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target of rapamycin

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https://www.readbyqxmd.com/read/28087344/up-regulation-of-the-active-form-of-small-gtpase-rab13-promotes-macroautophagy-in-vascular-endothelial-cells
#1
Lu Zhang, Fang Dai, LiuQing Cui, Bo Zhou, YuQi Guo
The importance of macroautophagy (hereafter referred to as autophagy) in vascular endothelial cell (VEC) biology and dysfunction is increasingly recognized, but the molecular mechanisms of autophagy in VECs in the presence of serum are still poorly understood. Previously, we identified pterostilbene as a potent autophagy inducer of VECs in the presence of serum. In this study, we used pterostilbene as a tool to induce VEC autophagy and identified the differentially expressed genes using high-throughput DAN microarray...
January 10, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28079897/tsc1-expression-by-dendritic-cells-is-required-to-preserve-t-cell-homeostasis-and-response
#2
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/28079894/mir-26-enhances-chemosensitivity-and-promotes-apoptosis-of-hepatocellular-carcinoma-cells-through-inhibiting-autophagy
#3
Fangfang Jin, Yanbo Wang, Mingzhen Li, Yanan Zhu, Hongwei Liang, Chen Wang, Feng Wang, Chen-Yu Zhang, Ke Zen, Limin Li
Hepatocellular carcinoma (HCC) generally possesses a high resistance to chemotherapy. Given that autophagy is an important factor promoting tumor chemoresistance and HCC express low level of miR-26, we aim to investigate the functional role of miR-26 in autophagy-mediated chemoresistance of HCC. We found that chemotherapeutic drug doxorubicin (Dox) induced autophagy but decreased the level of miR-26a/b in HCC cells. Activating autophagy using rapamycin can directly downregulate the level of miR-26a/b in HCC cells...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28078713/the-novel-mtor-complex-1-2-inhibitor-p529-inhibits-human-lung-myofibroblast-differentiation
#4
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/28077684/targeting-aurora-kinase-a-and-jak2-prevents-gvhd-while-maintaining-treg-and-antitumor-ctl-function
#5
Brian C Betts, Anandharaman Veerapathran, Joseph Pidala, Hua Yang, Pedro Horna, Kelly Walton, Christopher L Cubitt, Steven Gunawan, Harshani R Lawrence, Nicholas J Lawrence, Said M Sebti, Claudio Anasetti
Graft-versus-host disease (GVHD) is a leading cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation. T cell costimulation by CD28 contributes to GVHD, but prevention is incomplete when targeting CD28, downstream mammalian target of rapamycin (mTOR), or Aurora A. Likewise, interleukin-6 (IL-6)-mediated Janus kinase 2 (JAK2) signaling promotes alloreactivity, yet JAK2 inhibition does not eliminate GVHD. We provide evidence that blocking Aurora A and JAK2 in human T cells is synergistic in vitro, prevents xenogeneic GVHD, and maintains antitumor responses by cytotoxic T lymphocytes (CTLs)...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28074282/unique-findings-of-subependymal-giant-cell-astrocytoma-within-cortical-tubers-in-patients-with-tuberous-sclerosis-complex-a-histopathological-evaluation
#6
Joel S Katz, Hyman Frankel, Tracy Ma, David Zagzag, Benjamin Liechty, Bruria Ben Zeev, Michal Tzadok, Orrin Devinsky, Howard L Weiner, Jonathan Roth
INTRODUCTION: Tuberous sclerosis is associated with three central nervous system pathologies: cortical/subcortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Tubers are associated with epilepsy, which is often medication-resistant and often leads to resective surgery. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be effective reducing seizure burden in some patients with tuberous sclerosis complex (TSC)-related refractory epilepsy...
