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https://www.readbyqxmd.com/read/29750207/mechanistic-insights-into-the-differential-catalysis-by-rheb-and-its-mutants-y35a-and-y35a-d65a
#1
Chaithanya Kotyada, Aditi Maulik, Anand Srivastava, Mahavir Singh
RheB GTPase is a Ras-related molecular switch, which regulates the mTOR signaling pathway by cycling between the active [guanosine triphosphate (GTP)] state and inactive [guanine diphosphate (GDP)] state. Impairment of GTPase activity because of mutations in several small GTPases is known to be associated with several cancers. The conventional GTPase mechanism such as in H-Ras requires a conserved glutamine (Q64) in the switch-II region of RheB to align the catalytic water molecule for efficient GTP hydrolysis...
October 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/29743490/transcriptomic-analysis-of-crustacean-molting-gland-y-organ-regulation-via-the-mtor-signaling-pathway
#2
S Shyamal, S Das, A Guruacharya, D L Mykles, D S Durica
The intermolt crustacean Y-organ (YO) maintains a basal state mediated by pulsatile release of molt inhibiting hormone (MIH), a neuropeptide produced in the eyestalk ganglia, inhibiting YO ecdysteroidogenesis. Reduction of MIH results in YO activation and the animal enters premolt. In the crab, Gecarcinus lateralis, molting was induced by eyestalk ablation (ESA). ESA animals were injected with either rapamycin, an mTOR inhibitor, or DMSO vehicle at Day 0. YOs were harvested at 1, 3, and 7 days post-ESA and processed for high throughput RNA sequencing...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29720621/mtor-complexes-differentially-orchestrates-eosinophil-development-in-allergy
#3
Chen Zhu, Lixia Xia, Fei Li, Lingren Zhou, Qingyu Weng, Zhouyang Li, Yinfang Wu, Yuanyuan Mao, Chao Zhang, Yanping Wu, Miao Li, Songmin Ying, Zhihua Chen, Huahao Shen, Wen Li
Eosinophil infiltration is considered a hallmark in allergic airway inflammation, and the blockade of eosinophil differentiation may be an effective approach for treating eosinophil-related disorders. Mammalian target of rapamycin (mTOR) is a vital modulator in cell growth control and related diseases, and we have recently demonstrated that rapamycin can suppress eosinophil differentiation in allergic airway inflammation. Considering its critical role in haematopoiesis, we further investigated the role of mTOR in eosinophil differentiation in the context of asthmatic pathogenesis...
May 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29701696/estrogen-and-or-estrogen-receptor-%C3%AE-inhibits-bnip3-induced-apoptosis-and-autophagy-in-h9c2-cardiomyoblast-cells
#4
Bih-Cheng Chen, Yi-Jiun Weng, Marthandam Asokan Shibu, Chien-Kuo Han, Yueh-Sheng Chen, Chia-Yao Shen, Yueh-Min Lin, Vijaya Padma Viswanadha, Hsin-Yueh Liang, Chih-Yang Huang
The process of autophagy in heart cells maintains homeostasis during cellular stress such as hypoxia by removing aggregated proteins and damaged organelles and thereby protects the heart during the times of starvation and ischemia. However, autophagy can lead to substantial cell death under certain circumstances. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a hypoxia-induced marker, has been shown to induce both autophagy and apoptosis. A BNIP3-docked organelle, e.g., mitochondria, also determines whether autophagy or apoptosis will take place...
April 26, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29694882/cardiac-mtorc1-dysregulation-impacts-stress-adaptation-and-survival-in-huntington-s-disease
#5
Daniel D Child, John H Lee, Christine J Pascua, Yong Hong Chen, Alejandro Mas Monteys, Beverly L Davidson
Huntington's disease (HD) is a dominantly inherited neurological disorder caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT). But in addition to the neurological disease, mutant HTT (mHTT), which is ubiquitously expressed, impairs other organ systems. Indeed, epidemiological and animal model studies suggest higher incidence of and mortality from heart disease in HD. Here, we show that the protein complex mTORC1 is dysregulated in two HD mouse models through a mechanism that requires intrinsic mHTT expression...
April 24, 2018: Cell Reports
https://www.readbyqxmd.com/read/29677182/foxo-restricts-growth-and-differentiation-of-cells-with-elevated-torc1-activity-under-nutrient-restriction
#6
Katarzyna Nowak, Avantika Gupta, Hugo Stocker
TORC1, a central regulator of cell survival, growth, and metabolism, is activated in a variety of cancers. Loss of the tumor suppressors PTEN and Tsc1/2 results in hyperactivation of TORC1. Tumors caused by the loss of PTEN, but not Tsc1/2, are often malignant and have been shown to be insensitive to nutrient restriction (NR). In Drosophila, loss of PTEN or Tsc1 results in hypertrophic overgrowth of epithelial tissues under normal nutritional conditions, and an enhanced TORC1-dependent hyperplastic overgrowth of PTEN mutant tissue under NR...
