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https://www.readbyqxmd.com/read/28827765/opposite-feedback-from-mtorc1-to-h-ras-and-k-ras4b-downstream-of-srebp1
#1
Itziar M D Posada, Benoit Lectez, Farid A Siddiqui, Christina Oetken-Lindholm, Mukund Sharma, Daniel Abankwa
As a major growth factor transducer, Ras is an upstream activator of mTORC1, which further integrates nutrient and energy inputs. To ensure a contextual coupling of cell division via Ras/MAPK-signalling and growth via mTORC1-signalling, feedback loops from one pathway back to the other are required. Here we describe a novel feedback from mTORC1, which oppositely affects oncogenic H-ras- and K-ras-signalling output, and as a consequence stemness properties of tumourigenic cells. Amino acid stimulation of mTORC1 increases the processed form of SREBP1, a major lipidome regulator...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28810331/-effect-of-tsc2-gene-expression-downregulation-by-lentivirus-induced-rna-interference-on-u937-cell-line-and-its-mechanism
#2
Z F Xu, H X Liu, Y H Tan, X H Chen, F G Ren, Y F Zhang, J M Chang, N Zhang, J J Hu, H W Wang
Objective: To investigate the effect of biology and mTOR pathway activity of down-regulated TSC2 gene expression on U937 leukemia cells. Methods: Gene expression was down-regulated by lentivirus induced RNA interference on TSC2 high expressed U937 cell line; the proliferation, apoptosis and differentiation were detected by CCK-8 assay, colony formation assay and flow cytometry; the gene expression level and protein kinase activity were detected by qRT-PCR and Western blot. Results: Down-regulated expression of TSC2 gene promoted U937 cell proliferation and colony formation ability (P<0...
July 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28774889/a-dynamic-ribosomal-biogenesis-response-is-not-required-for-igf-1-mediated-hypertrophy-of-human-primary-myotubes
#3
Hannah Crossland, James A Timmons, Philip J Atherton
Increased ribosomal DNA transcription has been proposed to limit muscle protein synthesis, making ribosome biogenesis central to skeletal muscle hypertrophy. We examined the relationship between ribosomal RNA (rRNA) production and IGF-1-mediated myotube hypertrophy in vitro Primary skeletal myotubes were treated with IGF-1 (50 ng/ml) with or without 0.5 µM/L CX-5461 (CX), an inhibitor of RNA polymerase I. Myotube diameter, total protein, and RNA and DNA levels were measured along with markers of RNA polymerase I regulatory factors and regulators of protein synthesis...
August 3, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28771824/down-regulation-of-lncrna-neat1-alleviated-the-non-alcoholic-fatty-liver-disease-via-mtor-s6k1-signaling-pathway
#4
Xiang Wang
BACKGROUND: Without effective medical interventions for complete reverse of NAFLD, it needs to urgently explore the underlying molecular mechanisms of non-alcoholic fatty liver disease (NAFLD) to offer a novel therapeutic strategy for people suffering from NAFLD. METHODS: Sprague-Dawley (SD) rats were used to establish the NAFLD animal model. Lipofectamine 2000 was used to silence or over-express NEAT1. The expression of NEAT1 and the mRNA levels of ACC and FAS were determined by qRT-PCR...
August 3, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28763796/the-metabolic-regulator-mtorc1-controls-terminal-myeloid-differentiation
#5
Pui Y Lee, David B Sykes, Sarah Ameri, Demetrios Kalaitzidis, Julia F Charles, Nathan Nelson-Maney, Kevin Wei, Pierre Cunin, Allyn Morris, Astrid E Cardona, David E Root, David T Scadden, Peter A Nigrovic
Monocytes are derived from hematopoietic stem cells through a series of intermediate progenitor stages, but the factors that regulate this process are incompletely defined. Using a Ccr2/Cx3cr1 dual-reporter system to model murine monocyte ontogeny, we conducted a small-molecule screen that identified an essential role of mechanistic target of rapamycin complex 1 (mTORC1) in the development of monocytes and other myeloid cells. Confirmatory studies using mice with inducible deletion of the mTORC1 component Raptor demonstrated absence of mature circulating monocytes, as well as disruption in neutrophil and dendritic cell development, reflecting arrest of terminal differentiation at the granulocyte-monocyte progenitor stage...
