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https://www.readbyqxmd.com/read/28916818/identification-of-4-phenylquinolin-2-1h-one-as-a-specific-allosteric-inhibitor-of-akt
#1
Bill X Huang, Kenny Newcomer, Karl Kevala, Elena Barnaeva, Wei Zheng, Xin Hu, Samarjit Patnaik, Noel Southall, Juan Marugan, Marc Ferrer, Hee-Yong Kim
Akt plays a major role in tumorigenesis and the development of specific Akt inhibitors as effective cancer therapeutics has been challenging. Here, we report the identification of a highly specific allosteric inhibitor of Akt through a FRET-based high-throughput screening, and characterization of its inhibitory mechanism. Out of 373,868 compounds screened, 4-phenylquinolin-2(1H)-one specifically decreased Akt phosphorylation at both T308 and S473, and inhibited Akt kinase activity (IC50 = 6 µM) and downstream signaling...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28916338/structure-activity-relationship-study-of-small-molecule-inhibitors-of-the-deptor-mtor-interaction
#2
Jihye Lee, Yijiang Shi, Mario Vega, Yonghui Yang, Joseph Gera, Michael E Jung, Alan Lichtenstein
DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast...
September 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28888905/selective-interference-of-mtorc1-raptor-protects-against-human-disc-cellular-apoptosis-senescence-and-extracellular-matrix-catabolism-with-akt-and-autophagy-induction
#3
M Ito, T Yurube, K Kakutani, K Maeno, T Takada, Y Terashima, Y Kakiuchi, Y Takeoka, S Miyazaki, R Kuroda, K Nishida
OBJECTIVE: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates nutrients to execute cell growth and protein synthesis. We hypothesized that mTOR is essential for the intervertebral disc, the largest avascular, low-nutrient organ. Our objective was to elucidate roles of mTOR signaling in human disc cells. DESIGN: The mTOR exists in two complexes: mTORC1 containing regulatory-associated protein of mTOR (RAPTOR) and mTORC2 containing rapamycin-insensitive companion of mTOR (RICTOR)...
September 6, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28885497/influence-of-the-novel-atp-competitive-dual-mtorc1-2-inhibitor-azd2014-on-immune-cell-populations-and-heart-allograft-rejection
#4
Daniel Fantus, Helong Dai, Yoshihiro Ono, Alicia Watson, Shinichiro Yokota, Kanishka Mohib, Osamu Yoshida, Mark A Ross, Simon C Watkins, Bala Ramaswami, Anna Valusjkikh, David M Rothstein, Angus W Thomson
BACKGROUND: Little is known about how new generation adenosine triphosphate (ATP)-competitive mechanistic target of rapamycin (mTOR) kinase inhibitors (TORKinibs) affect immunity and allograft rejection. METHODS: mTOR complex (C) 1 and 2 signaling in dendritic cells (DC) and T cells was analyzed by Western blotting, while immune cell populations in normal and heart allograft recipient mice were analyzed by flow cytometry. Alloreactive T cell proliferation was quantified in MLR; intracellular cytokine production and serum antidonor IgG levels were determined by flow analysis and immunofluorescence staining used to detect IgG in allografts...
September 6, 2017: Transplantation
https://www.readbyqxmd.com/read/28877476/mtorc2-signaling-selectively-regulates-the-generation-and-function-of-tissue-resident-peritoneal-macrophages
#5
Min-Hee Oh, Samuel L Collins, Im-Hong Sun, Ada J Tam, Chirag H Patel, Matthew L Arwood, Yee Chan-Li, Jonathan D Powell, Maureen R Horton
Tissue-resident macrophages play critical roles in sentinel and homeostatic functions as well as in promoting inflammation and immunity. It has become clear that the generation of these cells is highly dependent upon tissue-specific cues derived from the microenvironment that, in turn, regulate unique differentiation programs. Recently, a role for GATA6 has emerged in the differentiation programming of resident peritoneal macrophages. We identify a critical role for mTOR in integrating cues from the tissue microenvironment in regulating differentiation and metabolic reprogramming...
