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https://www.readbyqxmd.com/read/29352507/nuclear-and-membrane-estrogen-receptor-antagonists-induce-similar-mtorc2-activation-reversible-changes-in-synaptic-protein-expression-and-actin-polymerization-in-the-mouse-hippocampus
#1
Fang-Zhou Xing, Yan-Gang Zhao, Yuan-Yuan Zhang, Li He, Ji-Kai Zhao, Meng-Ying Liu, Yan Liu, Ji-Qiang Zhang
AIMS: Estrogens play pivotal roles in hippocampal synaptic plasticity through nuclear receptors (nERs; including ERα and ERβ) and the membrane receptor (mER; also called GPR30), but the underlying mechanism and the contributions of nERs and mER remain unclear. Mammalian target of rapamycin complex 2 (mTORC2) is involved in actin cytoskeleton polymerization and long-term memory, but whether mTORC2 is involved in the regulation of hippocampal synaptic plasticity by ERs is unclear. METHODS: We treated animals with nER antagonists (MPP/PHTPP) or the mER antagonist (G15) alone or in combination with A-443654, an activator of mTORC2...
January 19, 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29334873/nobiletin-prevents-cadmium-induced-neuronal-apoptosis-by-inhibiting-reactive-oxygen-species-and-modulating-jnk-erk1-2-and-akt-mtor-networks-in-rats
#2
Youyang Qu, Yu Liu, Li Chen, Yanmei Zhu, Xingjun Xiao, Di Wang, Yulan Zhu
Objectives Cadmium (Cd), an extremely noxious environmental pollutant is known to induce oxidative stress leading to neurodegenerative diseases. Nobiletin, a citrus flavonoid is reported to possess various pharmacological properties. This study investigates the effects of nobiletin over Cd-induced neuronal apoptosis in rodent experimental model. Methods To separate group of male Sprague Dawley rats, Cd (2 mL/kg/day) was subcutaneously injected for one month which results in a dose level of 1 mg/kg Cd. Couple of days prior to Cd injection, the treatment group rats regularly received nobiletin (50, 100, or 200 mg/kg b...
January 16, 2018: Neurological Research
https://www.readbyqxmd.com/read/29328491/microrna-let-7a-regulates-cell-autophagy-by-targeting-rictor-in-gastric-cancer-cell-lines-mgc-803-and-sgc-7901
#3
Hao Fan, Mingkun Jiang, Bowen Li, Yu He, Chi Huang, Dakui Luo, Hao Xu, Li Yang, Jundong Zhou
miR-let-7a is the most widely studied miRNA, whose functions have been well-established by scientists in both carcinogenesis and progression of human cancer, including gastric cancer (GC). However, to date there is a lack of information concerning the relationship between miR-let-7a and cellular autophagy. Using western blotting and immunofluorescence, we determined that upregulation of miR-let-7a led to increased cellular autophagic level, whereas miR-let-7a suppression decreased autophagy activity in GC cells...
January 5, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29303510/loss-of-pten-synergizes-with-c-met-to-promote-hepatocellular-carcinoma-development-via-mtorc2-pathway
#4
Zhong Xu, Junjie Hu, Hui Cao, Maria G Pilo, Antonio Cigliano, Zixuan Shao, Meng Xu, Silvia Ribback, Frank Dombrowski, Diego F Calvisi, Xin Chen
Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Activation of the AKT/mTOR cascade is one of the most frequent events along hepatocarcinogenesis. mTOR is a serine/threonine kinase and presents in two distinct complexes: mTORC1 and mTORC2. While mTORC1 has been extensively studied in HCC, the functional contribution of mTORC2 during hepatocarcinogenesis has not been well characterized, especially in vivo. Pten expression is one of the major mechanisms leading to the aberrant activation of the AKT/mTOR signaling...
January 5, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29251327/survival-pathway-of-cholangiocarcinoma-via-akt-mtor-signaling-to-escape-raf-mek-erk-pathway-inhibition-by-sorafenib
#5
Kenta Yokoi, Akira Kobayashi, Hiroaki Motoyama, Masato Kitazawa, Akira Shimizu, Tsuyoshi Notake, Takahide Yokoyama, Tomio Matsumura, Michiko Takeoka, Shin-Ichi Miyagawa
Cholangiocarcinoma (CCC) is a strongly aggressive malignancy for which surgical resection is the only potential curative therapy. Sorafenib, a multikinase inhibitor of the RAF/MEK/ERK pathway, is a molecular-targeted drug that is approved for hepatocellular carcinoma (HCC) but not for CCC. The differences in signaling pathway characteristics under sorafenib treatment between HCC (HLF, Huh7, PLC/PRF/5) and CCC (RBE, YSCCC, Huh28) cell lines were therefore investigated using cell proliferation, western blotting, and apoptosis analyses...
