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https://www.readbyqxmd.com/read/27690010/recent-advances-in-understanding-amino-acid-sensing-mechanisms-that-regulate-mtorc1
#1
Liufeng Zheng, Wei Zhang, Yuanfei Zhou, Fengna Li, Hongkui Wei, Jian Peng
The mammalian target of rapamycin (mTOR) is the central regulator of mammalian cell growth, and is essential for the formation of two structurally and functionally distinct complexes: mTORC1 and mTORC2. mTORC1 can sense multiple cues such as nutrients, energy status, growth factors and hormones to control cell growth and proliferation, angiogenesis, autophagy, and metabolism. As one of the key environmental stimuli, amino acids (AAs), especially leucine, glutamine and arginine, play a crucial role in mTORC1 activation, but where and how AAs are sensed and signal to mTORC1 are not fully understood...
2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27609023/a-19-gene-expression-signature-as-a-predictor-of-survival-in-colorectal-cancer
#2
Nurul Ainin Abdul Aziz, Norfilza M Mokhtar, Roslan Harun, Md Manir Hossain Mollah, Isa Mohamed Rose, Ismail Sagap, Azmi Mohd Tamil, Wan Zurinah Wan Ngah, Rahman Jamal
BACKGROUND: Histopathological assessment has a low potential to predict clinical outcome in patients with the same stage of colorectal cancer. More specific and sensitive biomarkers to determine patients' survival are needed. We aimed to determine gene expression signatures as reliable prognostic marker that could predict survival of colorectal cancer patients with Dukes' B and C. METHODS: We examined microarray gene expression profiles of 78 archived tissues of patients with Dukes' B and C using the Illumina DASL assay...
2016: BMC Medical Genomics
https://www.readbyqxmd.com/read/27487210/mechanism-of-arginine-sensing-by-castor1-upstream-of-mtorc1
#3
Robert A Saxton, Lynne Chantranupong, Kevin E Knockenhauer, Thomas U Schwartz, David M Sabatini
The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7). Arginine activates mTORC1 upstream of the Rag family of GTPases, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1)...
August 11, 2016: Nature
https://www.readbyqxmd.com/read/26972053/the-castor-proteins-are-arginine-sensors-for-the-mtorc1-pathway
#4
Lynne Chantranupong, Sonia M Scaria, Robert A Saxton, Melanie P Gygi, Kuang Shen, Gregory A Wyant, Tim Wang, J Wade Harper, Steven P Gygi, David M Sabatini
Amino acids signal to the mTOR complex I (mTORC1) growth pathway through the Rag GTPases. Multiple distinct complexes regulate the Rags, including GATOR1, a GTPase activating protein (GAP), and GATOR2, a positive regulator of unknown molecular function. Arginine stimulation of cells activates mTORC1, but how it is sensed is not well understood. Recently, SLC38A9 was identified as a putative lysosomal arginine sensor required for arginine to activate mTORC1 but how arginine deprivation represses mTORC1 is unknown...
March 24, 2016: Cell
https://www.readbyqxmd.com/read/26884386/pulsatile-delivery-of-a-leucine-supplement-during-long-term-continuous-enteral-feeding-enhances-lean-growth-in-term-neonatal-pigs
#5
Claire Boutry, Samer W El-Kadi, Agus Suryawan, Julia Steinhoff-Wagner, Barbara Stoll, Renan A Orellana, Hanh V Nguyen, Scot R Kimball, Marta L Fiorotto, Teresa A Davis
Neonatal pigs are used as a model to study and optimize the clinical treatment of infants who are unable to maintain oral feeding. Using this model, we have previously shown that pulsatile administration of leucine during continuous feeding over 24 h via orogastric tube enhanced protein synthesis in skeletal muscle compared to continuous feeding alone. To determine the long-term effects of leucine pulses, neonatal piglets (n=11-12/group) were continuously fed formula via orogastric tube for 21 d with an additional parenteral infusion of either leucine (800 μmol·kg(-1)·h(-1), CON+LEU) or alanine (CON+ALA) for 1 h every 4 h...
February 16, 2016: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/26506891/the-amino-acid-transporter-slc38a9-regulates-mtorc1-and-autophagy
#6
EDITORIAL
Meiyan Jin, Daniel J Klionsky
The mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) is a master regulator of macroautophagy (hereafter autophagy) that responds to different environmental nutrients, including amino acids, glucose, and growth factors. The identity of the amino acid-sensing component of the MTORC1 machinery had remained elusive until a lysosomal low-affinity amino acid transporter, SLC38A9 (solute carrier family 38, member 9), was recently characterized as a novel component of the Ragulator-RRAG GTPase complex by 3 independent research groups...