September 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28872598/the-torc2-dependent-signaling-network-in-the-yeast-saccharomyces-cerevisiae
#6
REVIEW
Françoise M Roelants, Kristin L Leskoske, Maria Nieves Martinez Marshall, Melissa N Locke, Jeremy Thorner
To grow, eukaryotic cells must expand by inserting glycerolipids, sphingolipids, sterols, and proteins into their plasma membrane, and maintain the proper levels and bilayer distribution. A fungal cell must coordinate growth with enlargement of its cell wall. In Saccharomyces cerevisiae, a plasma membrane-localized protein kinase complex, Target of Rapamicin (TOR) complex-2 (TORC2) (mammalian ortholog is mTORC2), serves as a sensor and masterregulator of these plasma membrane- and cell wall-associated events by directly phosphorylating and thereby stimulating the activity of two types of effector protein kinases: Ypk1 (mammalian ortholog is SGK1), along with a paralog (Ypk2); and, Pkc1 (mammalian ortholog is PKN2/PRK2)...
September 5, 2017: Biomolecules
https://www.readbyqxmd.com/read/28857630/assessment-of-mtor-pathway-molecules-during-implantation-in-rats
#7
G Ekizceli, S Inan, G Oktem, E Onur, K Ozbilgin
Mammalian target of rapamycin (mTOR) is a member of the PI3K/Akt/mTOR signaling pathway that participates in cell growth, proliferation, protein synthesis, transcription, angiogenesis, apoptosis and autophagy. We investigated the role of mTOR and other signaling molecules in the rat uterus during implantation. Female pregnant rats were divided into three groups: embryonic days (ED) 4.5, 5.5 and 6.5 according to vaginal smears. Immunohistochemical staining of mTORC1, mTORC2, IGF1, PI3K, pAkt1/2/3, ERK1 and pERK1/2 was performed on formalin fixed, paraffin embedded uterine tissue samples...
August 31, 2017: Biotechnic & Histochemistry: Official Publication of the Biological Stain Commission
https://www.readbyqxmd.com/read/28834262/sex-differences-in-lifespan-extension-with-acarbose-and-17-%C3%AE-estradiol-gonadal-hormones-underlie-male-specific-improvements-in-glucose-tolerance-and-mtorc2-signaling
#8
Michael Garratt, Brian Bower, Gonzalo G Garcia, Richard A Miller
Interventions that extend lifespan in mice can show substantial sexual dimorphism. Here, we show that male-specific lifespan extension with two pharmacological treatments, acarbose (ACA) and 17-α estradiol (17aE2), is associated, in males only, with increased insulin sensitivity and improved glucose tolerance. Females, which show either smaller (ACA) or no lifespan extension (17aE2), do not derive these metabolic benefits from drug treatment. We find that these male-specific metabolic improvements are associated with enhanced hepatic mTORC2 signaling, increased Akt activity, and phosphorylation of FOXO1a - changes that might promote metabolic health and survival in males...
August 22, 2017: Aging Cell
https://www.readbyqxmd.com/read/28821013/rictor-positively-regulates-b-cell-receptor-signaling-by-modulating-actin-reorganization-via-ezrin
#9
Lu Huang, Yongjie Zhang, Chenguang Xu, Xiaomei Gu, Linlin Niu, Jinzhi Wang, Xiaoyu Sun, Xiaoming Bai, Xingtian Xuan, Qubei Li, Chunwei Shi, Bing Yu, Heather Miller, Gangyi Yang, Lisa S Westerberg, Wanli Liu, Wenxia Song, Xiaodong Zhao, Chaohong Liu
As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling...
August 2017: PLoS Biology
https://www.readbyqxmd.com/read/28819418/cenph-inhibits-rapamycin-sensitivity-by-regulating-golph3-dependent-mtor-signaling-pathway-in-colorectal-cancer
#10
Wei Wu, Fan Wu, Zaozao Wang, Jiabo Di, Jie Yang, Pin Gao, Beihai Jiang, Xiangqian Su
Background: Centromere protein H (CENPH) is known as a fundamental component of the active centromere complex, and its overexpression is correlated with poor prognosis in various solid tumors. mTOR inhibitor rapamycin has been shown to possess antitumor activity, as well as prevent intestinal tumorigenesis. However, the prognostic value of CENPH in colorectal cancer (CRC) and the role of CENPH in rapamycin sensitivity remain unknown. Materials and methods: The effect of CENPH on the cell proliferation, clonogenicity, and cell response to rapamycin in CRC were evaluated by MTT and/or colony formation assays...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28813526/mtor-has-a-developmental-stage-specific-role-in-mitochondrial-fitness-independent-of-conventional-mtorc1-and-mtorc2-and-the-kinase-activity
#11
Khalid W Kalim, Shuangmin Zhang, Xiaoyi Chen, Yuan Li, Jun-Qi Yang, Yi Zheng, Fukun Guo
The mammalian target of rapamycin (mTOR), present in mTOR complex 1 (mTORC1) and mTORC2, is a serine/threonine kinase that integrates nutrients, growth factors, and cellular energy status to control protein synthesis, cell growth, survival and metabolism. However, it remains elusive whether mTOR plays a developmental stage-specific role in tissue development and whether mTOR can function independent of its complexes and kinase activity. In this study, by inducible genetic manipulation approach, we investigated the role of mTOR and its dependence on mTOR complexes and kinase activity in mitochondrial fitness of early, progenitor stage (lineage-negative; Lin-) versus later, lineage-committed stage (lineage-positive; Lin+) of hematopoietic cells...