April 20, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29670079/upregulation-of-neuronal-astrocyte-elevated-gene-1-protects-nigral-dopaminergic-neurons-in-vivo
#7
Eunju Leem, Hyung-Jun Kim, Minji Choi, Sehwan Kim, Yong-Seok Oh, Kea Joo Lee, Young-Shik Choe, Jae-Young Um, Won-Ho Shin, Jae Yeong Jeong, Byung Kwan Jin, Dong Woon Kim, Catriona McLean, Paul B Fisher, Nikolai Kholodilov, Kwang Seok Ahn, Jae Man Lee, Un Ju Jung, Seok-Geun Lee, Sang Ryong Kim
The role of astrocyte elevated gene-1 (AEG-1) in nigral dopaminergic (DA) neurons has not been studied. Here we report that the expression of AEG-1 was significantly lower in DA neurons in the postmortem substantia nigra of patients with Parkinson's disease (PD) compared to age-matched controls. Similarly, decreased AEG-1 levels were found in the 6-hydroxydopamine (6-OHDA) mouse model of PD. An adeno-associated virus-induced increase in the expression of AEG-1 attenuated the 6-OHDA-triggered apoptotic death of nigral DA neurons...
April 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29625096/molecular-characterization-and-functional-analysis-of-components-of-the-tor-pathway-of-the-salmon-louse-lepeophtheirus-salmonis-kr%C3%A3-yer-1838
#8
Liv Sandlund, Heidi Kongshaug, Frank Nilsen, Sussie Dalvin
The salmon louse Lepeophtheirus salmonis (Copepods, Caligida) is a marine ectoparasite infecting salmonid fishes in the northern hemisphere. At present, salmon lice infections are the most severe disease problem in the salmon farming industry causing significant economic losses. Due to development of resistance towards available chemotherapeutants, it is clear that new chemotherapeutants or non-chemical control methods are essential to manage the parasite in the future. The TOR signaling pathway is present in all metazoans and is a major regulator of cellular activity according to nutrient availability...
April 3, 2018: Experimental Parasitology
https://www.readbyqxmd.com/read/29588502/extensive-molecular-tinkering-in-the-evolution-of-the-membrane-attachment-mode-of-the-rheb-gtpase
#9
Kristína Záhonová, Romana Petrželková, Matus Valach, Euki Yazaki, Denis V Tikhonenkov, Anzhelika Butenko, Jan Janouškovec, Štěpánka Hrdá, Vladimír Klimeš, Gertraud Burger, Yuji Inagaki, Patrick J Keeling, Vladimír Hampl, Pavel Flegontov, Vyacheslav Yurchenko, Marek Eliáš
Rheb is a conserved and widespread Ras-like GTPase involved in cell growth regulation mediated by the (m)TORC1 kinase complex and implicated in tumourigenesis in humans. Rheb function depends on its association with membranes via prenylated C-terminus, a mechanism shared with many other eukaryotic GTPases. Strikingly, our analysis of a phylogenetically rich sample of Rheb sequences revealed that in multiple lineages this canonical and ancestral membrane attachment mode has been variously altered. The modifications include: (1) accretion to the N-terminus of two different phosphatidylinositol 3-phosphate-binding domains, PX in Cryptista (the fusion being the first proposed synapomorphy of this clade), and FYVE in Euglenozoa and the related undescribed flagellate SRT308; (2) acquisition of lipidic modifications of the N-terminal region, namely myristoylation and/or S-palmitoylation in seven different protist lineages; (3) acquisition of S-palmitoylation in the hypervariable C-terminal region of Rheb in apusomonads, convergently to some other Ras family proteins; (4) replacement of the C-terminal prenylation motif with four transmembrane segments in a novel Rheb paralog in the SAR clade; (5) loss of an evident C-terminal membrane attachment mechanism in Tremellomycetes and some Rheb paralogs of Euglenozoa...
March 27, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29570707/long-lived-rodents-reveal-signatures-of-positive-selection-in-genes-associated-with-lifespan
#10
Arne Sahm, Martin Bens, Karol Szafranski, Susanne Holtze, Marco Groth, Matthias Görlach, Cornelis Calkhoven, Christine Müller, Matthias Schwab, Johann Kraus, Hans A Kestler, Alessandro Cellerino, Hynek Burda, Thomas Hildebrandt, Philip Dammann, Matthias Platzer
The genetics of lifespan determination is poorly understood. Most research has been done on short-lived animals and it is unclear if these insights can be transferred to long-lived mammals like humans. Some African mole-rats (Bathyergidae) have life expectancies that are multiple times higher than similar sized and phylogenetically closely related rodents. To gain new insights into genetic mechanisms determining mammalian lifespans, we obtained genomic and transcriptomic data from 17 rodent species and scanned eleven evolutionary branches associated with the evolution of enhanced longevity for positively selected genes (PSGs)...