February 2018: Oncology Reports
https://www.readbyqxmd.com/read/29233971/implication-of-4e-bp1-protein-dephosphorylation-and-accumulation-in-pancreatic-cancer-cell-death-induced-by-combined-gemcitabine-and-trail
#6
Androulla Elia, Ricky Henry-Grant, Charlotte Adiseshiah, Catherine Marboeuf, Rebecca J Buckley, Michael J Clemens, Satvinder Mudan, Stéphane Pyronnet
Pancreatic cancer cells show varying sensitivity to the anticancer effects of gemcitabine. However, as a chemotherapeutic agent, gemcitabine can cause intolerably high levels of toxicity and patients often develop resistance to the beneficial effects of this drug. Combination studies show that use of gemcitabine with the pro-apoptotic cytokine TRAIL can enhance the inhibition of survival and induction of apoptosis of pancreatic cancer cells. Additionally, following combination treatment there is a dramatic increase in the level of the hypophosphorylated form of the tumour suppressor protein 4E-BP1...
December 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29175420/%C3%AE-1a-adrenoceptors-activate-mtor-signalling-and-glucose-uptake-in-cardiomyocytes
#7
Masaaki Sato, Bronwyn A Evans, Anna L Sandström, Ling Yeong Chia, Saori Mukaida, Bui San Thai, Anh Nguyen, Linzi Lim, Christina Yr Tan, Jo-Anne Baltos, Paul J White, Lauren T May, Dana S Hutchinson, Roger J Summers, Tore Bengtsson
The capacity of G protein-coupled receptors to modulate mammalian target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signaling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the α1A-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised α1A-AR signalling in CHO-K1 cells co-expressing the human α1A-AR and GLUT4 (CHOα1AGLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ca2+ mobilization, and phosphorylation of mTOR, Akt, 5' adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein...
November 23, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29170376/cryo-em-structure-of-saccharomyces-cerevisiae-target-of-rapamycin-complex-2
#8
Manikandan Karuppasamy, Beata Kusmider, Taiana M Oliveira, Christl Gaubitz, Manoel Prouteau, Robbie Loewith, Christiane Schaffitzel
The target of rapamycin (TOR) kinase assembles into two distinct multiprotein complexes, conserved across eukaryote evolution. In contrast to TOR complex 1 (TORC1), TORC2 kinase activity is not inhibited by the macrolide rapamycin. Here, we present the structure of Saccharomyces cerevisiae TORC2 determined by electron cryo-microscopy. TORC2 contains six subunits assembling into a 1.4 MDa rhombohedron. Tor2 and Lst8 form the common core of both TOR complexes. Avo3/Rictor is unique to TORC2, but interacts with the same HEAT repeats of Tor2 that are engaged by Kog1/Raptor in mammalian TORC1, explaining the mutual exclusivity of these two proteins...
November 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/29161318/loss-of-mtorc2-signaling-in-oligodendrocyte-precursor-cells-delays-myelination
#9
Mark D Grier, Kathryn L West, Nathaniel D Kelm, Cary Fu, Mark D Does, Brittany Parker, Eleanor McBrier, Andre H Lagrange, Kevin C Ess, Robert P Carson
Myelin abnormalities are increasingly being recognized as an important component of a number of neurologic developmental disorders. The integration of many signaling pathways and cell types are critical for correct myelinogenesis. The PI3-K and mechanistic target of rapamycin (mTOR) pathways have been found to play key roles. mTOR is found within two distinct complexes, mTORC1 and mTORC2. mTORC1 activity has been shown to play a major role during myelination, while the role of mTORC2 is not yet well understood...