2017: PloS One
https://www.readbyqxmd.com/read/28789972/estrogen-receptor-alpha-and-beta-regulate-actin-polymerization-and-spatial-memory-through-an-src-1-mtorc2-dependent-pathway-in-the-hippocampus-of-female-mice
#12
Yangang Zhao, Li He, Yuanyuan Zhang, Jikai Zhao, Zhi Liu, Fangzhou Xing, Mengying Liu, Ziqi Feng, Wei Li, Jiqiang Zhang
Aging-related decline of estrogens, especially 17β-estradiol (E2), has been shown to play an important role in the impairment of learning and memory in dementias, such as Alzheimer's disease (AD), but the underlying molecular mechanisms are poorly understood. In this study, we first demonstrated decreases in E2 signaling (aromatase, classic estrogen receptor ERα and ERβ and their coactivator SRC-1), mTORC2 signaling (Rictor and phospho-AKTser473) and actin polymerization (phospho-Cofilin, Profilin-1 and the F-actin/G-actin ratio) in the hippocampus of old female mice compared with those levels detected in the adult hippocampus...
August 5, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28775290/ndrg1-promotes-adipocyte-differentiation-and-sustains-their-function
#13
Kai Cai, Rabih El-Merahbi, Mona Loeffler, Alexander E Mayer, Grzegorz Sumara
Adipocytes play a central role in maintaining metabolic homeostasis in the body. Differentiation of adipocyte precursor cells requires the transcriptional activity of peroxisome proliferator-activated receptor-γ (Pparγ) and CCAAT/enhancer binding proteins (C/Ebps). Transcriptional activity is regulated by signaling modules activated by a plethora of hormones and nutrients. Mechanistic target of rapamacin complexes (mTORC) 1 and 2 are central for the coordination of hormonal and nutritional inputs in cells and are essential for adipogenesis...
August 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28761330/epigenetic-memory-of-oxidative-stress-does-nephrilin-exert-its-protective-effects-via-rac1
#14
Desmond D Mascarenhas, David N Herndon, Istvan Arany
AIM: Nephrilin peptide, a designed inhibitor of Rictor complex (mTORC2), exerts pleiotropic protective effects in metabolic, xenobiotic and traumatic stress models. Stress can generate enduring epigenetic changes in gene function. In this work we examine the possibility that nephrilin treatment protects against acute and enduring global changes in oxidative metabolism, with a focus on the Rictor-complex-mediated activation of Rac1, a subunit of NADPH oxidase (Nox) via PKCs, Prex1 and p66shc...
2017: Biologics: Targets & Therapy
https://www.readbyqxmd.com/read/28754648/microtopographical-cues-promote-peripheral-nerve-regeneration-via-transient-mtorc2-activation
#15
Suzanne E Thomson, Chloe Charalambous, Carol-Anne Smith, Penelope M Tsimbouri, Theophile Déjardin, Paul J Kingham, Andrew M Hart, Mathis O Riehle
Despite microsurgical repair, recovery of function following peripheral nerve injury is slow and often incomplete. Outcomes could be improved by an increased understanding of the molecular biology of regeneration and by translation of experimental bioengineering strategies. Topographical cues have been shown to be powerful regulators of the rate and directionality of neurite regeneration, and in this study we investigated the downstream molecular effects of linear micropatterned structures in an organotypic explant model...
