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https://www.readbyqxmd.com/read/27903651/t-cells-encountering-myeloid-cells-programmed-for-amino-acid-dependent-immunosuppression-use-rictor-mtorc2-for-proliferative-checkpoint-decisions
#1
Lee-Ann Van de Velde, Chitra Subramanian, Amber M Smith, Luke Barron, Joseph E Qualls, Geoffrey Neale, Adolfo Alfonso-Pecchio, Suzanne Jackowski, Charles O Rock, Thomas A Wynn, Peter J Murray
Modulation of T cell proliferation and function by immunoregulatory myeloid cells is an essential means of preventing self-reactivity and restoring tissue homeostasis. Consumption of amino acids such as arginine and tryptophan by immunoregulatory macrophages is one pathway that suppresses local T cell proliferation. Using a reduced complexity in vitro macrophage: T cell co-culture system, we show that macrophage Arginase-1 (Arg1) is the only factor required by M2 macrophages to block T cells in G1, and this effect is mediated by L-arginine elimination rather than metabolite generation...
November 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27894090/gremlin-promotes-retinal-pigmentation-epithelial-rpe-cell-proliferation-migration-and-vegf-production-via-activating-vegfr2-akt-mtorc2-signaling
#2
Yuan Liu, Zhijun Chen, Haixia Cheng, Juan Chen, Jing Qian
Retinopathy of prematurity (ROP) is characterized by late-phase pathologic retinal vasoproliferation. Gremlin is a novel vascular endothelial growth factors (VEGF) receptor 2 (VEGFR2) agonist and promotes angiogenic response. We demonstrated that gremlin expression was significantly increased in retinas of ROP model mice, which was correlated with VEGF upregulation. In retinal pigmentation epithelial (RPE) cells, gremlin activated VEGFR2-Akt-mTORC2 (mammalian target of rapamycin complex 2) signaling, and promoted cell proliferation, migration and VEGF production...
November 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27884298/mhy1485-activates-mtor-and-protects-osteoblasts-from-dexamethasone
#3
Sai Zhao, Caiyun Chen, Shouguo Wang, Feng Ji, Yue Xie
Dexamethasone (Dex) exerts cytotoxic effects to cultured osteoblasts. The potential effect of MHY1485, a small-molecular mammalian target of rapamycin (mTOR) activator, against the process was studied here. In both osteoblastic MC3T3-E1 cells and primary murine osteoblasts, treatment with MHY1485 significantly ameliorated Dex-induced cell death and apoptosis. mTOR inhibition, through mTOR kinase inhibitor OSI-027 or mTOR shRNAs, abolished MHY1485-mediated osteoblast cytoprotection against Dex. Intriguingly, activation of mTOR complex (mTORC1), but not mTORC2, is required for MHY1485's anti-Dex activity...
December 9, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27873319/lung-neuroendocrine-tumours-deep-sequencing-of-the-four-who-histotypes-reveals-chromatin-remodelling-genes-as-major-players-and-a-prognostic-role-for-tert-rb1-men1-and-kmt2d
#4
Michele Simbolo, Andrea Mafficini, Katarzyna O Sikora, Matteo Fassan, Stefano Barbi, Vincenzo Corbo, Luca Mastracci, Borislav Rusev, Federica Grillo, Caterina Vicentini, Roberto Ferrara, Sara Pilotto, Federico Davini, Giuseppe Pelosi, Rita T Lawlor, Marco Chilosi, Giampaolo Tortora, Emilio Bria, Gabriella Fontanini, Marco Volante, Aldo Scarpa
Next-generation sequencing (NGS) was applied to 148 lung neuroendocrine tumours (LNET) comprising the 4 WHO classification categories: 53 typical carcinoid (TC), 35 atypical carcinoid (AC), 27 large cell neuroendocrine carcinoma (LCNEC), and 33 small cell lung carcinoma (SCLC). A discovery screen was conducted on 46 samples using whole-exome sequencing and high-coverage targeted sequencing of 418 genes. Eighty-eight recurrently mutated genes from both the discovery screen and current literature were verified in the 46 cases of the discovery screen and validated on additional 102 LNET by targeted NGS, and their prevalence was evaluated on the whole series...
November 22, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27866972/letrozole-regulates-actin-cytoskeleton-polymerization-dynamics-in-a-src-1-dependent-manner-in-the-hippocampus-of-mice
#5
Yangang Zhao, Yanlan Yu, Yuanyuan Zhang, Li He, Linli Qiu, Jikai Zhao, Mengying Liu, Jiqiang Zhang
In the hippocampus, local estrogens (E2) derived from testosterone that is catalyzed by aromatase play important roles in the regulation of hippocampal neural plasticity, but the underlying mechanisms remain unclear. The actin cytoskeleton contributes greatly to hippocampal synaptic plasticity; however, whether it is regulated by local E2 and the related mechanisms remain to be elucidated. In this study, we first examined the postnatal developmental profiles of hippocampal aromatase and specific proteins responsible for actin cytoskeleton dynamics...