May 26, 2017: Science Immunology
https://www.readbyqxmd.com/read/28744224/downregulated-translation-initiation-signaling-predisposes-low-birth-weight-neonatal-pigs-to-slower-rates-of-muscle-protein-synthesis
#6
Ying Chen, Sydney R McCauley, Sally E Johnson, Robert P Rhoads, Samer W El-Kadi
Low-birth-weight (LBWT) neonates experience restricted muscle growth in their perinatal life. Our aim was to investigate the mechanisms that contribute to slower skeletal muscle growth of LBWT neonatal pigs. Twenty-four 1-day old male LBWT (816 ± 55 g) and normal-birth-weight (NBWT; 1,642 ± 55 g) littermates (n = 12) were euthanized to collect blood and longissimus dorsi (LD) muscle subsamples. Plasma glucose, insulin, and insulin-like growth factor-I (IGF-I) were lower in LBWT compared with NBWT pigs. Muscle IGF-I mRNA expression were lower in LBWT than NBWT pigs...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28738378/akt-mtor-signaling-mediates-abnormalities-in-the-proliferation-and-apoptosis-of-ovarian-granulosa-cells-in-patients-with-polycystic-ovary-syndrome
#7
Wan-Juan Song, Xiaobo Shi, Jing Zhang, Luo Chen, Shu-Xin Fu, Yi-Ling Ding
BACKGROUND/AIMS: Abnormal apoptosis of granulosa cells (GCs) is thought to involve in the pathogenesis of polycystic ovary syndrome (PCOS); however, the associated cellular and molecular mechanisms remain unclear. METHODS: Primary GCs were obtained from healthy women and women with PCOS. The cell proliferation and apoptosis were analyzed in insulin-stimulated and insulin receptor gene (INSR) siRNA-transfected GCs. The protein expression of Akt-mTOR-S6K1 signal molecules was measured by Western blot...
July 22, 2017: Gynecologic and Obstetric Investigation
https://www.readbyqxmd.com/read/28731988/roles-of-mitogen-activating-protein-kinase-kinase-kinase-kinase-3-map4k3-in-preterm-skeletal-muscle-satellite-cell-myogenesis-and-mammalian-target-of-rapamycin-complex-1-mtorc1-activation-regulation
#8
Chu-Yi Guo, Mu-Xue Yu, Jie-Min Dai, Si-Nian Pan, Zhen-Tong Lu, Xiao-Shan Qiu, Si-Qi Zhuang
BACKGROUND Preterm skeletal muscle genesis is a paradigm for myogenesis. The role of mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3) in preterm skeletal muscle satellite cells myogenesis or its relationship to mammalian target of rapamycin complex 1 (mTORC1) activity have not been previously elaborated. MATERIAL AND METHODS Small interfering RNA (siRNA) interference technology was used to inhibit MAP4K3 expression. Leucine stimulation experiments were performed following MAP4K3-siRNA interference...
July 21, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28729914/effects-of-mtor-on-neurological-deficits-after-transient-global-ischemia
#9
Jihong Xing, Jian Lu
Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase and activation of its signal pathway plays an important role in regulating protein growth and synthesis as well as cell proliferation and survival. In the present study, we examined the contribution of mTOR and its downstream products to brain injuries and neurological deficiencies after cardiac arrest (CA) induced-transient global ischemia. CA was induced by asphyxia followed by cardiopulmonary resuscitation (CPR) in rats. Our results showed that expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1) and p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in CA rats compared to their controls...
2017: Translational Neuroscience
https://www.readbyqxmd.com/read/28728363/effect-of-different-levels-of-protein-concentrates-supplementation-on-the-growth-performance-plasma-amino-acids-profile-and-mtor-cascade-genes-expression-in-early-weaned-yak-calves
#10
Quhani Peng, Nazir Ahmad Khan, B Xue, T H Yan, Z S Ahmad Wang
Objective: Yak is anone of the most important livestock species in the alpine-meadow grasslands of Qinghai-Tibetan plateau. WeThis study evaluated the effects of different levels of protein concentrate supplementation on the growth performance of yak calves, and correlated the growth rate to the changes occurring in the plasma- amino acids, and -insulin profile, and to the signaling activity of mammalian target of rapamycin (mTOR) cascade, in order to characterize the mechanism through which the protein synthesis can be improved in early weaned yaks...
