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https://www.readbyqxmd.com/read/29053970/mtorc1-activator-slc38a9-is-required-to-efflux-essential-amino-acids-from-lysosomes-and-use-protein-as-a-nutrient
#1
Gregory A Wyant, Monther Abu-Remaileh, Rachel L Wolfson, Walter W Chen, Elizaveta Freinkman, Laura V Danai, Matthew G Vander Heiden, David M Sabatini
The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins...
October 19, 2017: Cell
https://www.readbyqxmd.com/read/29053266/structure-activity-relationships-of-new-natural-product-based-diaryloxazoles-with-selective-activity-against-androgen-receptor-positive-breast-cancer-cells
#2
Andrew J Robles, Shelby McCowen, Shengxin Cai, Michaels Glassman, Francisco Ruiz, Robert H Cichewicz, Stanton F McHardy, Susan L Mooberry
Targeted therapies for ER+/PR+ and HER2-amplified breast cancers have improved patient survival, but there are no therapies for triple negative breast cancers (TNBC) that lack expression of estrogen and progesterone receptors (ER/PR), or amplification or overexpression of HER2. Gene expression profiling of TNBC has identified molecular subtypes and representative cell lines. An extract of the Texas native plant Amyris texana was found to have selective activity against MDA-MB-453 cells, a model of the luminal androgen receptor (LAR) subtype of TNBC...
October 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29051320/combinatorial-treatment-with-mtor-inhibitors-and-streptozotocin-leads-to-synergistic-in-vitro-and-in-vivo-antitumor-effects-in-insulinoma-cells
#3
Julien Bollard, Céline Patte, Patrick Massoma, Isabelle Goddard, Nicolas Gadot, Noura Benslama, Valérie Hervieu, Carole Ferraro-Peyret, Martine Cordier-Bussat, Jean-Yves Scoazec, Colette Roche, Thomas Walter, Cécile Vercherat
Streptozotocin (STZ)-based chemotherapy is the first-line chemotherapy recommended for advanced pancreatic neuroendocrine tumors (pNETs), while targeted therapies, including mTOR inhibitors, are available in second-line treatment. Unfortunately objective response rates to both treatments are limited. Since mTOR pathway activation, commonly observed in pNETs, has been reported as one of the major mechanisms accounting for chemoresistance, we investigated the potential benefit of mTOR inhibition combined with STZ treatment in a subset of pNETs, namely insulinomas...
October 19, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29050198/mtorc1-autophagy-regulated-mertk-in-mutant-brafv600-melanoma-with-acquired-resistance-to-braf-inhibition
#4
Gongda Xue, Reto Kohler, Fengyuan Tang, Debby Hynx, Yuhua Wang, Francesca Orso, Vincent Prêtre, Reto Ritschard, Petra Hirschmann, Peter Cron, Tim Roloff, Reinhard Dummer, Mario Mandalà, Sandrine Bichet, Christel Genoud, Alexandra G Meyer, Manuele G Muraro, Giulio C Spagnoli, Daniela Taverna, Curzio Rüegg, Taha Merghoub, Daniela Massi, Huifang Tang, Mitchell P Levesque, Stephan Dirnhofer, Alfred Zippelius, Brian A Hemmings, Andreas Wicki
BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29049365/myd88-dependent-inflammasome-activation-and-autophagy-inhibition-contributes-to-ehrlichia-induced-liver-injury-and-toxic-shock
#5
Muhamuda Kader, Mounia El-Azher, Jennie Vorhauer, Bhushan B Kode, Jakob Z Wells, Donna Stolz, George Michalopoulos, Alan Wells, Melanie Scott, Nahed Ismail
Severe hepatic inflammation is a common cause of acute liver injury following systemic infection with Ehrlichia, obligate Gram-negative intracellular bacteria that lack lipopolysaccharide (LPS). We have previously shown that type I IFN (IFN-I) and inflammasome activation are key host-pathogenic mediators that promote excessive inflammation and liver damage following fatal Ehrlichia infection. However, the underlying signals and mechanisms that regulate protective immunity and immunopathology during Ehrlichia infection are not well understood...
