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https://www.readbyqxmd.com/read/28106162/heterogeneous-nuclear-ribonucleoprotein-m-associates-with-mtorc2-and-regulates-muscle-differentiation
#1
Wei-Yen Chen, Chia-Lung Lin, Jen-Hua Chuang, Fu-Yu Chiu, Yun-Ya Sun, Mei-Chih Liang, Yenshou Lin
Mammalian target of rapamycin (mTOR) plays a range of crucial roles in cell survival, growth, proliferation, metabolism, and morphology. However, mTOR forms two distinct complexes, mTOR complex 1 and mTOR complex 2 (mTORC1 and mTORC2), via association with a series of different components; this allows the complexes to execute their wide range of functions. This study explores further the composition of the mTORC2 complex. Utilizing Rictor knock-out cells, immunoprecipitation and mass spectrometry, a novel Rictor associated protein, heterogeneous nuclear ribonucleoprotein M (hnRNP M), was identified...
January 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28104700/inhibition-of-4ebp-phosphorylation-mediates-the-cytotoxic-effect-of-mtor-kinase-inhibitors-in-aggressive-b-cell-lymphomas
#2
Chengfeng Bi, Xuan Zhang, Ting Lu, Xiaoyan Zhang, Xianhuo Wang, Bin Meng, Huilai Zhang, Ping Wang, Julie M Vose, Wing C Chan, Timothy W McKeithan, Kai Fu
Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in eukaryotes. The second generation of mTOR kinase inhibitors (TORKi), directly targeting the mTOR catalytic site, are more effective than rapamycin and its analogs in cancer treatment, particularly in inducing apoptosis. However, the mechanism underlying the cytotoxic effect of TORKi remains elusive. Herein, we demonstrated that TORKi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP activation...
January 19, 2017: Haematologica
https://www.readbyqxmd.com/read/28101526/rapamycin-resistant-mtor-activity-is-required-for-sensory-axon-regeneration-induced-by-a-conditioning-lesion
#3
Weitao Chen, Na Lu, Yue Ding, Yuan Wang, Leung Ting Chan, Xu Wang, Xin Gao, Songshan Jiang, Kai Liu
Neuronal mammalian target of rapamycin (mTOR) activity is a critical determinant of the intrinsic regenerative ability of mature neurons in the adult central nervous system (CNS). However, whether its action also applies to peripheral nervous system (PNS) neurons after injury remains elusive. To address this issue unambiguously, we used genetic approaches to determine the role of mTOR signaling in sensory axon regeneration in mice. We showed that deleting mTOR in dorsal root ganglion (DRG) neurons suppressed the axon regeneration induced by conditioning lesions...
November 2016: ENeuro
https://www.readbyqxmd.com/read/28078715/mtorc2-regulates-multiple-aspects-of-nkt-cell-development-and-function
#4
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/28054037/gene-expression-alterations-in-the-medial-prefrontal-cortex-and-blood-cells-in-a-mouse-model-of-depression-during-menopause
#5
Shigeo Miyata, Masashi Kurachi, Noriko Sakurai, Yuchio Yanagawa, Yasuki Ishizaki, Masahiko Mikuni, Masato Fukuda
AIMS: The prevalence of major depressive disorder (MDD) is higher in women than in men, and this may be due to the decline in estrogen levels that occurs during the menopausal transition. We studied the biological alterations in the medial prefrontal cortex (mPFC), which is a region that is highly implicated in the neurobiology of MDD, and the blood cells (BCs) of ovariectomized (OVX) mice subjected to chronic mild stress (CMS), which represents a mouse model of depression during menopause...
December 2016: Heliyon
https://www.readbyqxmd.com/read/28049717/a-novel-hect-ubiquitin-ligase-regulating-chemotaxis-and-development-in-dictyostelium-discoideum
#6
Barbara Pergolizzi, Enrico Bracco, Salvatore Bozzaro
Cyclic AMP binding to G protein-coupled receptors orchestrates chemotaxis and development in Dictyostelium. By activating the RasC-TORC2-AKT/PKB module, cAMP regulates cell polarization during chemotaxis. TORC2 also mediates GPCR-dependent stimulation of adenylyl cyclase A (ACA), enhancing cAMP relay and developmental gene expression. Thus, mutants defective in the TORC2 Pia/Rictor subunit are impaired in chemotaxis and development. Near-saturation mutagenesis of a Pia/Rictor mutant by random gene disruption led to selection of two suppressor mutants, in which spontaneous chemotaxis and development were restored...
