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https://www.readbyqxmd.com/read/28092373/chronic-signaling-via-the-metabolic-checkpoint-kinase-mtorc1-induces-macrophage-granuloma-formation-and-marks-sarcoidosis-progression
#1
Monika Linke, Ha Thi Thanh Pham, Karl Katholnig, Thomas Schnöller, Anne Miller, Florian Demel, Birgit Schütz, Margit Rosner, Boris Kovacic, Nyamdelger Sukhbaatar, Birgit Niederreiter, Stephan Blüml, Peter Kuess, Veronika Sexl, Mathias Müller, Mario Mikula, Wolfram Weckwerth, Arvand Haschemi, Martin Susani, Markus Hengstschläger, Michael J Gambello, Thomas Weichhart
The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo...
January 16, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28089905/nudix-type-motif-2-contributes-to-cancer-proliferation-through-the-regulation-of-rag-gtpase-mediated-mammalian-target-of-rapamycin-complex-1-localization
#2
Ohman Kwon, Dongoh Kwak, Sang Hoon Ha, Hyeona Jeon, Mangeun Park, Yeonho Chang, Pann-Ghill Suh, Sung Ho Ryu
Lysosomal localization of mammalian target of rapamycin complex 1 (mTORC1) is a critical step for activation of the molecule. Rag GTPases are essential for this translocation. Here, we demonstrate that Nudix-type motif 2 (NUDT2) is a novel positive regulator of mTORC1 activation. Activation of mTORC1 is impaired in NUDT2-silenced cells. Mechanistically, NUDT2 binds to Rag GTPase and controls mTORC1 translocation to the lysosomal membrane. Furthermore, NUDT2-dependent mTORC1 regulation is critical for proliferation of breast cancer cells, as NUDT2-silenced cells arrest in G0/G1 phases...
January 12, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28089725/high-concentration-of-branched-chain-amino-acids-promotes-oxidative-stress-inflammation-and-migration-of-human-peripheral-blood-mononuclear-cells-via-mtorc1-activation
#3
Olha Zhenyukh, Esther Civantos, Marta Ruiz-Ortega, María Soledad Sánchez, Clotilde Vázquez, Concepción Peiró, Jesús Egido, Sebastián Mas
Leucine, isoleucine and valine are essential aminoacids termed branched-chain amino acids (BCAA) due to its aliphatic side-chain. In several pathological and physiological conditions increased BCAA plasma concentrations have been described. Elevated BCAA levels predict insulin resistance development. Moreover, BCAA levels higher than 2mmol/L are neurotoxic by inducing microglial activation in maple syrup urine disease. However, there are no studies about the direct effects of BCAA in circulating cells. We have explored whether BCAA could promote oxidative stress and pro-inflammatory status in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors...
January 12, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28089566/metformin-inhibits-hepatic-mtorc1-signaling-via-dose-dependent-mechanisms-involving-ampk-and-the-tsc-complex
#4
Jessica J Howell, Kristina Hellberg, Marc Turner, George Talbott, Matthew J Kolar, Debbie S Ross, Gerta Hoxhaj, Alan Saghatelian, Reuben J Shaw, Brendan D Manning
Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion...
December 30, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/28086984/deptor-not-only-a-mtor-inhibitor
#5
REVIEW
Valeria Catena, Maurizio Fanciulli
Deptor is an important protein that belongs to the mTORC1 and mTORC2 complexes, able to interact with mTOR and to inhibit its kinase activity. As a natural mTOR inhibitor, Deptor is involved in several molecular pathways, such as cell growth, apoptosis, autophagy and ER stress response. For this reason, Deptor seems to play an important role in controlling cellular homeostasis. Despite several recent insights characterizing Deptor functions and regulation, its complete role within cells has not yet been completely clarified...