November 17, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27863413/rictor-amplification-identifies-a-subgroup-in-small-cell-lung-cancer-and-predicts-response-to-drugs-targeting-mtor
#6
Nneha Sakre, Gary Wildey, Mohadese Behtaj, Adam Kresak, Michael Yang, Pingfu Fu, Afshin Dowlati
Small cell lung cancer (SCLC) is an aggressive cancer that represents ~15% of all lung cancers. Currently there are no targeted therapies to treat SCLC. Our genomic analysis of a metastatic SCLC cohort identified recurrent RICTOR amplification. Here, we examine the translational potential of this observation. RICTOR was the most frequently amplified gene observed (~14% patients), and co-amplified with FGF10 and IL7R on chromosome 5p13. RICTOR copy number variation correlated with RICTOR protein expression in SCLC cells...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27807348/mtorc1-and-mtorc2-regulate-skin-morphogenesis-and-epidermal-barrier-formation
#7
Xiaolei Ding, Wilhelm Bloch, Sandra Iden, Markus A Rüegg, Michael N Hall, Maria Leptin, Linda Partridge, Sabine A Eming
Mammalian target of rapamycin (mTOR), a regulator of growth in many tissues, mediates its activity through two multiprotein complexes, mTORC1 or mTORC2. The role of mTOR signalling in skin morphogenesis and epidermal development is unknown. Here we identify mTOR as an essential regulator in skin morphogenesis by epidermis-specific deletion of Mtor in mice (mTOR(EKO)). mTOR(EKO) mutants are viable, but die shortly after birth due to deficits primarily during the early epidermal differentiation programme and lack of a protective barrier development...
October 27, 2016: Nature Communications
https://www.readbyqxmd.com/read/27799302/proliferating-helper-t-cells-require-rictor-mtorc2-to-integrate-signals-from-limiting-environmental-amino-acids
#8
Lee-Ann Van de Velde, Peter J Murray
Antigen-stimulated T cells require elevated importation of essential and non-essential amino acids to generate large numbers of daughter cells necessary for effective immunity to pathogens. When amino acids are limiting, T cells arrest in the G1 phase of the cell cycle, suggesting they have specific sensing mechanisms to ensure sufficient amino acids are available for multiple rounds of daughter generation. We found activation of mTORC1, which is regulated by amino acid amounts, was uncoupled from limiting amino acids in the G1 phase of the cell cycle...
October 31, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27789731/evaluation-of-akt-and-rictor-expression-levels-in-astrocytomas-of-all-grades
#9
Arthur William Alvarenga, Luis Eduardo Machado, Bruna Roz Rodrigues, Fernanda Cristina Sulla Lupinacci, Paulo Sanemastu, Eduardo Matta, Martín Roffé, Luís Fernando Bleggi Torres, Isabela Werneck da Cunha, Vilma Regina Martins, Glaucia Noeli Maroso Hajj
The mammalian target of rapamycin (mTOR) binds to several protein partners and forms two complexes, termed mTOR complexes 1 and 2 (mTORC1/2), that differ in components, substrates, and regulation. mTORC2 contains the protein Rapamycin-insensitive companion of mTOR (RICTOR); phosphorylates kinases of the AGC family, such as Akt; and controls the cytoskeleton. Even though the regulation of mTORC2 activity remains poorly understood, the hyperactivation of this signaling pathway has been shown to contribute to the oncogenic properties of gliomas in experimental models...
October 27, 2016: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
https://www.readbyqxmd.com/read/27758884/mtorc2-signaling-drives-the-development-and-progression-of-pancreatic-cancer
#10
David R Driscoll, Saadia A Karim, Makoto Sano, David M Gay, Wright Jacob, Jun Yu, Yusuke Mizukami, Aarthi Gopinathan, Duncan I Jodrell, T R Jeffry Evans, Nabeel Bardeesy, Michael N Hall, Brian J Quattrochi, David S Klimstra, Simon T Barry, Owen J Sansom, Brian C Lewis, Jennifer P Morton
mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27735936/loss-of-rictor-with-aging-in-osteoblasts-promotes-age-related-bone-loss
#11
Pinling Lai, Qiancheng Song, Cheng Yang, Zhen Li, Sichi Liu, Bin Liu, Mangmang Li, Hongwen Deng, Daozhang Cai, Dadi Jin, Anling Liu, Xiaochun Bai
Osteoblast dysfunction is a major cause of age-related bone loss, but the mechanisms underlying changes in osteoblast function with aging are poorly understood. This study demonstrates that osteoblasts in aged mice exhibit markedly impaired adhesion to the bone formation surface and reduced mineralization in vivo and in vitro. Rictor, a specific component of the mechanistic target of rapamycin complex 2 (mTORC2) that controls cytoskeletal organization and cell survival, is downregulated with aging in osteoblasts...