January 3, 2017: Journal of Cell Science
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
#7
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/28030804/tumor-suppressive-microrna-218-inhibits-tumor-angiogenesis-via-targeting-the-mtor-component-rictor-in-prostate-cancer
#8
Bing Guan, Kaijie Wu, Jin Zeng, Shan Xu, Lijun Mu, Yang Gao, Ke Wang, Zhenkun Ma, Juanhua Tian, Qi Shi, Peng Guo, Xinyang Wang, Dalin He, Yuefeng Du
MicroRNAs, a kind of small non-coding RNAs, can regulate gene expression by targeting mRNAs for translational repression or degradation. Much evidence has suggested that miR-218 was a tumor suppressor in many human cancers including prostate cancer. However, the underlying role of miR-218 in tumor angiogenesis and the mechanisms in PCa and other cancers remains to be unclear. Here in this present study, we demonstrated that miR-218 inhibited the tumor angiogenesis of PCa cells in vitro and in vivo. RICTOR, the mTOR component 2, was a direct target of miR-218 and miR218-RICTOR-VEGFA axis was the mechanism inhibiting the tumor angiogenesis of PCa cells...
December 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/28028034/rapamycin-insensitive-companion-of-mtor-rictor-amplification-defines-a-subset-of-advanced-gastric-cancer-and-is-sensitive-to-azd2014-mediated-mtorc1-2-inhibition
#9
S T Kim, S Y Kim, S J Klempner, J Yoon, N Kim, S Ahn, H Bang, K-M Kim, W Park, S H Park, J O Park, Y S Park, H Y Lim, S H Lee, K Park, W K Kang, J Lee
PURPOSE: Targeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed. PATIENTS AND METHODS: Tumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets...
December 27, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28025080/expression-of-mtorc1-2-related-proteins-in-primary-and-brain-metastatic-lung-adenocarcinoma
#10
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/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
#11
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/27986865/crosstalks-via-mtorc2-can-explain-enhanced-activation-in-response-to-insulin-in-diabetic-patients
#12
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/27979659/quercetin-induces-autophagy-via-foxo1-dependent-pathways-and-autophagy-suppression-enhances-quercetin-induced-apoptosis-in-pasmcs-in-hypoxia
#13
Yuanzhou He, Xiaopei Cao, Pujian Guo, Xiaochen Li, Huihui Shang, Jin Liu, Min Xie, Yongjian Xu, Xiansheng Liu
Quercetin, an important dietary flavonoid has been demonstrated to potentially reverse or even prevent pulmonary arterial hypertension (PAH) progression. However, the effects of quercetin on apoptosis and autophagy in pulmonary arterial smooth muscle cells (PASMCs) have not yet been clearly elucidated. The current study found that quercetin significantly induce the apoptotic and autophagic capacities of PASMCs in vitro and in vivo in hypoxia. In addition, we found that quercetin increases FOXO1 (a major mediator in autophagy regulation) expression and transcriptional activity...
December 13, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27965359/activation-of-the-stress-response-kinase-jnk-attenuates-insulin-action-in-retina-through-a-p70s6k1-dependent-mechanism
#14
William P Miller, Suhana Ravi, Tony D Martin, Scot R Kimball, Michael D Dennis
Despite recent advances in therapeutics, diabetic retinopathy remains a leading cause of vision impairment. Improvement in the treatment of diabetic retinopathy requires a better understanding of the molecular mechanisms that cause neurovascular complications, particularly in type 2 diabetes. The complications of diabetic retinopathy are principally caused by hyperglycemia and reduced insulin-mediated signaling. The purpose of the present study was to evaluate the impact of early type 2 diabetes on retinal insulin signaling and evaluate the mechanism(s) responsible for the changes...
December 13, 2016: Journal of Biological Chemistry
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
#15
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/27903651/t-cells-encountering-myeloid-cells-programmed-for-amino-acid-dependent-immunosuppression-use-rictor-mtorc2-protein-for-proliferative-checkpoint-decisions
#16
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 are 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 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...
January 6, 2017: 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
#17
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
#18
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-world-health-organization-histotypes-reveals-chromatin-remodelling-genes-as-major-players-and-a-prognostic-role-for-tert-rb1-men1-and-kmt2d
#19
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 (LNETs) comprising the four World Health Organization classification categories: 53 typical carcinoid (TCs), 35 atypical carcinoid (ACs), 27 large-cell neuroendocrine carcinomas, and 33 small-cell lung carcinomas. A discovery screen was conducted on 46 samples by the use of 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 LNETs by targeted NGS; their prevalence was then 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
#20
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
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