July 25, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28747804/differential-signalling-and-kinetics-of-neutrophil-extracellular-trap-release-revealed-by-quantitative-live-imaging
#16
Maarten van der Linden, Geertje H A Westerlaken, Michiel van der Vlist, Joris van Montfrans, Linde Meyaard
A wide variety of microbial and inflammatory factors induce DNA release from neutrophils as neutrophil extracellular traps (NETs). Consensus on the kinetics and mechanism of NET release has been hindered by the lack of distinctive methods to specifically quantify NET release in time. Here, we validate and refine a semi-automatic live imaging approach for quantification of NET release. Importantly, our approach is able to correct for neutrophil input and distinguishes NET release from neutrophil death by other means, aspects that are lacking in many NET quantification methods...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28746918/differential-role-of-rapamycin-in-epidermis-induced-il-15-igf-1-secretion-via-activation-of-akt-mtorc2
#17
Yang Bai, Rui Xu, Xueyuan Zhang, Xiaorong Zhang, Xiaohong Hu, Yashu Li, Haisheng Li, Meixi Liu, Zhenggen Huang, Rongshuai Yan, Weifeng He, Gaoxing Luo, Jun Wu
Backgroud/Aims: The effects of rapamycin (RPM) on wound healing have been previously studied. However, reciprocal contradictory data have been reported, and the underlying mechanism remains unclear. This study aims to uncover differential role of RPM in regulation of wound healing and explore the possible mechanism. METHODS: C57BL/6J mice and epidermal cells were treated with different doses of RPM. The wound re-epithelialization was observed by hematoxylin and eosin (HE) staining. The expression of IL-15 and IGF-1 were detected by immunohistochemistry and quantitative real-time PCR...
July 26, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28733220/pan-mtor-inhibitor-mln0128-is-effective-against-intrahepatic-cholangiocarcinoma-induced-in-mice-by-akt-and-yap-co-expression
#18
Shanshan Zhang, Xinhua Song, Dan Cao, Zhong Xu, Biao Fan, Li Che, Junjie Hu, Bin Chen, Mingjie Dong, Maria G Pilo, Antonio Cigliano, Katja Evert, Silvia Ribback, Frank Dombrowski, Rosa M Pascale, Antonio Cossu, Gianpaolo Vidili, Alberto Porcu, Maria M Simile, Giovanni M Pes, Gianluigi Giannelli, John Gordan, Lixin Wei, Matthias Evert, Wenming Cong, Diego F Calvisi, Xin Chen
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second-generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. METHODS: We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis...
July 18, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28730764/mtor-deregulation-in-oral-cavity-squamous-cell-carcinoma
#19
Nicholas S Mastronikolis, Evangelos Tsiambas, Theodoros A Papadas, Panagiotis P Fotiades, Athanasios T Papadas, Stylianos N Mastronikolis, Ioannis Kastanioudakis, Vasileios Ragos
Signal transduction pathways consist of a variety of inter- and intra-cellular molecules. They act as supporting mechanisms for cell survival and homeostasis. Among them, the phosphatidylinositol 3-kinase (PI3K)/tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a crucial role in regulating normal cell growth based on growth factor receptors (GFRs) interaction, including epidermal GFR (type II-HER2) and insulin GFR (IGF)...
May 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/28723563/a-positive-feedback-loop-between-sestrin2-and-mtorc2-is-required-for-the-survival-of-glutamine-depleted-lung-cancer-cells
#20
Jun-Kyu Byun, Yeon-Kyung Choi, Ji-Hyun Kim, Ji Yun Jeong, Hui-Jeon Jeon, Mi-Kyung Kim, Ilseon Hwang, Shin-Yup Lee, You Mie Lee, In-Kyu Lee, Keun-Gyu Park
Proper regulation of mTORC1 and mTORC2 upon nutrient starvation is critical for cancer cell survival. Upregulation of Sestrin2 in response to glutamine deprivation rescues cell death by suppressing mTORC1. However, the contribution of mTORC2 to Sestrin2-mediated mTORC1 suppression remains unclear. Here, we report that both Sestrin2 and mTORC2 are upregulated in glutamine-depleted lung cancer cells. Moreover, glutamine depletion caused Sestrin2 to associate with mTORC2, which was required for the increase in Sestrin2 protein stability and the reduction in mTORC1 activity...
July 18, 2017: Cell Reports
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