October 19, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29044175/a-skeletal-muscle-model-of-infantile-onset-pompe-disease-with-patient-specific-ips-cells
#6
Takeshi Yoshida, Tomonari Awaya, Tatsuya Jonouchi, Ryo Kimura, Shigemi Kimura, Takumi Era, Toshio Heike, Hidetoshi Sakurai
Pompe disease is caused by an inborn defect of lysosomal acid α-glucosidase (GAA) and is characterized by lysosomal glycogen accumulation primarily in the skeletal muscle and heart. Patients with the severe type of the disease, infantile-onset Pompe disease (IOPD), show generalized muscle weakness and heart failure in early infancy. They cannot survive over two years. Enzyme replacement therapy with recombinant human GAA (rhGAA) improves the survival rate, but its effect on skeletal muscle is insufficient compared to other organs...
October 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29041842/identifying-novel-small-molecule-antagonists-for-mlst8-protein-using-computational-approaches
#7
Tuleshwori Devi Sapam, Anbumani Velmurugan Ilavarasi, Bhagath Kumar Palaka, Elakkiya Elumalai, Nirmala Devi Kanika, Dinakara Rao Ampasala
Mammalian lethal with SEC13 protein 8 (mLST8), is an indispensable protein subunit of mammalian target of rapamycin (mTOR) signaling pathway that interacts with the kinase domain of mTOR protein, thereby stabilizing its active site. Experimental studies reported the over expression of mLST8 in human colon and prostate cancers by activation of both mTORC1/2 complexes and subsequent downstream substrates leading to tumor progression. Considering its role, targeting mLST8 protein would be a therapeutic approach against tumor progression in colon and prostate cancers...
October 17, 2017: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/29040000/methionine-induces-lat1-expression-in-dairy-cow-mammary-gland-by-activating-the-mtorc1-signaling-pathway
#8
Xiaoyu Duan, Ye Lin, He Lv, Yang Yang, Hongtao Jiao, Xiaoming Hou
Methionine is the limiting amino acid for milk protein synthesis in dairy cows. The effect of methionine availability on milk protein synthesis is dependent on its active transport into cells through amino acid transporters. L-type amino acid transporter 1 (LAT1), which induces the transport of neutral amino acids, is highly expressed in lactating mammary gland. However, the effect of methionine on LAT1 expression and the mechanism governing this process in dairy cow mammary gland are poorly understood. In this study, we show that treatment of dairy cow mammary epithelial cells with increasing concentrations of methionine for 24 h resulted in increased expression of LAT1 and its associated protein 4F2 heavy chain (4F2hc)...
October 17, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/29039501/isoimperatorin-ameliorates-osteoarthritis-by-downregulating-the-mammalian-target-of-rapamycin-c1-signaling-pathway
#9
Jiayao Ouyang, Huaji Jiang, Hang Fang, Wenbo Cui, Daozhang Cai
Osteoarthritis (OA) is the most common disease of the joints, and is characterized by the breakdown of cartilage and degradation of the extracellular matrix. OA causes a high level of patient suffering and incurs large societal costs; however, the current strategies for treating OA are restricted due to limited understanding of the underlying molecular and cellular mechanisms. In the present study, the beneficial effects of isoimperatorin (Iso) were investigated using an experimental mouse model of OA, and its mechanism of action on primary chondrocytes was elucidated...
October 12, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29035972/hyperammonemia-and-proteostasis-in-cirrhosis
#10
Srinivasan Dasarathy, Maria Hatzoglou
PURPOSE OF REVIEW: Skeletal muscle loss or sarcopenia is a frequent complication of cirrhosis that adversely affects clinical outcomes. As skeletal muscle is the largest store of proteins in the body, proteostasis or protein homeostasis is required for maintenance of muscle mass. This review will focus on disordered skeletal muscle proteostasis in liver disease. RECENT FINDINGS: Increased skeletal muscle uptake of ammonia initiates responses that result in disordered proteostasis including impaired protein synthesis and increased autophagy...
October 14, 2017: Current Opinion in Clinical Nutrition and Metabolic Care
https://www.readbyqxmd.com/read/29035283/mtorc1-stimulates-phosphatidylcholine-synthesis-to-promote-triglyceride-secretion
#11
William J Quinn, Min Wan, Swapnil V Shewale, Rebecca Gelfer, Daniel J Rader, Morris J Birnbaum, Paul M Titchenell
Liver triacylglycerol (TAG) synthesis and secretion are closely linked to nutrient availability. After a meal, hepatic TAG formation from fatty acids is decreased, largely due to a reduction in circulating free fatty acids (FFA). Despite the postprandial decrease in FFA-driven esterification and oxidation, VLDL-TAG secretion is maintained to support peripheral lipid delivery and metabolism. The regulatory mechanisms underlying the postprandial control of VLDL-TAG secretion remain unclear. Here, we demonstrated that the mTOR complex 1 (mTORC1) is essential for this sustained VLDL-TAG secretion and lipid homeostasis...