January 13, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28079897/tsc1-expression-by-dendritic-cells-is-required-to-preserve-t-cell-homeostasis-and-response
#6
Yuechen Luo, Wenwen Li, Gang Yu, Juan Yu, Ling Han, Ting Xue, Zhina Sun, Song Chen, Chunming Fang, Chunxiao Zhao, Qing Niu, Fei Yang, Zhongchao Han, Tao Cheng, Yun Zeng, Fang Liao, Guogang Xu, Xiaoming Feng
Dendritic cells (DCs) are pivotal to the induction of adaptive T-cell immune responses. Recent evidence highlights a critical role of tuberous sclerosis complex 1 (Tsc1), a primarily upstream negative regulator of mammalian target of rapamycin (mTOR), in DC development, but whether and how Tsc1 directly regulate mature DC function in vivo remains elusive. Here we show that selective disruption of Tsc1 in DCs results in a lymphoproliferative disorder with the spontaneous activation of T cells. Tsc1 deficiency results in the activation of mTORC1-PPARγ pathway, which leads to the upregulation of neuropilin-1 (Nrp1) expression on DCs to stimulate naive T-cell proliferation...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28078757/lamellar-events-related-to-insulin-like-growth-factor-1-receptor-signaling-in-two-models-relevant-to-endocrinopathic-laminitis
#7
H E Lane, T A Burns, O C Hegedus, M R Watts, P S Weber, K A Woltman, R J Geor, L J McCutcheon, S C Eades, L E Mathes, J K Belknap
BACKGROUND: Insulin dysregulation, obesity, and exposure to high-non structural carbohydrate (NSC) forage are risk factors for equine metabolic syndrome (EMS)-associated laminitis (EMSAL); high systemic insulin concentrations in EMSAL are proposed to induce cellular dysregulation in the digital lamellae through activation of the IGF-1 receptor. OBJECTIVES: To use a dietary challenge model (DCM) and a euglycemic hyperinsulinemic clamp (EHC) model to assess lamellar growth factor-related signaling...
January 11, 2017: Equine Veterinary Journal
https://www.readbyqxmd.com/read/28078713/the-novel-mtor-complex-1-2-inhibitor-p529-inhibits-human-lung-myofibroblast-differentiation
#8
Keith T Ferguson, Elizabeth E Torr, Ksenija Bernau, Jonathan Leet, Davis Sherris, Nathan Sandbo
Idiopathic pulmonary fibrosis is a progressive and deadly disorder with very few therapeutic options. Palomid 529 (8-(1-hydroxyethyl)-2-methoxy-3-(4-methoxybenzyloxy)-benzo[c]chromen-6-one; P529) is a novel dual inhibitor of mechanistic target of rapamycin complex 1/2 (mTORC1/2). In these studies, we investigated the effect of P529 on TGF-β-dependent signaling and myofibroblast differentiation. TGF-β-induced phosphorylation of the mTORC1 targets, p70 S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), were both dose dependently inhibited by P529 in human lung fibroblasts with maximal inhibition occurring between 10-20 µM...
January 11, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28077803/gerosuppression-by-pan-mtor-inhibitors
#9
Olga V Leontieva, Mikhail V Blagosklonny
Rapamycin slows organismal aging and delays age-related diseases, extending lifespan in numerous species. In cells, rapamycin and other rapalogs such as everolimus suppress geroconversion from quiescence to senescence. Rapamycin inhibits some, but not all, activities of mTOR. Recently we and others demonstrated that pan-mTOR inhibitors, known also as dual mTORC1/C2 inhibitors, suppress senescent phenotype. As a continuation of these studies, here we investigated in detail a panel of pan-mTOR inhibitors, to determine their optimal gerosuppressive concentrations...
December 30, 2016: Aging
https://www.readbyqxmd.com/read/28071763/starved-epithelial-cells-uptake-extracellular-matrix-for-survival
#10
Taru Muranen, Marcin P Iwanicki, Natasha L Curry, Julie Hwang, Cory D DuBois, Jonathan L Coloff, Daniel S Hitchcock, Clary B Clish, Joan S Brugge, Nada Y Kalaany
Extracellular matrix adhesion is required for normal epithelial cell survival, nutrient uptake and metabolism. This requirement can be overcome by oncogene activation. Interestingly, inhibition of PI3K/mTOR leads to apoptosis of matrix-detached, but not matrix-attached cancer cells, suggesting that matrix-attached cells use alternate mechanisms to maintain nutrient supplies. Here we demonstrate that under conditions of dietary restriction or growth factor starvation, where PI3K/mTOR signalling is decreased, matrix-attached human mammary epithelial cells upregulate and internalize β4-integrin along with its matrix substrate, laminin...