2017: PloS One
https://www.readbyqxmd.com/read/29156676/uncoupling-torc2-from-agc-kinases-inhibits-tumour-growth
#10
Angus J M Cameron, Selvaraju Veeriah, Jacqueline J T Marshall, Elizabeth R Murray, Banafshé Larijani, Peter J Parker
Mammalian target of rapamycin (mTOR) is a central regulator of growth and metabolism. mTOR resides in two distinct multi-protein complexes - mTORC1 and mTORC2 - with distinct upstream regulators and downstream targets. While it is possible to specifically inhibit mTORC1 with rapamycin, or inhibit both mTOR complexes together with ATP pocket directed mTOR kinase inhibitors, it is not possible to assess the specific roles for mTORC2 pharmacologically. To overcome this, we have developed a novel, inducible, dominant negative system for disrupting substrate recruitment to mTORC2...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29113267/overexpression-of-rictor-protein-in-colorectal-cancer-is-correlated-with-tumor-progression-and-prognosis
#11
Lifeng Wang, Jia Qi, Jinlong Yu, Haijin Chen, Zhaowei Zou, Xiaohua Lin, Linlang Guo
In order to understand the clinical significance of rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) in colorectal cancer (CRC), 62 CRC tissue samples excised during operations were evaluated by immunohistochemistry. Analysis of the association between the expression level of Rictor protein and clinicopathological parameters demonstrated that the expression level of Rictor in CRC tissues was significantly higher than that in paracarcinoma tissues (P<0.0001). In cellular experiments, this result was further confirmed by comparing differences in Rictor expression between the CRC cell lines HCT116, SW480 and LoVo, and the human normal liver cell line HL-7702...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29104218/evolutionary-conservation-of-the-components-in-the-tor-signaling-pathways
#12
REVIEW
Hisashi Tatebe, Kazuhiro Shiozaki
Target of rapamycin (TOR) is an evolutionarily conserved protein kinase that controls multiple cellular processes upon various intracellular and extracellular stimuli. Since its first discovery, extensive studies have been conducted both in yeast and animal species including humans. Those studies have revealed that TOR forms two structurally and physiologically distinct protein complexes; TOR complex 1 (TORC1) is ubiquitous among eukaryotes including animals, yeast, protozoa, and plants, while TOR complex 2 (TORC2) is conserved in diverse eukaryotic species other than plants...
November 1, 2017: Biomolecules
https://www.readbyqxmd.com/read/29102771/il-13-enhances-mesenchymal-transition-of-pulmonary-artery-endothelial-cells-via-down-regulation-of-mir-424-503-in-vitro
#13
Koichi Takagi, Munekazu Yamakuchi, Takahiro Matsuyama, Kiyotaka Kondo, Akifumi Uchida, Shunsuke Misono, Teruto Hashiguchi, Hiromasa Inoue
Pulmonary arterial hypertension (PAH) has a major effect on life expectancy with functional degeneracy of the lungs and right heart. Interleukin-13 (IL-13), one of the type 2 cytokines mainly associated with allergic diseases, has recently been reported to be associated with Schistosomiasis-associated PAH which shares pathological features with other forms of PAH, such as idiopathic PAH and connective tissue disease-associated PAH. But a direct pathological role of IL-13 in the development of PAH has not been explored...
November 1, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29077002/the-role-of-mammalian-target-of-rapamycin-mtor-in-insulin-signaling
#14
REVIEW
Mee-Sup Yoon
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that controls a wide spectrum of cellular processes, including cell growth, differentiation, and metabolism. mTOR forms two distinct multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are characterized by the presence of raptor and rictor, respectively. mTOR controls insulin signaling by regulating several downstream components such as growth factor receptor-bound protein 10 (Grb10), insulin receptor substrate (IRS-1), F-box/WD repeat-containing protein 8 (Fbw8), and insulin like growth factor 1 receptor/insulin receptor (IGF-IR/IR)...
October 27, 2017: Nutrients
https://www.readbyqxmd.com/read/29072256/rapamycin-inhibits-ox-ldl-induced-inflammation-in-human-endothelial-cells-in-vitro-by-inhibiting-the-mtorc2-pkc-c-fos-pathway
#15
Juan-Juan Sun, Xiao-Wei Yin, Hui-Hui Liu, Wen-Xiu Du, Lu-Yao Shi, Ya-Bo Huang, Fen Wang, Chun-Feng Liu, Yong-Jun Cao, Yan-Lin Zhang
Rapamycin and its derivative possess anti-atherosclerosis activity, but its effects on adhesion molecule expression and macrophage adhesion to endothelial cells during atherosclerosis remain unclear. In this study we explored the effects of rapamycin on ox-LDL-induced adhesion molecule expression and macrophage adhesion to endothelial cells in vitro and the underlying mechanisms. Ox-LDL (6-48 μg/mL) dose-dependently increased the protein levels of two adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and E-selectin, in human umbilical vein endothelial cells (HUVECs), whereas pretreatment with rapamycin (1-10 μmol/L) dose-dependently inhibited ox-LDL-induced increase in the adhesion molecule expression and macrophage adhesion to endothelial cells...