January 10, 2017: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
https://www.readbyqxmd.com/read/28072818/glucose-abl1-tor-signaling-modulates-cell-cycle-tuning-to-control-terminal-appressorial-cell-differentiation
#7
Margarita Marroquin-Guzman, Guangchao Sun, Richard A Wilson
The conserved target of rapamycin (TOR) pathway integrates growth and development with available nutrients, but how cellular glucose controls TOR function and signaling is poorly understood. Here, we provide functional evidence from the devastating rice blast fungus Magnaporthe oryzae that glucose can mediate TOR activity via the product of a novel carbon-responsive gene, ABL1, in order to tune cell cycle progression during infection-related development. Under nutrient-free conditions, wild type (WT) M. oryzae strains form terminal plant-infecting cells (appressoria) at the tips of germ tubes emerging from three-celled spores (conidia)...
January 10, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28071663/covalent-modification-of-pericardial-patches-for-sustained-rapamycin-delivery-inhibits-venous-neointimal-hyperplasia
#8
Hualong Bai, Jung Seok Lee, Elizabeth Chen, Mo Wang, Ying Xing, Tarek M Fahmy, Alan Dardik
Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours...
January 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28070992/molecular-signal-networks-and-regulating-mechanisms-of-the-unfolded-protein-response
#9
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/28070042/-effect-of-jianpi-jiedu-formula-on-tumor-angiogenesis-relevant-genes-expression-in-colorectal-cancer
#10
Dan Mao, Sanlin Lei, Jin'an Ma, Li Shi, Shaofan Zhang, Jianhua Huang, Xinyi Liu, Dengfeng Ding, Yingjin Zhang, Lei Feng, Sifang Zhang
To investigate the effect of the jianpi-jiedu formula (JPJD) on the expression of angiogenesis-relevant genes in colon cancer.
 Methods: Crude extract was obtained from JPJD by water extract method. The effect of JPJD crude extract on colon cancer cell proliferation capacity was determined by MTT assays. The IC50 value was calculated by GraphPad Prism5 software. Affymetrix gene expression profiling chip was used to detect significant differences in expressions of genes after JPJD intervention, and pathway enrichment analysis was performed to analyze the differentially expressed genes...
December 28, 2016: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
https://www.readbyqxmd.com/read/28069950/chronic-innate-immune-activation-of-tbk1-suppresses-mtorc1-activity-and-dysregulates-cellular-metabolism
#11
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
#12
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/28069741/tor-complex-2-regulated-protein-kinase-fpk1-stimulates-endocytosis-via-inhibition-of-ark1-prk1-related-protein-kinase-akl1-in-saccharomyces-cerevisiae
#13
Françoise M Roelants, Kristin L Leskoske, Ross T A Pedersen, Alexander Muir, Jeffrey M-H Liu, Gregory C Finnigan, Jeremy Thorner
Depending on the stress, plasma membrane alterations activate or inhibit yeast Target of Rapamycin (TOR) Complex 2, which, in turn, upregulates or downregulates the activity of its essential downstream effector, protein kinase Ypk1. Through phosphorylation of multiple substrates, Ypk1 controls many processes that restore homeostasis. One such substrate is protein kinase Fpk1, which is negatively regulated by Ypk1. Fpk1 phosphorylates and stimulates flippases that translocate aminoglycerophospholipids from the outer to the inner leaflet of the plasma membrane...
January 9, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28069738/fbxl5-inactivation-in-mouse-brain-induces-aberrant-proliferation-of-neural-stem-progenitor-cells
#14
Takayoshi Yamauchi, Masaaki Nishiyama, Toshiro Moroishi, Atsuki Kawamura, Keiichi I Nakayama
FBXL5 is the substrate recognition subunit of an SCF-type ubiquitin ligase that serves as a master regulator of iron metabolism in mammalian cells. We previously showed that mice with systemic deficiency of FBXL5 fail to sense intracellular iron levels and die in utero at embryonic day (E) 8.5 as a result of iron overload and subsequent oxidative stress. This early embryonic mortality has thus impeded study of the role of FBXL5 in brain development. We have now generated mice lacking FBXL5 specifically in Nestin-expressing neural stem-progenitor cells (NSPCs) in the brain...