March 23, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29543440/multiplexed-real-time-nmr-gtpase-assay-for-simultaneous-monitoring-of-multiple-gef-activities-from-human-cancer-cells-and-organoids
#11
Teklab Gebregiworgis, Christopher Boyd Marshall, Tadateru Nishikawa, Nikolina Radulovich, María-José Sandi, Zhenhao Fang, Robert Rottapel, Ming-Sound Tsao, Mitsuhiko Ikura
Small GTPases (sGTPases) are critical switch-like regulators that mediate several important cellular functions and are often mutated in human cancers. They are activated by guanine nucleotide exchange factors (GEFs), which specifically catalyze the exchange of GTP for GDP. GEFs coordinate signaling networks in normal cells, and are frequently deregulated in cancers. sGTPase signaling pathways are complex and interconnected; however, most GEF assays do not reveal such complexity. In this communication, we describe the development of a unique real-time NMR-based multiplexed GEF assay that employs distinct isotopic labeling schemes for each sGTPase protein to enable simultaneous observation of six proteins of interest...
March 15, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29515755/cgef-1-regulates-mtorc1-signaling-during-adult-longevity-and-stress-response-in-c-elegans
#12
Yujie Li, Sandra Finkbeiner, Athina Ganner, Julia Gerber, Marinella Klein, Manuel Grafe, Jakob Kandzia, Antje Thien, Kathrin Thedieck, Gerhard Breves, Thomas Jank, Ralf Baumeister, Gerd Walz, Elke Neumann-Haefelin
The mechanistic target of rapamycin (mTOR) kinase is central to metabolism and growth, and has a conserved role in aging. mTOR functions in two complexes, mTORC1 and mTORC2. In diverse eukaryotes, inhibition of mTORC1 signaling increases lifespan. mTORC1 transduces anabolic signals to stimulate protein synthesis and inhibits autophagy. In this study, we demonstrate that CGEF-1, the C. elegans homolog of the human guanine nucleotide exchange factor Dbl, is a novel binding partner of RHEB-1 and activator of mTORC1 signaling in C...
February 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29512299/translocation-and-protein-complex-co-localization-of-mtor-is-associated-with-postprandial-myofibrillar-protein-synthesis-at-rest-and-after-endurance-exercise
#13
Sidney Abou Sawan, Stephan van Vliet, Justin T Parel, Joseph W Beals, Michael Mazzulla, Daniel W D West, Andrew Philp, Zhong Li, Scott A Paluska, Nicholas A Burd, Daniel R Moore
Translocation and colocalization of mechanistic target of rapamycin complex 1 (mTORC1) with regulatory proteins represents a critical step in translation initiation of protein synthesis in vitro. However, mechanistic insight into the control of postprandial skeletal muscle protein synthesis rates at rest and after an acute bout of endurance exercise in humans is lacking. In crossover trials, eight endurance-trained men received primed-continuous infusions of L-[ring-2 H5 ]phenylalanine and consumed a mixed-macronutrient meal (18 g protein, 60 g carbohydrates, 17 g fat) at rest (REST) and after 60 min of treadmill running at 70% VO2peak (EX)...
March 2018: Physiological Reports
https://www.readbyqxmd.com/read/29499960/mir-185-inhibits-fibrogenic-activation-of-hepatic-stellate-cells-and-prevents-liver-fibrosis
#14
Li Zhou, Shunai Liu, Ming Han, Yanhua Ma, Shenghu Feng, Jing Zhao, Hongping Lu, Xiaoxue Yuan, Jun Cheng
Recent studies have shown the effect of microRNAs on HSC activation and transformation, which is essential for the pathogenesis of liver fibrosis. In our study, we explored the role of miR-185 in liver fibrosis. Plasma miR-185 was detected in hepatitis B virus-related liver fibrosis patients (S2/3, n = 10) by Illumina HiSeq sequencing, and healthy volunteers were selected (n = 8) as the control group. We found that the plasma miR-185 level in fibrosis patients was significantly downregulated. CCl4 -induced fibrosis tissues in mouse livers and TGF-β1-activated HSCs also presented downregulated miR-185 concomitant with an increased expression of RHEB and RICTOR...