June 27, 2017: Asian-Australasian Journal of Animal Sciences
https://www.readbyqxmd.com/read/28716954/synaptically-driven-phosphorylation-of-ribosomal-protein-s6-is-differentially-regulated-at-active-synapses-versus-dendrites-and-cell-bodies-by-mapk-and-pi3k-mtor-signaling-pathways
#11
Patricia Salgado Pirbhoy, Shannon Farris, Oswald Steward
High-frequency stimulation of the medial perforant path triggers robust phosphorylation of ribosomal protein S6 (rpS6) in activated dendritic domains and granule cell bodies. Here we dissect the signaling pathways responsible for synaptically driven rpS6 phosphorylation in the dentate gyrus using pharmacological agents to inhibit PI3-kinase/mTOR and MAPK/ERK-dependent kinases. Using phospho-specific antibodies for rpS6 at different sites (ser235/236 versus ser240/244), we show that delivery of the PI3-kinase inhibitor, wortmannin, decreased rpS6 phosphorylation throughout the somatodendritic compartment (granule cell layer, inner molecular layer, outer molecular layer), especially in granule cell bodies while sparing phosphorylation at activated synapses (middle molecular layer)...
August 2017: Learning & Memory
https://www.readbyqxmd.com/read/28686577/mtor-raptor-signaling-is-critical-for-skeletogenesis-in-mice-through-the-regulation-of-runx2-expression
#12
Qinggang Dai, Zhan Xu, Xuhui Ma, Ningning Niu, Siru Zhou, Furong Xie, Lingyong Jiang, Jun Wang, Weiguo Zou
The mammalian target of rapamycin (mTOR)/regulatory-associated protein of mTOR (Raptor) pathway transmits and integrates different signals including growth factors, nutrients, and energy metabolism. Nearly all these signals have been found to play roles in skeletal biology. However, the contribution of mTOR/Raptor to osteoblast biology in vivo remains to be elucidated as the conclusions of recent studies are controversial. Here we report that mice with a deficiency of either mTOR or Raptor in preosteoblasts exhibited clavicular hypoplasia and delayed fontanelle fusion, similar to those found in human patients with cleidocranial dysplasia (CCD) haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2) or those identified in Runx2(+/-) mice...
July 7, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28670488/identification-of-ring-box-2-as-a-potential-target-for-combating-colorectal-cancer-growth-and-metastasis
#13
Xiao-Yu Wu, Jian Fang, Zhao-Jin Wang, Che Chen, Jia-Yun Liu, Guan-Nan Wu, Xue-Quan Yao, Fu-Kun Liu, Xin Zhou
Development of cancer metastasis is a key contributor to mortality in patients with colorectal cancer. High expression of RING-box 2 (RBX2) in cancer cells is known to play a key role in tumor progression. However, the role of RBX2 in colorectal cancer progression is not well elucidated. In this study, we silenced RBX2 via CRISPR/Cas9 in two colorectal cancer cell lines, HCT116 and SW480. RBX2 knockout attenuated proliferation, colony formation and enhanced sensitivity of colorectal cancer cells to paclitaxel treatment...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28650797/larp1-functions-as-a-molecular-switch-for-mtorc1-mediated-translation-of-an-essential-class-of-mrnas
#14
Sungki Hong, Mallory A Freeberg, Ting Han, Avani Kamath, Yao Yao, Tomoko Fukuda, Tsukasa Suzuki, John K Kim, Ken Inoki
The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5'TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5'TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5' and 3'UTRs of RP mRNAs and inhibits their translation...