January 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28070992/molecular-signal-networks-and-regulating-mechanisms-of-the-unfolded-protein-response
#11
Jing Gong, Xing-Zhi Wang, Tao Wang, Jiao-Jiao Chen, Xiao-Yuan Xie, Hui Hu, Fang Yu, Hui-Lin Liu, Xing-Yan Jiang, Han-Dong Fan
Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum (ER). One of the primary mechanisms is the unfolded protein response (UPR). In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein (BiP) interacts with the three sensors (protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1α (IRE1α))...
2017: Journal of Zhejiang University. Science. B
https://www.readbyqxmd.com/read/28069950/chronic-innate-immune-activation-of-tbk1-suppresses-mtorc1-activity-and-dysregulates-cellular-metabolism
#12
Maroof Hasan, Vijay K Gonugunta, Nicole Dobbs, Aktar Ali, Guillermo Palchik, Maria A Calvaruso, Ralph J DeBerardinis, Nan Yan
Three-prime repair exonuclease 1 knockout (Trex1(-/-)) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1(-/-) mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism...
January 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28069808/kinetic-modeling-and-analysis-of-the-akt-mechanistic-target-of-rapamycin-complex-1-mtorc1-signaling-axis-reveals-cooperative-feedforward-regulation
#13
Anisur Rahman, Jason M Haugh
Mechanistic target of rapamycin complex 1 (mTORC1) controls biosynthesis and has been implicated in uncontrolled cell growth in cancer. Although many details of mTORC1 regulation are well understood, a systems-level, predictive framework synthesizing those details is currently lacking. We constructed various mathematical models of mTORC1 activation mediated by Akt and aligned the model outputs to kinetic data acquired for growth factor-stimulated cells. A model based on a putative feedforward loop orchestrated by Akt consistently predicted how the pathway was altered by depletion of key regulatory proteins...
January 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28069737/mtorc1-plays-an-important-role-in-skeletal-development-by-controlling-pre-osteoblast-differentiation
#14
Stephen Fitter, Mary P Matthews, Sally K Martin, Jianling Xie, Soo Siang Ooi, Carl R Walkley, John D Codrington, Markus A Ruegg, Michael N Hall, Christopher G Proud, Stan Gronthos, Andrew C W Zannettino
The mammalian target of rapamycin complex 1 (mTORC1) is activated by extracellular factors that control bone accrual. However, the direct role of this complex in osteoblast biology remains to be determined. To investigate this question, we disrupted mTORC1 function in pre-osteoblasts by targeted deletion of Raptor (Rptor) in Osterix-expressing cells. Deletion of Rptor resulted in reduced limb length that was associated with smaller epiphyseal growth plates in the postnatal skeleton. Rptor deletion caused a marked reduction in pre- and post-natal bone accrual, which was evident in skeletal elements derived from both intramembranous and endochondrial ossification...
January 9, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28068384/hypoxia-regulates-mtorc1-mediated-keratinocyte-motility-and-migration-via-the-ampk-pathway
#15
Tiantian Yan, Junhui Zhang, Di Tang, Xingyue Zhang, Xupin Jiang, Liping Zhao, Qiong Zhang, Dongxia Zhang, Yuesheng Huang
Keratinocyte migration, the initial event and rate-limiting step in wound healing, plays a vital role in restoration of the intact skin barrier, also known as re-epithelialization. After acute tissue injury, hypoxic microenvironment gradually develops and acts as an early stimulus to initiate the healing process. Although we have previously found that hypoxia induces keratinocyte migration, the underlying mechanism remains unknown. Here, we first observed that hypoxia increased mTORC1 activity. Recombinant lentivirus vector and Rapamycin were used for silencing mTORC1 in HaCaT cells and primary mouse keratinocytes (MKs)...