March 2, 2018: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29467900/overexpression-of-rheb-is-associated-with-metastasis-and-poor-prognosis-in-hepatocellular-carcinoma
#15
Fuchen Liu, Zeya Pan, Jinmin Zhang, Junsheng Ni, Chao Wang, Zhenguang Wang, Fangming Gu, Wei Dong, Weiping Zhou, Hui Liu
Aberrant expression of Ras homolog enriched in brain (RHEB) has been observed in a variety of cancer tissues and is closely associated with clinicopathological features. However, the expression profile of RHEB in patients with hepatocellular carcinoma (HCC) and its clinical signature with underlying mechanisms have not been explored thus far. To analyze the association between RHEB expression and clinicopathological features, the RHEB expression levels were determined in the present study using gene microarrays, immunohistochemistry and western blotting in 60 liver cancer tissues and 35 normal liver tissues...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29453976/cell-type-specific-expression-of-constitutively-active-rheb-promotes-regeneration-of-bulbospinal-respiratory-axons-following-cervical-sci
#16
Mark W Urban, Biswarup Ghosh, Laura R Strojny, Cole G Block, Sara M Blazejewski, Megan C Wright, George M Smith, Angelo C Lepore
Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality in individuals suffering from traumatic cervical spinal cord injury (SCI). Repair of CNS axons after SCI remains a therapeutic challenge, despite current efforts. SCI disrupts inspiratory signals originating in the rostral ventral respiratory group (rVRG) of the medulla from their phrenic motor neuron (PhMN) targets, resulting in loss of diaphragm function. Using a rat model of cervical hemisection SCI, we aimed to restore rVRG-PhMN-diaphragm circuitry by stimulating regeneration of injured rVRG axons via targeted induction of Rheb (ras homolog enriched in brain), a signaling molecule that regulates neuronal-intrinsic axon growth potential...
May 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29447953/dendrite-growth-and-the-effect-of-ectopic-rheb-expression-on-cortical-neurons
#17
Aidan M Sokolov, Caitlin M Seluzicki, Mary C Morton, David M Feliciano
Ras homology enriched in brain (Rheb) is a GTPase that activates the protein kinase mammalian Target of Rapamycin (mTOR). Rheb mutations cause intellectual delay and megalencephaly. mTOR hyperactivation causes a constellation of neurodevelopmental disorders called "mTOR-opathies" that are frequently accompanied by hyperexcitable cortical malformations. Cortical malformations within the anterior cingulate cortex (ACC) and somatosensory cortex (SSC) frequently colocalize with hyperexcitability. Although Rheb and mTOR are implicated in the formation of cortical lesions, seizure activity, and defects in neuronal migration, the contribution of Rheb to changes in neuron size and dendrite morphology is not well established...
April 3, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29422542/protection-of-nigral-dopaminergic-neurons-by-aav1-transduction-with-rheb-s16h-against-neurotoxic-inflammation-in-vivo
#18
Sehwan Kim, Gyeong Joon Moon, Yong-Seok Oh, Jungha Park, Won-Ho Shin, Jae Yeong Jeong, Kwang Shik Choi, Byung Kwan Jin, Nikolai Kholodilov, Robert E Burke, Hyung-Jun Kim, Chang Man Ha, Seok-Geun Lee, Sang Ryong Kim
We recently reported that adeno-associated virus serotype 1 (AAV1) transduction of murine nigral dopaminergic (DA) neurons with constitutively active ras homolog enriched in brain with a mutation of serine to histidine at position 16 [Rheb(S16H)] induced the production of neurotrophic factors, resulting in neuroprotective effects on the nigrostriatal DA system in animal models of Parkinson's disease (PD). To further investigate whether AAV1-Rheb(S16H) transduction has neuroprotective potential against neurotoxic inflammation, which is known to be a potential event related to PD pathogenesis, we examined the effects of Rheb(S16H) expression in nigral DA neurons under a neurotoxic inflammatory environment induced by the endogenous microglial activator prothrombin kringle-2 (pKr-2)...
February 9, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29416624/1-25-dihydroxyvitamin-d-3-inhibits-the-proliferation-of-rat-mesangial-cells-induced-by-high-glucose-via-ddit4
#19
Da-Peng Chen, Ye-Ping Ma, Li Zhuo, Zheng Zhang, Gu-Ming Zou, Yue Yang, Hong-Mei Gao, Wen-Ge Li
1,25-Dihydroxyvitamin D3 (1,25(OH)2 D3 ) is a secosteroid with antiproliferative property. It also plays a pivotal renoprotective role in diabetic nephropathy. We investigated whether 1,25(OH)2 D3 could inhibit the proliferation of rat mesangial cells exposed to high glucose via the DNA-damage-inducible transcript 4/mammalian target of rapamycin(DDIT4/mTOR) pathway. The cell proliferation rate and cell cycle duration were measured using cell counting kit-8 assay and flow cytometry. Protein expression was assayed by Western blot...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416044/a-small-molecule-inhibitor-of-rheb-selectively-targets-mtorc1-signaling
#20
Sarah J Mahoney, Sridhar Narayan, Lisa Molz, Lauren A Berstler, Seong A Kang, George P Vlasuk, Eddine Saiah
The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling...
February 7, 2018: Nature Communications
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