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https://www.readbyqxmd.com/read/28086984/deptor-not-only-a-mtor-inhibitor
#1
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/28078715/mtorc2-regulates-multiple-aspects-of-nkt-cell-development-and-function
#2
Tammarah Sklarz, Peng Guan, Mercy Gohil, Renee M Cotton, Moyar Q Ge, Angela Haczku, Rupali Das, Martha S Jordan
Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and lysing targets following TCR recognition of lipid antigens. Based on their ability to secrete IFN-γ, IL-4 and IL-17A, iNKT-cells are classified as NKT-1, NKT-2 and NKT-17 subsets, respectively. The molecular pathways regulating iNKT-cell fate are not fully defined. Recent studies implicate Rictor, a required component of mTORC2, in the development of select iNKT-cell subsets, however these reports are conflicting...
January 12, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28078713/the-novel-mtor-complex-1-2-inhibitor-p529-inhibits-human-lung-myofibroblast-differentiation
#3
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/28065789/choline-kinase-alpha-mediates-interactions-between-the-epidermal-growth-factor-receptor-and-mtorc2-in-hepatocellular-carcinoma-cells-to-promote-drug-resistance-and-xenograft-tumor-progression
#4
Xi-Meng Lin, Liang Hu, Jin Gu, Ruo-Yu Wang, Liang Li, Jing Tang, Bao-Hua Zhang, Xing-Zhou Yan, Yan-Jing Zhu, Cong-Li Hu, Wei-Ping Zhou, Shao Li, Jing-Feng Liu, Frank J Gonzalez, Meng-Chao Wu, Hong-Yang Wang, Lei Chen
BACKGROUND & AIMS: Choline kinase alpha (CHKA) catalyzes conversion of choline to phosphocholine and can contribute to carcinogenesis. Little is known about the role of CHKA in the pathogenesis of hepatocellular carcinoma (HCC). METHODS: We performed whole-exome and transcriptome sequence analyses of 9 paired HCC and non-tumor adjacent tissues. We performed tissue chip analyses of 120 primary HCC and non-tumor adjacent tissues from patients who received surgery in Shanghai, China from January 2006 through December 2009; 48 sets of specimens (HCC and non-tumor adjacent tissues) were also analyzed...
January 5, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28035937/mtorc2-rictor-in-alzheimer-s-disease-and-reversal-of-amyloid-%C3%AE-expression-induced-insulin-resistance-and-toxicity-in-rat-primary-cortical-neurons
#5
Han-Kyu Lee, Bumsup Kwon, Cynthia A Lemere, Suzanne de la Monte, Kyohei Itamura, Austin Y Ha, Henry W Querfurth
Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer's disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples...
December 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28025104/adrenoceptors-promote-glucose-uptake-into-adipocytes-and-muscle-by-an-insulin-independent-signalling-pathway-involving-mechanistic-target-of-rapamycin-complex-2
#6
Saori Mukaida, Bronwyn A Evans, Tore Bengtsson, Dana S Hutchinson, Masaaki Sato
Uptake of glucose into skeletal muscle and adipose tissue plays a vital role in metabolism and energy balance. Insulin released from β-islet cells of the pancreas promotes glucose uptake in these target tissues by stimulating translocation of GLUT4 transporters to the cell surface. This process is complex, involving signalling proteins including the mechanistic (or mammalian) target of rapamycin (mTOR) and Akt that intersect with multiple pathways controlling cell survival, growth and proliferation. mTOR exists in two forms, mTOR complex 1 (mTORC1), and mTOR complex 2 (mTORC2)...
December 23, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28025080/expression-of-mtorc1-2-related-proteins-in-primary-and-brain-metastatic-lung-adenocarcinoma
#7
Ildikó Krencz, Anna Sebestyén, Katalin Fábián, Ágnes Márk, Judit Moldvay, András Khoor, László Kopper, Judit Pápay
Brain metastases are common complications of adenocarcinomas of the lung and are associated with a poor prognosis. Although an increasing amount of data indicates that dysregulated activity of mammalian target of rapamycin (mTOR) can influence the metastatic potential of various tumors, the role of mTOR complexes in the development of brain metastases from adenocarcinomas of the lung is largely unknown. To estimate mTOR activity, we studied the expression of mTOR related proteins (mTORC1: p-mTOR, p-S6; mTORC2: p-mTOR, Rictor) in primary (n=67) and brain metastatic (n=67) lung adenocarcinomas, including 15 paired tissue samples, using immunohistochemistry and tissue microarrays...