2017: PloS One
https://www.readbyqxmd.com/read/28068143/adaptations-to-excess-choline-in-insulin-resistant-and-pcyt2-deficient-skeletal-muscle
#16
Adrian Taylor, Laila Cigana Schenkel, Maiya Yokich, Marica Bakovic
It was hypothesized that choline supplementation in insulin resistant (IR) CTP:phosphoethanolamine cytidylyltransferase deficient (Pcyt2(+/-)) mice would ameliorate muscle function by remodeling glucose and fatty acid (FA) metabolism. Pcyt2(+/-) mice either received no treatment or were allowed access to 2 mg/mL choline in drinking water for 4 weeks. Skeletal muscle was harvested from choline treated and untreated mice. Lipid analysis and metabolic gene expression and signaling pathways were compared between untreated Pcyt2(+/-) mice, treated Pcyt2(+/-) mice, and Pcyt2(+/+) mice...
September 6, 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/28067669/targeting-deregulated-ampk-mtorc1-pathways-improves-muscle-function-in-myotonic-dystrophy-type-i
#17
Marielle Brockhoff, Nathalie Rion, Kathrin Chojnowska, Tatiana Wiktorowicz, Christopher Eickhorst, Beat Erne, Stephan Frank, Corrado Angelini, Denis Furling, Markus A Rüegg, Michael Sinnreich, Perrine Castets
Myotonic dystrophy type I (DM1) is a disabling multisystemic disease that predominantly affects skeletal muscle. It is caused by expanded CTG repeats in the 3'-UTR of the dystrophia myotonica protein kinase (DMPK) gene. RNA hairpins formed by elongated DMPK transcripts sequester RNA-binding proteins, leading to mis-splicing of numerous pre-mRNAs. Here, we have investigated whether DM1-associated muscle pathology is related to deregulation of central metabolic pathways, which may identify potential therapeutic targets for the disease...
January 9, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28061838/cryptotanshinone-activates-ampk-tsc2-axis-leading-to-inhibition-of-mtorc1-signaling-in-cancer-cells
#18
Wenxing Chen, Yanhong Pan, Siliang Wang, Yuping Liu, Guangying Chen, Liang Zhou, Wenting Ni, Aiyun Wang, Yin Lu
BACKGROUND: Cryptotanshinone (CPT), a fat-soluble phenanthraquinone from Salvia miltiorrhiza Bunge, has been demonstrated to inhibit phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), a couple of direct downstream effectors of the mammalian target of rapamycin complex 1 (mTORC1), resulting in cancer cell arrested in G0 phase and subsequent inhibition of proliferation. However, its concrete molecular mechanism about how CPT inhibits mTORC1 signaling pathway is unclear...
January 7, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28059666/mtorc1-mediated-nrbf2-phosphorylation-functions-as-a-switch-for-the-class-iii-ptdins3k-and-autophagy
#19
Xi Ma, Shen Zhang, Long He, Yueguang Rong, Livia Wilz Brier, Qiming Sun, Rong Liu, Weiliang Fan, She Chen, Zhenyu Yue, Joungmok Kim, Kun-Liang Guan, Defa Li, Qing Zhong
NRBF2/Atg38 has been identified as the fifth subunit of the macroautophagic/autophagic class III phosphatidylinositol 3-kinase (PtdIns3K) complex, along with ATG14/Barkor, BECN1/Vps30, PIK3R4/p150/Vps15 and PIK3C3/Vps34. However, its functional mechanism and regulation are not fully understood. Here, we report that NRBF2 is a fine tuning regulator of PtdIns3K controlled by phosphorylation. Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished...
January 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28059583/mir7-3hg-a-myc-dependent-modulator-of-cell-proliferation-inhibits-autophagy-by-a-regulatory-loop-involving-ambra1
#20
Mariacristina Capizzi, Flavie Strappazzon, Valentina Cianfanelli, Elena Papaleo, Francesco Cecconi
Macroautophagy/autophagy is a tightly regulated intracellular catabolic pathway involving the lysosomal degradation of cytoplasmic organelles and proteins to be recycled into metabolic precursors. AMBRA1 (autophagy and beclin 1 regulator 1) has a central role in the autophagy signaling network; it acts upstream of MTORC1-dependent autophagy by stabilizing the kinase ULK1 (unc-51 like autophagy activating kinase 1) and by favoring autophagosome core complex formation. AMBRA1 also regulates the cell cycle by modulating the activity of the phosphatase PPP2/PP2A (protein phosphatase 2) and degradation of MYC...
January 6, 2017: Autophagy
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