October 13, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27731345/mtor-is-critical-for-intestinal-t-cell-homeostasis-and-resistance-to-citrobacter-rodentium
#12
Xingguang Lin, Jialong Yang, Jinli Wang, Hongxiang Huang, Hong-Xia Wang, Pengcheng Chen, Shang Wang, Yun Pan, Yu-Rong Qiu, Gregory A Taylor, Bruce A Vallance, Jimin Gao, Xiao-Ping Zhong
T-cells play an important role in promoting mucosal immunity against pathogens, but the mechanistic basis for their homeostasis in the intestine is still poorly understood. We report here that T-cell-specific deletion of mTOR results in dramatically decreased CD4 and CD8 T-cell numbers in the lamina propria of both small and large intestines under both steady-state and inflammatory conditions. These defects result in defective host resistance against a murine enteropathogen, Citrobacter rodentium, leading to the death of the animals...
October 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27729429/mtor-activity-and-its-prognostic-significance-in-human-colorectal-carcinoma-depending-on-c1-and-c2-complex-related-protein-expression
#13
Tamás Sticz, Anna Molnár, Ágnes Márk, Melinda Hajdu, Noémi Nagy, Gyula Végső, Tamás Micsik, László Kopper, Anna Sebestyén
AIMS: Tumour heterogeneity and altered activation of signalling pathways play important roles in therapy resistance. The PI3K/Akt/mTOR signalling network is a well-known regulator of several functions that contribute to tumour growth. mTOR exists in two functionally different multiprotein complexes. We aimed to determine mTOR activity-related proteins in clinically followed, conventionally treated colon carcinomas and to analyse the correlation between clinical data and mTORC1 and mTORC2 activity...
October 11, 2016: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/27716847/lowered-expression-of-tumor-suppressor-candidate-myo1c-stimulates-cell-proliferation-suppresses-cell-adhesion-and-activates-akt
#14
Kittichate Visuttijai, Jennifer Pettersson, Yashar Mehrbani Azar, Iman van den Bout, Charlotte Örndal, Janusz Marcickiewicz, Staffan Nilsson, Michael Hörnquist, Björn Olsson, Katarina Ejeskär, Afrouz Behboudi
Myosin-1C (MYO1C) is a tumor suppressor candidate located in a region of recurrent losses distal to TP53. Myo1c can tightly and specifically bind to PIP2, the substrate of Phosphoinositide 3-kinase (PI3K), and to Rictor, suggesting a role for MYO1C in the PI3K pathway. This study was designed to examine MYO1C expression status in a panel of well-stratified endometrial carcinomas as well as to assess the biological significance of MYO1C as a tumor suppressor in vitro. We found a significant correlation between the tumor stage and lowered expression of MYO1C in endometrial carcinoma samples...
2016: PloS One
https://www.readbyqxmd.com/read/27697526/bcka-down-regulates-mtorc2-akt-signal-and-enhances-apoptosis-susceptibility-in-cardiomyocytes
#15
Xiong Guo, Chong Huang, Kun Lian, Shan Wang, Huishou Zhao, Feng Yan, Xiaomeng Zhang, Jinglong Zhang, Huaning Xie, Rui An, Ling Tao
Diabetic mellitus (DM) portends poor prognosis concerning pressure overloaded heart disease. Branched-chain amino acids (BCAAs), elements of essential amino acids, have been found altered in its catabolism in diabetes decades ago. However, the relationship between BCAAs and DM induced deterioration of pressure overloaded heart disease remains controversial. This study is aimed to investigate the particular effect of BCKA, a metabolite of BCAA, on myocardial injury induced by pressure overloaded. Primary cardiomyocytes were incubated with or without BCKA and followed by treatment with isoproterenol (ISO); then cell viability was detected by CCK8 and apoptosis was examined by TUNNEL stain and caspase-3 activity analysis...
