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https://www.readbyqxmd.com/read/29673648/s6-kinase-1-plays-a-key-role-in-mitochondrial-morphology-and-cellular-energy-flow
#1
Quangdon Tran, Jae-Hun Jung, Jisoo Park, Hyunji Lee, Youngeun Hong, Hyeonjeong Cho, Minhee Kim, Sungjin Park, So-Hee Kwon, Seon-Hwan Kim, George Thomas, Kwang Pyo Kim, Myung-Haing Cho, Jongsun Park
Mitochondrial morphology, which is associated with changes in metabolism, cell cycle, cell development and cell death, is tightly regulated by the balance between fusion and fission. In this study, we found that S6 kinase 1 (S6K1) contributes to mitochondrial dynamics, homeostasis and function. Mouse embryo fibroblasts lacking S6K1 (S6K1-KO MEFs) exhibited more fragmented mitochondria and a higher level of Dynamin related protein 1 (Drp1) and active Drp1 (pS616) in both whole cell extracts and mitochondrial fraction...
April 16, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29665055/s6k1-controls-epigenetic-plasticity-for-the-expression-of-pancreatic-%C3%AE-%C3%AE-cell-marker-genes
#2
Sang Ah Yi, Jieun Lee, Jong Woo Park, Jihoon Han, Min Gyu Lee, Ki Hong Nam, Jee Hun Park, Hwamok Oh, Sung Jin Ahn, Saetbyul Kim, So Hee Kwon, Dong-Gyu Jo, Jeung-Whan Han
The failure of insulin production by pancreatic β cells is a common hallmark of type 1 diabetes mellitus (T1DM). Because administration of exogenous insulin is associated with diabetes-derived complications, endogenous α to β cell transition can be an attractive alternative. Although decreased β cell size and hypoinsulinaemia have been observed in S6K1-deficient mice, the molecular mechanism underlying the involvement of S6K1 in the transcriptional regulation of insulin remains elusive. Here, we show that the hypoinsulinaemic phenotype of S6K1-deficient mice stems from the dysregulated transcription of a set of genes required for insulin and glucagon production...
April 17, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29628303/overexpression-of-tfeb-drives-a-pleiotropic-neurotrophic-effect-and-prevents-parkinson-s-disease-related-neurodegeneration
#3
Albert Torra, Annabelle Parent, Thais Cuadros, Beatriz Rodríguez-Galván, Esther Ruiz-Bronchal, Andrea Ballabio, Analía Bortolozzi, Miquel Vila, Jordi Bové
The possible implication of transcription factor EB (TFEB) as a therapeutic target in Parkinson's disease has gained momentum since it was discovered that TFEB controls lysosomal biogenesis and autophagy and that its activation might counteract lysosomal impairment and protein aggregation. However, the majority of putative direct targets of TFEB described to date is linked to a range of biological processes that are not related to the lysosomal-autophagic system. Here, we assessed the effect of overexpressing TFEB with an adeno-associated viral vector in mouse substantia nigra dopaminergic neurons...
February 27, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29621478/hyperglycemia-induced-bcl-2-bax-mediated-apoptosis-of-schwann-cells-via-mtorc1-s6k1-inhibition-in-diabetic-peripheral-neuropathy
#4
Lin Zhu, Jun Hao, Meijuan Cheng, Cuihong Zhang, Chunxiu Huo, Yaping Liu, Wei Du, Xianghong Zhang
Schwann cell apoptosis is one of the characteristics of diabetic peripheral neuropathy (DPN). The mammalian target of rapamycin (mTOR) is a multifunctional signaling pathway that regulates cell apoptosis in various types of tissues and cells. To investigate whether the mTOR pathway is involved in cell apoptosis in the Schwann cells of DPN, diabetic mice and rat Schwann cells (RSC96) were chosen to detect phospho-mTOR (Ser 2448), phospho-S6K1 (Thr 389), phospho-4EBP1 (Thr 37/46), Bcl-2, Bax and cleaved caspase-3 by diverse pathological and biological techniques...
April 2, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29617677/the-mtor-kinase-inhibitor-cz415-inhibits-human-papillary-thyroid-carcinoma-cell-growth
#5
Xiaobin Li, Zongze Li, Yimin Song, Wenjing Liu, Ziwen Liu
BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) plays an important role in papillary thyroid carcinoma (PTC) cell progression. CZ415 is a novel, highly-efficient and specific mTOR kinase inhibitor. The current study tested the potential anti-tumor activity of CZ415 in human PTC cells. METHODS: The established (TPC-1 cell line) and primary human PTC cells were treated with CZ415. Cell survival and growth were tested by Cell Counting Kit-8 assay and BrdU ELISA assay, respectively...