December 23, 2016: Human Pathology
https://www.readbyqxmd.com/read/28004151/reciprocal-regulation-of-mtor-complexes-in-pancreatic-islets-from-humans-with-type-2-diabetes
#8
Ting Yuan, Sahar Rafizadeh, Kanaka Durga Devi Gorrepati, Blaz Lupse, Jose Oberholzer, Kathrin Maedler, Amin Ardestani
AIMS/HYPOTHESIS: Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of nutritional status at the cellular and organismic level. While mTORC1 mediates beta cell growth and expansion, its hyperactivation has been observed in pancreatic islets from animal models of type 2 diabetes and leads to beta cell loss. We sought to determine whether such mTORC1 activation occurs in humans with type 2 diabetes or in metabolically stressed human islets and whether mTORC1 blockade can restore beta cell function of diabetic islets...
December 21, 2016: Diabetologia
https://www.readbyqxmd.com/read/28002802/dual-inhibition-of-the-pi3k-akt-mtor-pathway-suppresses-the-growth-of-leiomyosarcomas-but-leads-to-erk-activation-through-mtorc2-biological-and-clinical-implications
#9
Benjamin Fourneaux, Vanessa Chaire, Carlo Lucchesi, Marie Karanian, Raphael Pineau, Audrey Laroche-Clary, Antoine Italiano
The PI3K/AKT/mTOR pathway plays a crucial role in the development of leiomyosarcomas (LMSs). In this study, we tested the efficacy of dual PI3K/mTOR (BEZ235), PI3K (BKM120) and mTOR (everolimus) inhibitors in three human LMS cell lines. In vitro and in vivo studies using LMS cell lines showed that BEZ235 has a significantly higher anti-tumor effect than either BKM120 or everolimus, resulting in a greater reduction in tumor growth and more pronounced inhibitory effects on mitotic activity and PI3K/AKT/mTOR signaling...
December 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27993679/epigenetic-activation-of-sin1-promotes-nsclc-cell-proliferation-and-metastasis-by-affecting-the-epithelial-mesenchymal-transition
#10
Zhongwu Hu, Yaqin Wang, Yuemei Wang, Bao Zang, Hongxia Hui, Zhenbing You, Xiaowei Wang
Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is an essential component of mTORC2. Previous studies have shown that SIN1 is a key regulator of Akt pathway which plays an important role in various pathological conditions including cancer. While its effects and mechanisms on the progression of NSCLC remain unknown. In this study, we report that SIN1 is able to promote the growth and migration of NSCLC cells both in vitro and in vivo. Overexpression of SIN1 promoted A549 and H1299 cells proliferation by both MTT and colony formation assays...
December 18, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27986865/crosstalks-via-mtorc2-can-explain-enhanced-activation-in-response-to-insulin-in-diabetic-patients
#11
Rasmus Magnusson, Mika Gustafsson, Gunnar Cedersund, Peter Strålfors, Elin Nyman
The molecular mechanisms of insulin resistance in type 2 diabetes have been extensively studied in primary human adipocytes, and mathematical modelling has clarified the central role of attenuation of mTORC1 activity in the diabetic state. Attenuation of mTORC1 in diabetes quells insulin signalling network-wide, except for the mTORC2-catalysed phosphorylation of PKB at serine-473, which is increased. This unique increase could potentially be explained by feedback and inter-branch crosstalk signals. To examine if such mechanisms operate in adipocytes, we herein analysed data from an un-biased phosphoproteomic screen in 3T3-L1 adipocytes...
December 16, 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27974744/notch-regulates-th17-differentiation-and-controls-trafficking-of-il-17-and-metabolic-regulators-within-th17-cells-in-a-context-dependent-manner
#12
Manuel Coutaz, Benjamin P Hurrell, Floriane Auderset, Haiping Wang, Stefanie Siegert, Gerard Eberl, Ping-Chih Ho, Freddy Radtke, Fabienne Tacchini-Cottier
Th17 cells play critical roles in host defense and autoimmunity. Emerging data support a role for Notch signaling in Th17 cell differentiation but whether it is a positive or negative regulator remains unclear. We report here that T cell-specific deletion of Notch receptors enhances Th17 cell differentiation in the gut, with a corresponding increase in IL-17 secretion. An increase in Th17 cell frequency was similarly observed following immunization of T cell specific Notch mutant mice with OVA/CFA. However, in this setting, Th17 cytokine secretion was impaired, and increased intracellular retention of IL-17 was observed...