October 16, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29033323/mtorc1-phosphorylates-acetyltransferase-p300-to-regulate-autophagy-and-lipogenesis
#12
Wei Wan, Zhiyuan You, Yinfeng Xu, Li Zhou, Zhunlv Guan, Chao Peng, Catherine C L Wong, Hua Su, Tianhua Zhou, Hongguang Xia, Wei Liu
Acetylation is increasingly recognized as one of the major post-translational mechanisms for the regulation of multiple cellular functions in mammalian cells. Acetyltransferase p300, which acetylates histone and non-histone proteins, has been intensively studied in its role in cell growth and metabolism. However, the mechanism underlying the activation of p300 in cells remains largely unknown. Here, we identify the homeostatic sensor mTORC1 as a direct activator of p300. Activated mTORC1 interacts with p300 and phosphorylates p300 at 4 serine residues in the C-terminal domain...
October 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29030394/ptdins3p-controls-mtorc1-signaling-through-lysosomal-positioning
#13
Zhi Hong, Nina Marie Pedersen, Ling Wang, Maria Lyngaas Torgersen, Harald Stenmark, Camilla Raiborg
The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase complex that localizes to lysosomes to up-regulate anabolic processes and down-regulate autophagy. Although mTORC1 is known to be activated by lysosome positioning and by amino acid-stimulated production of phosphatidylinositol 3-phosphate (PtdIns3P) by the lipid kinase VPS34/PIK3C3, the mechanisms have been elusive. Here we present results that connect these seemingly unrelated pathways for mTORC1 activation. Amino acids stimulate recruitment of the PtdIns3P-binding protein FYCO1 to lysosomes and promote contacts between FYCO1 lysosomes and endoplasmic reticulum that contain the PtdIns3P effector Protrudin...
October 13, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29029434/silencing-protein-kinase-c-%C3%AE-by-microrna-25-5p-activates-ampk-signaling-and-inhibits-colorectal-cancer-cell-proliferation
#14
Shihu Zhang, Yiyang Zhang, Qing Cheng, Zhaoqun Ma, Guanwen Gong, Zhengming Deng, Kun Xu, Gaoyuan Wang, Yousong Wei, Xiaoping Zou
Developing novel strategies against human colorectal cancer (CRC) cells is needed. Activation of AMP-activated protein kinase (AMPK) could possibly inhibit CRC cells. Protein kinase C ζ (PKCζ) is an AMPK negative regulator. Here we found that PKCζ expression was significantly elevated in human colon cancer tissues and CRC cells. PKCζ upregulation was correlated with AMPK in-activation and mTOR complex 1 (mTORC1) over-activation. Reversely, PKCζ shRNA knockdown activated AMPK signaling and inhibited HT-29 cell proliferation...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29029388/rapamycin-induced-mir-21-promotes-mitochondrial-homeostasis-and-adaptation-in-mtorc1-activated-cells
#15
Hilaire C Lam, Heng-Jia Liu, Christian V Baglini, Harilaos Filippakis, Nicola Alesi, Julie Nijmeh, Heng Du, Alicia Llorente Lope, Katherine A Cottrill, Adam Handen, John M Asara, David J Kwiatkowski, Issam Ben-Sahra, William M Oldham, Stephen Y Chan, Elizabeth P Henske
mTORC1 hyperactivation drives the multi-organ hamartomatous disease tuberous sclerosis complex (TSC). Rapamycin inhibits mTORC1, inducing partial tumor responses; however, the tumors regrow following treatment cessation. We discovered that the oncogenic miRNA, miR-21, is increased in Tsc2-deficient cells and, surprisingly, further increased by rapamycin. To determine the impact of miR-21 in TSC, we inhibited miR-21 in vitro. miR-21 inhibition significantly repressed the tumorigenic potential of Tsc2-deficient cells and increased apoptosis sensitivity...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29027899/metformin-extends-c-elegans-lifespan-through-lysosomal-pathway
#16
Jie Chen, Yuhui Ou, Yi Li, Shumei Hu, Li-Wa Shao, Ying Liu
Metformin, a widely used first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan and delay the onset of age-related diseases. However, its primary locus of action remains unclear. Using a pure in vitro reconstitution system, we demonstrate that metformin acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 and AMPK, two hubs governing metabolic programs. We further show in Caenorhabditis elegans that both v-ATPase-mediated TORC1 inhibition and v-ATPase-AXIN/LKB1-mediated AMPK activation contribute to the lifespan extension effect of metformin...