2015: Autophagy
https://www.readbyqxmd.com/read/26431368/slc38a9-a-lysosomal-amino-acid-transporter-at-the-core-of-the-amino-acid-sensing-machinery-that-controls-mtorc1
#7
Manuele Rebsamen, Giulio Superti-Furga
The mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) acts as a crucial regulator of cellular metabolism by integrating growth factor presence, energy and nutrient availability to coordinate anabolic and catabolic processes, and controls cell growth and proliferation. Amino acids are critical for MTORC1 activation, but the molecular mechanisms involved in sensing their presence are just beginning to be understood. We recently reported that the previously uncharacterized amino acid transporter SLC38A9 is a member of the lysosomal sensing machinery that signals amino acid availability to MTORC1...
June 2, 2016: Autophagy
https://www.readbyqxmd.com/read/25963655/amino-acid-dependent-mtorc1-regulation-by-the-lysosomal-membrane-protein-slc38a9
#8
Jennifer Jung, Heide Marika Genau, Christian Behrends
The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many cues, such as nutrient status and energy level. Amino acids induce mTORC1 activation on lysosomes via the small Rag GTPases and the Ragulator complex, thereby controlling protein translation and cell growth. Here, we identify the human 11-pass transmembrane protein SLC38A9 as a novel component of the Rag-Ragulator complex. SLC38A9 localizes with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases in an amino acid-sensitive and nucleotide binding state-dependent manner...
July 2015: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/25567906/metabolism-lysosomal-amino-acid-transporter-slc38a9-signals-arginine-sufficiency-to-mtorc1
#9
Shuyu Wang, Zhi-Yang Tsun, Rachel L Wolfson, Kuang Shen, Gregory A Wyant, Molly E Plovanich, Elizabeth D Yuan, Tony D Jones, Lynne Chantranupong, William Comb, Tim Wang, Liron Bar-Peled, Roberto Zoncu, Christoph Straub, Choah Kim, Jiwon Park, Bernardo L Sabatini, David M Sabatini
The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid-sensitive fashion...
January 9, 2015: Science
https://www.readbyqxmd.com/read/25561175/slc38a9-is-a-component-of-the-lysosomal-amino-acid-sensing-machinery-that-controls-mtorc1
#10
Manuele Rebsamen, Lorena Pochini, Taras Stasyk, Mariana E G de Araújo, Michele Galluccio, Richard K Kandasamy, Berend Snijder, Astrid Fauster, Elena L Rudashevskaya, Manuela Bruckner, Stefania Scorzoni, Przemyslaw A Filipek, Kilian V M Huber, Johannes W Bigenzahn, Leonhard X Heinz, Claudine Kraft, Keiryn L Bennett, Cesare Indiveri, Lukas A Huber, Giulio Superti-Furga
Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses. mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H(+)-ATPase. Here we describe the uncharacterized human member 9 of the solute carrier family 38 (SLC38A9) as a lysosomal membrane-resident protein competent in amino acid transport...
March 26, 2015: Nature
https://www.readbyqxmd.com/read/24762746/new-genetic-biomarkers-predicting-azathioprine-blood-concentrations-in-combination-therapy-with-5-aminosalicylic-acid
#11
Kazuhiko Uchiyama, Tomohisa Takagi, Yasunori Iwamoto, Norihiko Kondo, Tetsuya Okayama, Naohisa Yoshida, Kazuhiro Kamada, Kazuhiro Katada, Osamu Handa, Takeshi Ishikawa, Hiroaki Yasuda, Junichi Sakagami, Hideyuki Konishi, Nobuaki Yagi, Yuji Naito, Yoshito Itoh
BACKGROUND AND AIMS: Azathioprine (AZA) is widely used for the treatment of inflammatory bowel disease (IBD) patients. AZA is catabolized by thiopurine S-methyltransferase (TPMT), which exhibits genetic polymorphisms. It has also been reported that 5-aminosalicylic acid (5-ASA) inhibits TPMT activity, and that increased 6-thioguanine nucleotide (6-TGN, a metabolite of AZA) blood concentrations result in an increased number of ADRs. In this study, single nucleotide polymorphisms (SNPs) related to differential gene expression affecting AZA drug metabolism in combination therapy with 5-ASA were examined...
2014: PloS One
https://www.readbyqxmd.com/read/23462296/microarray-based-detection-and-expression-analysis-of-abc-and-slc-transporters-in-drug-resistant-ovarian-cancer-cell-lines
#12
REVIEW
Radosław Januchowski, Piotr Zawierucha, Małgorzata Andrzejewska, Marcin Ruciński, Maciej Zabel
Multiple drug resistance of cancer cells is multifactorial. A microarray technique may provide information about new candidate genes playing a role in drug resistance. Drug membrane transporters from ABC and SLC families play a main role in this phenomenon. This study demonstrates alterations in ABC and SLC gene expression levels in methotrexate, cisplatin, doxorubicin, vincristine, topotecan and paclitaxel-resistant variant of W1 ovarian cancer cell line. Resistant W1 cell lines were derived by stepwise selection of cells in increasing concentration of drugs...
April 2013: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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