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Emil Rindom, Kristian Vissing
Loss of skeletal muscle myofibrillar protein with disease and/or inactivity can severely deteriorate muscle strength and function. Strategies to counteract wasting of muscle myofibrillar protein are therefore desirable and invite for considerations on the potential superiority of specific modes of resistance exercise and/or the adequacy of low load resistance exercise regimens as well as underlying mechanisms. In this regard, delineation of the potentially mechanosensitive molecular mechanisms underlying muscle protein synthesis (MPS), may contribute to an understanding on how differentiated resistance exercise can transduce a mechanical signal into stimulation of muscle accretion...
2016: Frontiers in Physiology
Takashi Ode, Katarzyna A Podyma-Inoue, Kazue Terasawa, Jin-Ichi Inokuchi, Toshihide Kobayashi, Tetsuro Watabe, Yuichi Izumi, Miki Hara-Yokoyama
Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism, and cell differentiation. Recent studies have revealed that the recruitment of mTORC1 to lysosomes is essential for its activation. The ceramide analogue 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a well known glycosphingolipid synthesis inhibitor, also affects the structures and functions of various organelles, including lysosomes and endoplasmic reticulum (ER). We investigated whether PDMP regulates the mTORC1 activity through its effects on organellar behavior...
November 16, 2016: Experimental Cell Research
Daniel Z Bar, Chayki Charar, Yosef Gruenbaum
The mechanistic target of rapamycin (mTOR) is an evolutionary conserved protein with a serine/threonine kinase activity that regulates cell growth, proliferation, motility, survival, protein synthesis, autophagy and transcription. It is embedded in 2 large protein complexes: mTORC1 and mTORC2. Regulation of specific mTOR pathway functions depends on multiple GTPases, that act either as regulators of mTOR protein complexes, coupling energy availability with mTORC1 activity, or as downstream effectors of both mTORC1 and mTORC2...
November 17, 2016: Small GTPases
Elena E Gorbunova, Matthew J Simons, Irina N Gavrilovskaya, Erich R Mackow
: Andes virus (ANDV) predominantly infects microvascular endothelial cells (MECs) and nonlytically causes an acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). In HPS patients, virtually every pulmonary MEC is infected, MECs are enlarged, and infection results in vascular leakage and highly lethal pulmonary edema. We observed that MECs infected with the ANDV hantavirus or expressing the ANDV nucleocapsid (N) protein showed increased size and permeability by activating the Rheb and RhoA GTPases...
October 25, 2016: MBio
Olha M Strilbytska, Uliana V Semaniuk, Kenneth B Storey, Bruce A Edgar, Oleh V Lushchak
The TOR (target of rapamycin) signaling pathway and the transcriptional factor Myc play important roles in growth control. Myc acts, in part, as a downstream target of TOR to regulate the activity and functioning of stem cells. Here we explore the role of TOR-Myc axis in stem and progenitor cells in the regulation of lifespan, stress resistance and metabolism in Drosophila. We found that both overexpression of rheb and myc-rheb in midgut stem and progenitor cells decreased the lifespan and starvation resistance of flies...
September 29, 2016: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
H Latsoudis, M-F Mashreghi, J R Grün, H-D Chang, B Stuhlmueller, A Repa, I Gergiannaki, E Kabouraki, T Haeupl, A Radbruch, P Sidiropoulos, D Kardassis, D T Boumpas, G N Goulielmos
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent, acute and self-limiting attacks of fever. Mutations in MEFV gene encoding pyrin account for FMF but the high number of heterozygote patients with typical symptoms of the disease has driven a number of alternative aetiopathogenic hypotheses. The MEFV gene was knocked down in human myelomonocytic cells that express endogenous pyrin to identify deregulated microRNAs (miRNAs). Microarray analyses revealed 29 significantly differentially expressed miRNAs implicated in pathways associated with cellular integrity and survival...
September 16, 2016: Journal of Cellular Physiology
Pra da Rosa, Amp Dau, M P De Cesaro, J T Dos Santos, B G Gasperin, R Duggavathi, V Bordignon, Pbd Gonçalves
The LH surge induces functional and morphological changes in granulosa cells. Mechanistic target of rapamycin (mTOR) is an integrator of signalling pathways in multiple cell types. We hypothesized that mTOR kinase activity integrates and modulates molecular pathways induced by LH in granulosa cells during the preovulatory period. Cows were ovariectomized and granulosa cells collected at 0, 3, 6, 12 and 24 hr after GnRH injection. While RHEB mRNA levels increased at 3 and 6 hr, returning to basal levels by 12 hr after GnRH treatment, RHOA mRNA levels increased at 6 hr and remained high thereafter...