December 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27960162/the-mtorc2-akt-nf%C3%AE%C2%BAb-pathway-mediated-activation-of-trpc6-participates-in-adriamycin-induced-podocyte-apoptosis
#13
Hai-Tao Zhang, Wei-Wei Wang, Li-Hong Ren, Xia-Xia Zhao, Zhi-Hui Wang, De-Li Zhuang, Yun-Nuo Bai
BACKGROUND/AIMS: Although increased expression and gain function of transient receptor potential cation channel 6 (TRPC6) has been associated with the pathogenesis of some proteinuric glomerular diseases, it remains elusive how TRPC6 participates in the process of podocyte damage. METHODS: The potential signaling responsible for TRPC6 activation was investigated using immunoblot assays in an in vitro podocyte injury model induced by Adriamycin (ADR). Podocyte apoptosis was measured using FITC-conjugated Annexin V and Propidium Iodide staining...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27959383/combination-of-metformin-and-sorafenib-suppresses-proliferation-and-induces-autophagy-of-hepatocellular-carcinoma-via-targeting-the-mtor-pathway
#14
Sunbin Ling, Lei Song, Ning Fan, Tingting Feng, Lu Liu, Xu Yang, Mingjie Wang, Yanling Li, Yu Tian, Feng Zhao, Ying Liu, Qihong Huang, Zhaoyuan Hou, Fei Xu, Lei Shi, Yan Li
The multi‑kinase inhibitor sorafenib is the only drug for which randomized control trials have shown improved patient survival in advanced hepatocellular carcinoma (HCC). However, life expectancy is extended in these cases by only a few months. The anti‑type II diabetes agent metformin was used in this study in an effort to find a more efficient approach to HCC treatment. Sorafenib effectively reversed the activation status of mTORC2 induced by metformin and enhanced the suppression of the mTORC1 and MAPK pathway by metformin in HCC cells, which may be responsible for reduced proliferation upon combined treatment...
January 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/27956700/mtorc1-and-2-coordinate-transcriptional-and-translational-reprogramming-in-resistance-to-dna-damage-and-replicative-stress-in-breast-cancer-cells
#15
Deborah Silvera, Amanda Ernlund, Rezina Arju, Eileen Connolly, Viviana Volta, Jinhua Wang, Robert J Schneider
MTOR COORDINATES GROWTH SIGNALS WITH METABOLIC PATHWAYS AND PROTEIN SYNTHESIS, AND IS HYPERACTIVATED IN MANY HUMAN CANCERS MTOR EXISTS IN TWO COMPLEXES, MTORC1 THAT STIMULATES PROTEIN, LIPID AND RIBOSOME BIOSYNTHESIS, AND MTORC2 THAT REGULATES CYTOSKELETON FUNCTIONS WHILE MTOR IS KNOWN TO BE INVOLVED IN THE DNA DAMAGE RESPONSE, LITTLE IS ACTUALLY KNOWN REGARDING THE FUNCTIONS OF MTORC1 COMPARED TO MTORC2 IN THIS REGARD, OR THE RESPECTIVE IMPACT ON TRANSCRIPTIONAL VERSUS TRANSLATIONAL REGULATION WE SHOW THAT MTORC1 AND MTORC2 ARE BOTH REQUIRED TO ENACT DNA DAMAGE REPAIR AND CELL SURVIVAL, RESULTING IN INCREASED CANCER CELL SURVIVAL DURING DNA DAMAGE TOGETHER MTORC1 AND 2 ENACT COORDINATED TRANSCRIPTION AND TRANSLATION OF PROTECTIVE CELL CYCLE, DNA REPLICATION, RECOMBINATION AND REPAIR GENES THIS COORDINATED TRANSCRIPTIONAL-TRANSLATIONAL RESPONSE TO DNA DAMAGE WAS NOT IMPAIRED BY RAPALOG INHIBITION OF MTORC1 OR INDEPENDENT INHIBITION OF MTORC1 OR MTORC2, BUT WAS BLOCKED BY INHIBITION OF MTORC1/2 ONLY MTORC1/2 INHIBITION REVERSED CANCER CELL RESISTANCE TO DNA DAMAGE AND REPLICATIVE STRESS, INCREASED TUMOR CELL KILLING AND TUMOR CONTROL BY DNA DAMAGE THERAPIES IN ANIMAL MODELS WHEN COMBINED WITH DNA DAMAGE, INHIBITION OF MTORC1/2 MORE STRONGLY BLOCKED TRANSCRIPTIONAL INDUCTION THAN TRANSLATION OF DNA REPLICATION, SURVIVAL, AND DNA DAMAGE RESPONSE MRNAS...
