism. Here we examined the hypothesis that impairment of protective PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6 nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and sham-operated rats served as controls (Sham group). Infarct size as a percentage of area at risk after ischemia/reperfusion was significantly larger in the SNx group than in the Sham group (56...
May 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28417246/mammalian-target-of-rapamycin-mtor-as-a-potential-therapeutic-target-in-various-diseases
#17
REVIEW
Avileen Kaur, Saurabh Sharma
Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that belongs to Phosphatidylinositol-3-kinase related kinase superfamily. The signaling pathways of mTOR are integrated through the protein complexes of mTORC1 and mTORC2. mTORC1 controls protein synthesis, cell growth, proliferation, autophagy, cell metabolism, and stress responses, whereas mTORC2 seems to regulate cell survival and polarity. Dysregulation of the mTOR pathway has been implicated in the pathophysiology of a number of disease conditions, including cancer, cardiovascular, neurodegenerative, and various renal diseases...
June 2017: Inflammopharmacology
https://www.readbyqxmd.com/read/28410220/reprogramming-induced-by-isoliquiritigenin-diminishes-melanoma-cachexia-through-mtorc2-akt-gsk3%C3%AE-signaling
#18
Xiao-Yu Chen, De-Fang Li, Ji-Chun Han, Bo Wang, Zheng-Ping Dong, Li-Na Yu, Zhao-Hai Pan, Chuan-Jun Qu, Ying Chen, Shi-Guo Sun, Qiu-Sheng Zheng
Isoliquiritigenin (ISL), a member of the flavonoids, is known to have anti-tumor activity in vitro and in vivo. The effect of ISL on reprogramming in cancer cells, however, remains elusive. In this study, we investigated the effect of ISL on reprogramming in human melanoma A375 cells. ISL (15 μg/ml) significantly inhibited A375 cell proliferation, anchorage independent cell proliferation and G2/M cell cycle arrest after ISL exposure for 24 h. However, there were no significant changes in apoptosis rate. Terminal differentiation indicators (melanin content, melanogenesis mRNA expression, tyrosinase (TYR) activity) were all up-regulated by ISL treatment...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404914/the-preclinical-assessment-of-xl388-a-mtor-kinase-inhibitor-as-a-promising-anti-renal-cell-carcinoma-agent
#19
Zuquan Xiong, Yiwen Zang, Shan Zhong, Lujia Zou, Yishuo Wu, Shenghua Liu, Zujun Fang, Zhoujun Shen, Qiang Ding, Shanwen Chen
XL388 is a mammalian target of rapamycin (mTOR) kinase inhibitor. We demonstrated that XL388 inhibited survival and proliferation of renal cell carcinoma (RCC) cell lines (786-0 and A549) and primary human RCC cells. XL388 activated caspase-dependent apoptosis in the RCC cells. XL388 blocked mTOR complex 1 (mTORC1) and mTORC2 activation, and depleted hypoxia-inducible factor 1α (HIF1α) and HIF-2α expression in RCC cells. Yet, XL388 was ineffective in RCC cells with mTOR shRNA knockdown or kinase-dead mutation...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404689/methoxyluteolin-inhibits-neuropeptide-stimulated-tnf-cxcl8-and-vegf-release-via-mtor-activation-from-human-mast-cells
#20
Arti B Patel, Theoharis C Theoharides
Mast cells (MC) are critical for allergic reactions, but are also important in inflammatory processes. Stimulation by neuropeptides, such as substance P (SP) and neurotensin (NT) leads to release of pre-formed molecules stored in numerous MC secretory granules and newly-synthesized pro-inflammatory mediators, including tumor necrosis factor (TNF), interleukin 8 (CXCL8) and vascular endothelial growth factor (VEGF). Here, we investigate the role of mammalian target of rapamycin (mTOR) signaling in the stimulation of cultured human LAD2 MC by NT or SP, and the inhibitory effect of the natural flavonoids 3',4',5,7-tetrahydroxyflavone (luteolin) and its novel structural analog 3 ',4',5,7-tetramethoxyluteolin (methoxyluteolin)...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
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