March 28, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29605662/the-mtor-cell-signaling-pathway-is-crucial-to-the-long-term-protective-effects-of-ischemic-postconditioning-against-stroke
#6
Peng Wang, Rong Xie, Michelle Cheng, Robert Sapolsky, Xunming Ji, Heng Zhao
Ischemic postconditioning (IPostC) protects against stroke, but few have studied the pathophysiological mechanisms of its long-term protective effects. Here, we investigated whether the mTOR pathway is involved in the long-term protective effects of IPostC. Stroke was induced in rats by distal middle cerebral artery occlusion (dMCAo) combined with 30 min of bilateral common carotid artery (CCA) occlusion, and IPostC was induced after the CCA release. Injury size and behavioral tests were measured up to 3 weeks post stroke...
March 29, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29588411/the-p85-isoform-of-the-kinase-s6k1-functions-as-a-secreted-oncoprotein-to-facilitate-cell-migration-and-tumor-growth
#7
Jianjun Zhang, Jianping Guo, Xing Qin, Bin Wang, Linli Zhang, Yingnan Wang, Wenjian Gan, Pier Paolo Pandolfi, Wantao Chen, Wenyi Wei
Cancer cells can remodel surrounding microenvironments to facilitate cell growth, invasion, and migration by secreting proteins that educate surrounding stromal cells. We report that p85S6K1 , the longest isoform of S6K (ribosomal protein S6 kinase), but not the shorter isoform p70S6K1 or p56S6K2 , was secreted from cancer cells through its HIV TAT-like, N-terminal six-arginine motif. The exogenously produced p85S6K1 protein entered cultured transformed and nontransformed cells to promote or confer malignant behaviors, leading to increased cell growth and migration...
March 27, 2018: Science Signaling
https://www.readbyqxmd.com/read/29587559/-express-involvement-of-pro-inflammation-signal-pathway-in-inhibitory-effects-of-rapamycin-on-oxaliplatin-induced-neuropathic-pain
#8
Zongsheng Duan, Zhenbo Su, Xiaochuan Pang, Hushan Wang
BACKGROUND: Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, one of the main limiting complications of OXL is painful peripheral neuropathy. The purpose of this study was to examine the underlying mechanisms by which mammalian target of rapamycin (mTOR) and its signal are responsible for OXL evoked-neuropathic pain. METHODS: Neuropathic pain was induced by intraperitoneal injection of OXL in rats...
January 1, 2018: Molecular Pain
https://www.readbyqxmd.com/read/29584425/leucine-promotes-the-growth-of-fetal-pigs-by-increasing-protein-synthesis-through-the-mtor-signaling-pathway-in-longissimus-dorsi-muscle-at-late-gestation
#9
Chaoxian Wang, Fang Chen, Wenfei Zhang, Shihai Zhang, Kui Shi, Hanqing Song, Yijiang Wang, Sun Woo Kim, Wutai Guan
Leucine (Leu) plays an important role in protein synthesis and metabolism. The present study tested whether Leu supplementation in the diet for sows during late pregnancy could improve piglet birth weight, and also investigated the possible underlying mechanism. Two hundreds sows at day 70 of pregnancy were selected and assigned to four groups fed with following four diets until farrowing respectively: corn and soybean meal-based diet group (CON), CON + 0.40% Leu, CON + 0.80% Leu and CON + 1.20% Leu. We found that supplementing with 0...
March 27, 2018: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29571618/insight-on-alpps-associating-liver-partition-and-portal-vein-ligation-for-staged-hepatectomy-mechanisms-activation-of-mtor-pathway
#10
Mario Uribe, Sebastián Uribe-Echevarría, Carlos Mandiola, María I Zapata, Francisco Riquelme, Pamela Romanque
BACKGROUND: ALPPS procedure has been introduced to increase the volume of future liver remnant. The mechanisms underlying the accelerated regeneration observed with ALPPS are unknown. It was hypothesized that AMPK/mTOR is activated as an integrating pathway for metabolic signals leading to proliferation and cell growth. Our aim was to analyze increase in liver volume, proliferation parameters and expression of AMPK/mTOR pathway-related molecules in patients undergoing ALPPS. METHODS: A single center prospective study of patients undergoing ALPPS was performed from 2013 to 2015...