June 26, 2017: ELife
https://www.readbyqxmd.com/read/28650457/fibroblast-growth-factor-19-regulates-skeletal-muscle-mass-and-ameliorates-muscle-wasting-in-mice
#15
Bérengère Benoit, Emmanuelle Meugnier, Martina Castelli, Stéphanie Chanon, Aurélie Vieille-Marchiset, Christine Durand, Nadia Bendridi, Sandra Pesenti, Pierre-Axel Monternier, Anne-Cécile Durieux, Damien Freyssenet, Jennifer Rieusset, Etienne Lefai, Hubert Vidal, Jérôme Ruzzin
The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro...
August 2017: Nature Medicine
https://www.readbyqxmd.com/read/28638350/branched-chain-amino-acid-ingestion-stimulates-muscle-myofibrillar-protein-synthesis-following-resistance-exercise-in-humans
#16
Sarah R Jackman, Oliver C Witard, Andrew Philp, Gareth A Wallis, Keith Baar, Kevin D Tipton
The ingestion of intact protein or essential amino acids (EAA) stimulates mechanistic target of rapamycin complex-1 (mTORC1) signaling and muscle protein synthesis (MPS) following resistance exercise. The purpose of this study was to investigate the response of myofibrillar-MPS to ingestion of branched-chain amino acids (BCAAs) only (i.e., without concurrent ingestion of other EAA, intact protein, or other macronutrients) following resistance exercise in humans. Ten young (20.1 ± 1.3 years), resistance-trained men completed two trials, ingesting either 5...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28633336/a278c-mutation-of-dihydropteridine-reductase-decreases-autophagy-via-mtor-signaling
#17
Qin Si, Sifan Sun, Yanting Gu
Dihydropteridine reductase (QDPR) plays an important role in the recycling of BH4 and is closely related to oxidative stress. We have previously reported that the overexpression of QDPR in human kidney HEK293T cells significantly protected against oxidative stress, and these beneficial effects were abolished by A278C mutation. To evaluate the effect of wild-type and mutant QDPR on autophagy and its mechanism in HEK293T cells, we constructed the wild-type and mutant QDPR expression plasmids and transfected them into HEK293T cells...
August 1, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28626016/the-mtor-substrate-s6-kinase-1-s6k1-is-a-negative-regulator-of-axon-regeneration-and-a-potential-drug-target-for-central-nervous-system-injury
#18
Hassan Al-Ali, Ying Ding, Tatiana Slepak, Wei Wu, Yan Sun, Yania Martinez, Xiao-Ming Xu, Vance P Lemmon, John L Bixby
The mammalian target of rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Although axon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold...
July 26, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28625872/decreased-enteritis-resistance-ability-by-dietary-low-or-excess-levels-of%C3%A2-lipids-through-impairing-the-intestinal-physical-and-immune-barriers-function-of-young-grass-carp-ctenopharyngodon-idella
#19
Lin Feng, Pei-Jun Ni, Wei-Dan Jiang, Pei Wu, Yang Liu, Jun Jiang, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Xu Tang, He-Qun Shi, Xiao-Qiu Zhou
The current study explores the hypothesis that low or excess levels of lipids decrease the enteritis resistance ability through impairing the intestinal physical and immune barrier function of young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp with an average initial weight of 261.41 ± 0.53 g were fed diets containing six graded levels of lipids at 5.9, 21.4, 36.0, 50.2, 66.6 and 80.1 g/kg for 8 weeks. After that, a challenge trial was conducted by injection of Aeromonas hydrophila over 2 weeks...
August 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28623128/targeting-pi3k-akt-mtor-by-ly3023414-inhibits-human-skin-squamous-cell-carcinoma-cell-growth-in%C3%A2-vitro-and-in%C3%A2-vivo
#20
Ying Zou, Minggai Ge, Xuemin Wang
Abnormal activation of PI3K-AKT-mTOR signaling is detected in human skin squamous cell carcinoma (SCC). LY3023414 is a novel, potent, and orally bio-available PI3K-AKT-mTOR inhibitor. Its activity against human skin SCC cells was tested. We demonstrated that LY3023414 was cytotoxic when added to established (A431 line) and primary (patient-derived) human skin SCC cells. LY3023414 induced G0/1-S arrest and inhibited proliferation of skin SCC cells. Moreover, LY3023414 induced activation of caspase-3/-9 and apoptosis in skin SCC cells...
August 19, 2017: Biochemical and Biophysical Research Communications
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