December 12, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27935857/potentiation-of-the-anticancer-effects-of-everolimus-using-a-dual-mtorc1-2-inhibitor-in-hepatocellular-carcinoma-cells
#16
Jong-Ok Kim, Kee-Hwan Kim, In Sang Song, Kwang-Sik Cheon, Ok-Hee Kim, Sang Chul Lee, Sang Kuon Lee, Say-June Kim
There is lots of evidence to support the critical involvement of mTOR signaling in the carcinogenesis of hepatocellular carcinoma (HCC). However, it has not been determined how the roles of individual mTORC1 and mTORC2 inhibitors played in the HCC therapeutics. We thus compared the effects of everolimus, Ku0063794, and a combination of the two therapies on HCC cells, using various in vitro studies (HepG2, Hep3B, and Huh7 cells), ex vivo culturing of HCC tissues obtained from patients, and the in vivo mouse xenograft model of HCC cells...
December 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27926859/rapamycin-reverses-metabolic-deficits-in-lamin-a-c-deficient-mice
#17
Chen-Yu Liao, Sydney S Anderson, Nicole H Chicoine, Jarrott R Mayfield, Emmeline C Academia, Joy A Wilson, Chalermkwan Pongkietisak, Morgan A Thompson, Earl P Lagmay, Delana M Miller, Yueh-Mei Hsu, Mark A McCormick, Monique N O'Leary, Brian K Kennedy
The role of the mTOR inhibitor, rapamycin, in regulation of adiposity remains controversial. Here, we evaluate mTOR signaling in lipid metabolism in adipose tissues of Lmna(-/-) mice, a mouse model for dilated cardiomyopathy and muscular dystrophy. Lifespan extension by rapamycin is associated with increased body weight and fat content, two phenotypes we link to suppression of elevated energy expenditure. In both white and brown adipose tissue of Lmna(-/-) mice, we find that rapamycin inhibits mTORC1 but not mTORC2, leading to suppression of elevated lipolysis and restoration of thermogenic protein UCP1 levels, respectively...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27925683/inorganic-polyphosphate-a-key-modulator-of-inflammation
#18
REVIEW
Seyed Mahdi Hassanian, Amir Avan, Abdolreza Ardeshirylajimi
Inorganic polyphosphate (PolyP) is a molecule with prothrombotic and proinflammatory properties in blood. PolyP activates the NF-κB signaling pathway, increases the expression of cell surface adhesion molecules and disrupts the vascular barrier integrity of endothelial cells. PolyP-induced NF-κB activation and vascular hyperpermeability are regulated by the mTORC1 and mTORC2 pathways, respectively. Through interaction with RAGE and P2Y1 receptors, PolyP dramatically amplifies the proinflammatory responses of nuclear proteins...
December 7, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27922192/evidence-for-pipecolate-oxidase-in-mediating-protection-against-hydrogen-peroxide-stress
#19
Sathish Kumar Natarajan, Ezhumalai Muthukrishnan, Oleh Khalimonchuk, Justin L Mott, Donald F Becker
Pipecolate, an intermediate of the lysine catabolic pathway, is oxidized to Δ(1) -piperideine-6-carboxylate (P6C) by the flavoenzyme l-pipecolate oxidase (PIPOX). P6C spontaneously hydrolyzes to generate α-aminoadipate semialdehyde, which is then converted into α-aminoadipate acid by α-aminoadipatesemialdehyde dehydrogenase. l-pipecolate was previously reported to protect mammalian cells against oxidative stress. Here, we examined whether PIPOX is involved in the mechanism of pipecolate stress protection...
December 6, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27911920/sirna-targeting-mtor-effectively-prevents-the-proliferation-and-migration-of-human-lens-epithelial-cells
#20
Chunmei Zhang, Jingjing Liu, Na Jin, Guiming Zhang, Yahui Xi, Hongling Liu
Posterior capsule opacification (PCO) is the most common complication that causes visual decrease after extracapsular cataract surgery. The primary cause of PCO formation is the proliferation of the residual lens epithelial cells (LECs). The mammalian target of rapamycin (mTOR) plays an important role in the growth and migration of LECs. In the current study, we used small interfering RNA (siRNA) to specifically attenuate mTOR in human lens epithelial B3 cells (HLE B3). We aimed to examine the effect of mTOR-siRNA on the proliferation, migration and epithelial-to-mesenchymal transition (EMT) of HLE B3 cells and explore the underlying mechanisms...
2016: PloS One
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