September 30, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27690224/critical-roles-of-mtor-complex-1-and-2-for-t-follicular-helper-cell-differentiation-and-germinal-center-responses
#16
Jialong Yang, Xingguang Lin, Yun Pan, Jinli Wang, Pengcheng Chen, Hongxiang Huang, Hai-Hui Xue, Jimin Gao, Xiao-Ping Zhong
T follicular helper (Tfh) cells play critical roles for germinal center responses and effective humoral immunity. We report here that mTOR in CD4 T cells is essential for Tfh differentiation. In Mtor(f/f)-Cd4Cre mice, both constitutive and inducible Tfh differentiation is severely impaired, leading to defective germinal center B cell formation and antibody production. Moreover, both mTORC1 and mTORC2 contribute to Tfh and GC B cell development but may do so via distinct mechanisms. mTORC1 mainly promotes CD4 T cell proliferation to reach the cell divisions necessary for Tfh differentiation, while Rictor/mTORC2 regulates Tfh differentiation by promoting Akt activation and TCF1 expression without grossly influencing T cell proliferation...
September 30, 2016: ELife
https://www.readbyqxmd.com/read/27676404/rictor-polymorphisms-affect-efficiency-of-platinum-based-chemotherapy-in-chinese-non-small-cell-lung-cancer-patients
#17
Shiming Wang, Xiao Song, Xiaoying Li, Xueying Zhao, Hongyan Chen, Jiucun Wang, Junjie Wu, Zhiqiang Gao, Ji Qian, Baohui Han, Chunxue Bai, Qiang Li, Daru Lu
AIM: We investigated the association between RICTOR polymorphisms and clinical outcomes of platinum-based chemotherapy for Chinese non-small-cell lung cancer patients. MATERIALS & METHODS: Ten tag SNPs were genotyped in 1004 patients to assess their association with clinical benefit, overall survival, progression-free survival, gastrointestinal toxicity, neutropenia, anemia and thrombocytopenia. RESULTS: rs6878291 was significantly associated with clinical benefit (odds ratio: 2...
October 2016: Pharmacogenomics
https://www.readbyqxmd.com/read/27663077/gonadotropin-releasing-hormone-activation-of-the-mtorc2-rictor-complex-regulates-actin-remodeling-and-erk-activity-in-l%C3%AE-t2-cells
#18
Brian S Edwards, William J Isom, Amy M Navratil
The mammalian target of rapamycin (mTOR) assembles into two different multi-protein complexes, mTORC1 and mTORC2. The mTORC2 complex is distinct due to the unique expression of the specific core regulatory protein Rictor (rapamycin-insensitive companion of mTOR). mTORC2 has been implicated in regulating actin cytoskeletal reorganization but its role in gonadotrope function is unknown. Using the gonadotrope-derived LβT2 cell line, we find that the GnRH agonist buserelin (GnRHa) phosphorylates both mTOR and Rictor...
January 5, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27649066/calpain-activated-mtorc2-akt-pathway-mediates-airway-smooth-muscle-remodelling-in-asthma
#19
S-S Rao, Q Mu, Y Zeng, P-C Cai, F Liu, J Yang, Y Xia, Q Zhang, L-J Song, L-L Zhou, F-Z Li, Y-X Lin, J Fang, P A Greer, H-Z Shi, W-L Ma, Y Su, H Ye
BACKGROUND: Allergic asthma is characterized by inflammation and airway remodelling. Airway remodelling with excessive deposition of extracellular matrix (ECM) and larger smooth muscle mass are correlated with increased airway responsiveness and asthma severity. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodelling. However, the role of calpain in airway smooth muscle remodelling remains unknown. OBJECTIVE: To investigate the role of calpain in asthmatic airway remodelling as well as the underlying mechanism...
September 20, 2016: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27611085/novel-protective-mechanism-of-reducing-renal-cell-damage-in-diabetes-activation-ampk-by-aicar-increased-nrf2-ogg1-proteins-and-reduced-oxidative-dna-damage
#20
Samy L Habib, Anamika Yadav, Dawit Kidane, Robert H Weiss, Sitai Liang
Exposure of renal cells to high glucose (HG) during diabetes has been recently proposed to be involved in renal injury. In the present study, we investigated a potential mechanism by which AICAR treatment regulates the DNA repair enzyme, 8-oxoG-DNA glycosylase (OGG1) in renal proximal tubular mouse cells exposed to HG and in kidney of db/db mice. Cells treated with HG for 2 days show inhibition in OGG1 promoter activity as well as OGG1 and Nrf2 protein expression. In addition, activation of AMPK by AICAR resulted in an increase raptor phosphorylation at Ser(792) and leads to increase the promoter activity of OGG1 through upregulation of Nrf2...
September 9, 2016: Cell Cycle
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