January 9, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28069737/mtorc1-plays-an-important-role-in-skeletal-development-by-controlling-pre-osteoblast-differentiation
#15
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/28069465/effect-of-rnai-mediated-knockdown-of-nltor-gene-on-fertility-of-male-nilaparvata-lugens
#16
Ji-Chong Zhuo, Jian Xue, Jia-Bao Lu, Hai-Jian Huang, Hai-Jun Xu, Chuan-Xi Zhang
The target gene of rapamycin (TOR) is conserved from invertebrates to vertebrates, and plays critical roles in cell growth, nutrient sensing, lifespan and reproduction. In this paper, we employed RNA interference (RNAi) to study the function of TOR in male brown planthoppers (BPH), Nilaparvata lugens. Here we discovered that no offspring was produced when wildtype females BPH mated with NlTOR RNAi males. To understand the influence of NlTOR on male BPH infertility, we dissected the reproductive system of a NlTOR RNAi male, and found that the testes were normal and the seminal vesicles were full of sperm, while the accessory gland was poorly developed after knocking down NlTOR expression...
January 7, 2017: Journal of Insect Physiology
https://www.readbyqxmd.com/read/28068944/the-acceleration-of-glucose-accumulation-in-renal-cell-carcinoma-assessed-by-fdg-pet-ct-demonstrated-acquisition-of-resistance-to-tyrosine-kinase-inhibitor-therapy
#17
Noboru Nakaigawa, Keiichi Kondo, Daiki Ueno, Kazuhiro Namura, Kazuhide Makiyama, Kazuki Kobayashi, Koichi Shioi, Ichiro Ikeda, Takeshi Kishida, Tomohiro Kaneta, Ryogo Minamimoto, Ukihide Tateishi, Tomio Inoue, Masahiro Yao
BACKGROUND: Tyrosine-kinase inhibitor (TKI) targeting angiogenesis improves the prognosis of patients with metastatic renal cell carcinoma (RCC), but its effect is temporary. In order to understand the mechanism by which RCC acquires resistance to TKI, we investigated the change of glucose accumulation in RCC by FDG PET/CT when they demonstrated progression disease (PD) against TKI. METHODS: We monitored the FDG accumulation in RCC of 38 patients treated with TKI by 162 PET/CT sequentially until they were judged to demonstrate PD...
January 9, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28067669/targeting-deregulated-ampk-mtorc1-pathways-improves-muscle-function-in-myotonic-dystrophy-type-i
#18
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/28067204/cd9-monoclonal-antibody-conjugated-pegylated-liposomes-for-targeted-delivery-of-rapamycin-in-the-treatment-of-cellular-senescence
#19
Hanh Thuy Nguyen, Raj Kumar Thapa, Beom Soo Shin, Jee-Heon Jeong, Jae-Ryong Kim, Chul Soon Yong, Jong Oh Kim
Premature cellular senescence refers to the state of irreversible cell cycle arrest due to DNA damage or other stresses. In this study, CD9 monoclonal antibody (CD9mAb) was successfully conjugated to the surface of PEGylated liposomes for targeted delivery of rapamycin (LR-CD9mAb) to overcome senescence of CD9 receptor-overexpressing cells. LR-CD9mAb has a small particle size (143.3 �� 2.4 nm), narrow size distribution (polydispersity index: 0.220 �� 0.036), and negative zeta potential (���14...
January 9, 2017: Nanotechnology
https://www.readbyqxmd.com/read/28064447/up-regulation-of-mir-497-confers-resistance-to-temozolomide-in-human-glioma-cells-by-targeting-mtor-bcl-2
#20
Danhua Zhu, Ming Tu, Bo Zeng, Lin Cai, Weiming Zheng, Zhipeng Su, Zhengquan Yu
The occurrence of an inherent or acquired resistance to temozolomide (TMZ) is a major burden for patients suffering from glioma. Recently, studies have demonstrated that microRNAs play an important role in the regulation of tumor properties in cancers. However, whether miR-497 contributes to glioma resistance to chemotherapy is not fully understood. In this study, we showed that the expression of miR-497 was markedly up-regulated in TMZ-resistant glioma cells; high miR-497 expression level was associated with TMZ-resistant phenotype of glioma cells...
January 8, 2017: Cancer Medicine
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