October 13, 2017: ELife
https://www.readbyqxmd.com/read/29025968/activation-of-ampk-mtorc1-mediated-autophagy-by-metformin-reverses-clk1-deficiency-sensitized-dopaminergic-neuronal-death
#17
Qiuting Yan, Chaojun Han, Guanghui Wang, John L Waddington, Longtai Zheng, Xuechu Zhen
The autophagy-lysosome pathway (ALP) plays a critical role in the pathology of Parkinson's disease (PD). Clk1 (coq7) is a mitochondrial hydroxylase that is essential for Coenzyme Q (ubiquinone) biosynthesis. We have reported previously that Clk1 regulates microglia activation via modulating microglia metabolic reprogramming, which contributes to dopaminergic neuronal survival. This study explored the direct effect of Clk1 on dopaminergic neuronal survival. We demonstrated that Clk1 deficiency inhibited dopaminergic neuronal autophagy in cultured MN9D dopaminergic neurons and in SNc of Clk+/- mutant mice and consequently sensitized dopaminergic neuron damage and behavioral defects...
October 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29025710/opposing-actions-of-akt-protein-kinase-b-isoforms-in-vascular-smooth-muscle-injury-and-therapeutic-response
#18
Yu Jin, Yi Xie, Allison C Ostriker, Xinbo Zhang, Renjing Liu, Monica Y Lee, Kristen L Leslie, Waiho Tang, Jing Du, Seung Hee Lee, Yingdi Wang, William C Sessa, John Hwa, Jun Yu, Kathleen A Martin
OBJECTIVE: Drug-eluting stent delivery of mTORC1 (mammalian target of rapamycin complex 1) inhibitors is highly effective in preventing intimal hyperplasia after coronary revascularization, but adverse effects limit their use for systemic vascular disease. Understanding the mechanism of action may lead to new treatment strategies. We have shown that rapamycin promotes vascular smooth muscle cell differentiation in an AKT2-dependent manner in vitro. Here, we investigate the roles of AKT (protein kinase B) isoforms in intimal hyperplasia...
October 12, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29024810/magea6-promotes-human-glioma-cell-survival-via-targeting-ampk%C3%AE-1
#19
Si-Jian Pan, Jie Ren, Hong Jiang, Wei Liu, Liang-Yun Hu, Yi-Xin Pan, Bomin Sun, Qing-Fang Sun, Liu-Guan Bian
Melanoma antigen A6 (MAGEA6)/TRIM28 complex is a cancer-specific ubiquitin ligase, which degradates tumor suppressor protein AMP-activated protein kinase (AMPK). We show that MAGEA6 is uniquely expressed in human glioma tissues and cells, which is correlated with AMPKα1 downregulation. It is yet absent in normal brain tissues and human astrocytes/neuronal cells. MAGEA6 knockdown by targeted-shRNA in glioma cells restored AMPKα1 expression, causing mTORC1 in-activation and cell death/apoptosis. Reversely, AMPKα1 knockdown or mutation ameliorated glioma cell death by MAGEA6 shRNA...
October 9, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29022902/differential-regulation-of-spermatogenic-process-by-lkb1-isoforms-in-mouse-testis
#20
Feifei Kong, Mei Wang, Xiaojing Huang, Qiuling Yue, Xiang Wei, Xiaowei Dou, Xiaoxu Peng, Yuanyuan Jia, Ke Zheng, Tinghe Wu, Jun Yan, Jing Li
Liver serine/threonine kinase B1 (LKB1) is a tumor suppressor associated with the pathogenesis of Peutz-Jeghers syndrome. Affected males are at increased risk of developing Sertoli cell tumors and display defective spermatogenesis. Male mice lacking the short isoform (Lkb1S) of Lkb1 were sterile and exhibited abnormal spermiogenesis. In addition to the short isoform, the long isoform of Lkb1 (Lkb1L) is also expressed in testis; however, the requirement of the long isoform for fertility and the functional difference between the isoforms remain unknown...
October 12, 2017: Cell Death & Disease
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