October 26, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29070461/-rictor-mtorc2-regulates-blood-testis-barrier-and-spermatogenesis-in-mice
#16
He-Ling Dong, Hong-Yuan Wu, You Fu, Meng Dai, Xiao-Chun Bai, Hong Wang
OBJECTIVE: To investigate the role of Rictor/mTORC2 in the formation of blood testis barrier (BTB), testicular development, and spermatogenesis. METHODS: Amh Cre positive mice homozygous for rictor loxP with Sertoli cell specific deletion of rictor were obtained by cross breeding Amh Cre mice with rictor loxP mice. The histology of the reproductive organs, seminiferous tubules and epididymis of the transgenic mice was observed with HE staining. The cell subgroups of the germ cells in the seminiferous tubule were detected by flow cytometry with propidium iodide labeling...
October 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/29059166/mtorc2-akt-hsf1-hur-constitute-a-feed-forward-loop-regulating-rictor-expression-and-tumor-growth-in-glioblastoma
#17
B Holmes, A Benavides-Serrato, R S Freeman, K A Landon, T Bashir, R N Nishimura, J Gera
Overexpression of Rictor has been demonstrated to result in increased mechanistic target of rapamycin C2 (mTORC2) nucleation and activity leading to tumor growth and increased invasive characteristics in glioblastoma multiforme (GBM). However, the mechanisms regulating Rictor expression in these tumors is not clearly understood. In this report, we demonstrate that Rictor is regulated at the level of mRNA translation via heat-shock transcription factor 1 (HSF1)-induced HuR activity. HuR is shown to directly bind the 3' untranslated region of the Rictor transcript and enhance translational efficiency...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/29019056/physical-exercise-modulates-l-dopa-regulated-molecular-pathways-in-the-mptp-mouse-model-of-parkinson-s-disease
#18
Cornelius J H M Klemann, Helena Xicoy, Geert Poelmans, Bas R Bloem, Gerard J M Martens, Jasper E Visser
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor dysfunction. Physical exercise improves these symptoms in PD patients. To explore the molecular mechanisms underlying the beneficial effects of physical exercise, we exposed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP)-treated mice to a four-week physical exercise regimen, and subsequently explored their motor performance and the transcriptome of multiple PD-linked brain areas...
October 10, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28986255/down-regulation-of-peroxiredoxin-3-in-3t3-l1-adipocytes-leads-to-oxidation-of-rictor-in-the-mammalian-target-of-rapamycin-complex-2-mtorc2
#19
Dalay H Olson, Joel S Burrill, Jovan Kuzmicic, Wendy S Hahn, Ji-Man Park, Do-Hyung Kim, David A Bernlohr
Mitochondrially-derived oxidative stress has been implicated in the development of obesity-induced insulin resistance and is correlated with down regulation of Peroxiredoxin-3 (Prdx3). Prdx3 knockout mice exhibit whole-body insulin resistance, while Prdx3 transgenic animals remain insulin sensitive when placed on a high fat diet. To define the molecular events linking mitochondrial oxidative stress to insulin action, Prdx3 was silenced in 3T3-L1 adipocytes (Prdx3 KD) and the resultant cells evaluated for mitochondrial function, endoplasmic reticulum stress (ER stress), mitochondrial unfolded protein response (mtUPR) and insulin signaling...
November 25, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28979705/targeting-mtorc2-component-rictor-inhibits-cell-proliferation-and-promotes-apoptosis-in-gastric-cancer
#20
Yu-Hai Bian, Jia Xu, Wen-Yi Zhao, Zi-Zhen Zhang, Lin Tu, Hui Cao, Zhi-Gang Zhang
The mammalian target of rapamycin (mTOR) kinase acts downstream of phosphoinositide 3-kinase/Akt and plays an important role in tumor growth and progression of gastric cancer. It is well characterized that mTOR complex1 (mTORC1) controls cell metabolism and proliferation, whereas the contribution of mTOR complex2 (mTORC2) and its key component, Rictor, remains poorly understood. Therefore, we investigated clinical significance of Rictor expression by immunohistochemical analysis of 391 tissue samples from gastric cancer patients...
2017: American Journal of Translational Research
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