March 20, 2018: HPB: the Official Journal of the International Hepato Pancreato Biliary Association
https://www.readbyqxmd.com/read/29559270/selenium-deficiency-impaired-immune-function-of-the-immune-organs-in-young-grass-carp-ctenopharyngodon-idella
#11
Lin Zheng, Lin Feng, Wei-Dan Jiang, Pei Wu, Ling Tang, Sheng-Yao Kuang, Yun-Yun Zeng, Xiao-Qiu Zhou, Yang Liu
This study aimed to investigate the effects of dietary selenium on resistance to skin haemorrhages and lesions and on immune function as well as the underlying mechanisms of those effects in the head kidney, spleen and skin of young grass carp (Ctenopharyngodon idella). A total of 540 healthy grass carp with initial body weight (226.48 ± 0.68 g) were randomly divided into six groups and fed six separate diets with graded dietary levels of selenium (0.025, 0.216, 0.387, 0.579, 0.795 and 1.049 mg/kg diet) for 80 days...
March 17, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29554013/high-frequency-neuromuscular-electrical-stimulation-increases-anabolic-signaling
#12
Joni A Mettler, Dillon M Magee, Barbara M Doucet
PURPOSE: Neuromuscular electrical stimulation (NMES) is commonly used in rehabilitation settings to increase muscle mass and strength. However, the effects of NMES on muscle growth are not clear and no human studies have compared anabolic signaling between low-frequency (LF-) and high-frequency (HF-) NMES. The purpose of this study was to determine the skeletal muscle anabolic signaling response to an acute bout of LF- and HF-NMES. METHODS: Eleven young healthy volunteers (6 men; 5 women) received an acute bout of LF- (20 Hz) and HF- (60 Hz) NMES...
March 16, 2018: Medicine and Science in Sports and Exercise
https://www.readbyqxmd.com/read/29548998/mtorc1-pathway-disruption-abrogates-the-effects-of-the-ciliary-neurotrophic-factor-on-energy-balance-and-hypothalamic-neuroinflammation
#13
Caroline André, Caterina Catania, Julie Remus-Borel, Elodie Ladeveze, Thierry Leste-Lasserre, Wilfrid Mazier, Elke Binder, Delphine Gonzales, Samantha Clark, Omar Guzman-Quevedo, Djoher Nora Abrous, Sophie Layé, Daniela Cota
Ciliary neurotrophic factor (CNTF) potently decreases food intake and body weight in diet-induced obese mice by acting through neuronal circuits and pathways located in the arcuate nucleus (ARC) of the hypothalamus. CNTF also exerts pro-inflammatory actions within the brain. Here we tested whether CNTF modifies energy balance by inducing inflammatory responses in the ARC and whether these effects depend upon the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which regulates both energy metabolism and inflammation...
March 13, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29544771/dietary-myo-inositol-deficiency-decreased-intestinal-immune-function-related-to-nf-%C3%AE%C2%BAb-and-tor-signaling-in-the-intestine-of-young-grass-carp-ctenopharyngodon-idella
#14
Shuang-An Li, Wei-Dan Jiang, Lin Feng, Yang Liu, Pei Wu, Jun Jiang, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Juan Yang, Xu Tang, He-Qun Shi, Xiao-Qiu Zhou
In this study, we investigated the effects of dietary myo-inositol on the intestinal immune barrier function and related signaling pathway in young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (221.33 ± 0.84 g) were fed six diets containing graded levels of myo-inositol (27.0, 137.9, 286.8, 438.6, 587.7 and 737.3 mg/kg) for 10 weeks. After the growth trial, fish were challenged with Aeromonas hydrophila. The results indicated that compared with the optimal dietary myo-inositol level, myo-inositol deficiency (27...
March 12, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29540819/inhibition-of-p70-s6-kinase-activity-by-a77-1726-induces-autophagy-and-enhances-the-degradation-of-superoxide-dismutase-1-sod1-protein-aggregates
#15
Jing Sun, Yarong Mu, Yuanyuan Jiang, Ruilong Song, Jianxin Yi, Jingsong Zhou, Jun Sun, Xinan Jiao, Richard A Prinz, Yi Li, Xiulong Xu
Autophagy plays a central role in degrading misfolded proteins such as mutated superoxide dismutase 1 (SOD1), which forms aggregates in motor neurons and is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is activated when UNC-51-like kinase 1 (ULK1) is phosphorylated at S555 and activated by AMP-activated protein kinase (AMPK). Autophagy is suppressed when ULK1 is phosphorylated at S757 by the mechanistic target of rapamycin (mTOR). Whether p70 S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, can also regulate autophagy remains uncertain...
March 14, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29537893/inhibition-of-mtor-s6k1-4e-bp1-signaling-by-nutraceutical-sirt1-modulators
#16
Sara Bianchi, Luca Giovannini
The mTOR pathway plays a crucial role in many human diseases, mostly associated with an over hyperactivity of the mTOR signaling, which makes its inhibitors potentially effective therapeutics. Thus, it is important to consider not only the mTOR pathway, but also all those factors that play a key role in its regulation, such as SIRT1 and AMPK. We previously demonstrated the role of some nutraceutical SIRT1 modulators in AMPK and mTOR pathway, showing the presence of a synergistic effect. Now we take further our research by evaluating the effect of berberine, quercetin, tyrosol, and ferulic acid on the mTOR/S6K1/4E-BP1 signaling, along with the existence of any synergistic effect between the following associations: berberine + tyrosol, tyrosol + ferulic acid, ferulic acid + quercetin...
April 2018: Nutrition and Cancer
https://www.readbyqxmd.com/read/29523872/the-mtor-s6-kinase-pathway-promotes-stress-granule-assembly
#17
Aristeidis P Sfakianos, Laura E Mellor, Yoke Fei Pang, Paraskevi Kritsiligkou, Hope Needs, Hussein Abou-Hamdan, Laurent Désaubry, Gino B Poulin, Mark P Ashe, Alan J Whitmarsh
Stress granules are cytoplasmic mRNA-protein complexes that form upon the inhibition of translation initiation and promote cell survival in response to environmental insults. However, they are often associated with pathologies, including neurodegeneration and cancer, and changes in their dynamics are implicated in ageing. Here we show that the mTOR effector kinases S6 kinase 1 (S6K1) and S6 kinase 2 (S6K2) localise to stress granules in human cells and are required for their assembly and maintenance after mild oxidative stress...
March 9, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29507620/s6k1-phosphorylation-dependent-degradation-of-mxi1-by-%C3%AE-trcp-ubiquitin-ligase-promotes-myc-activation-and-radioresistance-in-lung-cancer
#18
Yumei Huang, Kaishun Hu, Sheng Zhang, Xiaorong Dong, Zhongyuan Yin, Rui Meng, Yingchao Zhao, Xiaofang Dai, Tao Zhang, Kunyu Yang, Li Liu, Kai Huang, Shaojun Shi, Yu Zhang, Junjie Chen, Gang Wu, Shuangbing Xu
Rationale: Mxi1 is regarded as a potential tumor suppressor protein that antagonizes the transcriptional activity of proto-oncogene Myc. However, the clinical significances and underlying mechanisms by which Mxi1 is regulated in lung cancer remain poorly understood. Methods: Mass spectrometry analysis and immunoprecipitation assay were utilized to detect the protein-protein interaction. The phosphorylation of Mxi1 was evaluated by in vitro kinase assays. Poly-ubiquitination of Mxi1 was examined by in vivo ubiquitination assay...
2018: Theranostics
https://www.readbyqxmd.com/read/29496905/control-of-hyperglycemia-in-male-mice-by-leflunomide-mechanisms-of-action
#19
Junhong Chen, Jing Sun, Michelle E Doscas, Jin Ye, Ashley J Williamson, Yanchun Li, Yi Li, Richard A Prinz, Xiulong Xu
p70 S6 kinase (S6K1) is a serine/threonine kinase that phosphorylates the insulin receptor substrate-1 (IRS-1) at serine 1101 and desensitizes insulin receptor signaling. S6K1 hyperactivation due to overnutrition leads to hyperglycemia and type 2 diabetes. Our recent study showed that A77 1726, the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide, is an inhibitor of S6K1. Whether leflunomide can control hyperglycemia and sensitize the insulin receptor has not been tested. Here we report that A77 1726 increased AKTS473/T308 and S6K1T389 phosphorylation but decreased S6S235/236 and IRS-1S1101 phosphorylation in 3T3-L1 adipocytes, C2C12 and L6 myotubes...
April 2018: Journal of Endocrinology
https://www.readbyqxmd.com/read/29496665/a-pre-existing-rare-pik3cae545k-subpopulation-confers-clinical-resistance-to-mek-plus-cdk4-6-inhibition-in-nras-melanoma-and-is-dependent-on-s6k1-signaling
#20
Gabriele Romano, Pei-Ling Chen, Ping Song, Jennifer L McQuade, Roger J Liang, Mingguang Liu, Whijae Roh, Dzifa Y Duose, Fernando Cl Carapeto, Jun Li, Jessica Lf Teh, Andrew E Aplin, Merry Chen, Jianhua Zhang, Alexander J Lazar, Michael A Davies, P Andrew Futreal, Rodabe N Amaria, David Y Zhang, Jennifer A Wargo, Lawrence N Kwong
Combined MEK and CDK4/6 inhibition (MEKi+CDK4i) has shown promising clinical outcomes in NRAS mutant melanoma patients. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi+CDK4i therapy but subsequently developed resistance. Whole exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K pre-existed in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multi-region sampling due to PIK3CAE545K being non-uniformly distributed...
March 1, 2018: Cancer Discovery
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