October 2016: Reproduction in Domestic Animals, Zuchthygiene
Naoki Nitta, Satoshi Nakasu, Ayako Shima, Kazuhiko Nozaki
BACKGROUND: Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) acts as a downstream effector of phosphatidyl-inositol-3 kinase, which is frequently hyperactivated in glioblastoma multiforme and links to cell signaling in cellular proliferation, differentiation, metabolism, and survival. Although many studies have suggested the importance of mTORC1 in tumorigenesis, its role remains unclear in brain tumors other than glioblastoma. METHODS: In the present study, we evaluated the activation of mTORC1 in 24 cases of primary central nervous system lymphoma (PCNSL)...
2016: Surgical Neurology International
Reinhard Zech, Stephan Kiontke, Uwe Mueller, Andrea Oeckinghaus, Daniel Kümmel
Tuberous sclerosis complex (TSC) is caused by mutations in the TSC1 and TSC2 tumor suppressor genes. The gene products hamartin and tuberin form the TSC complex that acts as GTPase-activating protein for Rheb and negatively regulates the mammalian target of rapamycin complex 1 (mTORC1). Tuberin contains a RapGAP homology domain responsible for inactivation of Rheb, but functions of other protein domains remain elusive. Here we show that the TSC2 N terminus interacts with the TSC1 C terminus to mediate complex formation...
September 16, 2016: Journal of Biological Chemistry
Di Wu, Michelle C Klaw, Nikolai Kholodilov, Robert E Burke, Megan R Detloff, Marie-Pascale Côté, Veronica J Tom
While the peripheral branch of dorsal root ganglion neurons (DRG) can successfully regenerate after injury, lesioned central branch axons fail to regrow across the dorsal root entry zone (DREZ), the interface between the dorsal root and the spinal cord. This lack of regeneration is due to the limited regenerative capacity of adult sensory axons and the growth-inhibitory environment at the DREZ, which is similar to that found in the glial scar after a central nervous system (CNS) injury. We hypothesized that transduction of adult DRG neurons using adeno-associated virus (AAV) to express a constitutively-active form of the GTPase Rheb (caRheb) will increase their intrinsic growth potential after a dorsal root crush...
2016: Frontiers in Molecular Neuroscience
Daniel Z Bar, Chayki Charar, Jehudith Dorfman, Tam Yadid, Lionel Tafforeau, Denis L J Lafontaine, Yosef Gruenbaum
Dietary restriction (DR) is a metabolic intervention that extends the lifespan of multiple species, including yeast, flies, nematodes, rodents, and, arguably, rhesus monkeys and humans. Hallmarks of lifelong DR are reductions in body size, fecundity, and fat accumulation, as well as slower development. We have identified atx-2, the Caenorhabditis elegans homolog of the human ATXN2L and ATXN2 genes, as the regulator of these multiple DR phenotypes. Down-regulation of atx-2 increases the body size, cell size, and fat content of dietary-restricted animals and speeds animal development, whereas overexpression of atx-2 is sufficient to reduce the body size and brood size of wild-type animals...
August 9, 2016: Proceedings of the National Academy of Sciences of the United States of America
Flávia de Toledo Frias, Mariana de Mendonça, Amanda Roque Martins, Ana Flávia Gindro, Bruno Cogliati, Rui Curi, Alice Cristina Rodrigues
High-fat diet (HFD) feeding causes insulin resistance (IR) in skeletal muscle of mice, which affects skeletal muscle metabolism and function. The involvement of muscle-specific microRNAs in the evolution of skeletal muscle IR during 4, 8, and 12 weeks in HFD-induced obese mice was investigated. After 4 weeks in HFD, mice were obese, hyperglycemic, and hyperinsulinemic; however, their muscles were responsive to insulin stimuli. Expressions of MyomiRs (miR-1, miR-133a, and miR-206) measured in soleus muscles were not different from those found in control mice...
2016: Frontiers in Endocrinology
Tom Mejuch, Herbert Waldmann
Protein lipidation is one of the major post-translational modifications (PTM) of proteins. The attachment of the lipid moiety frequently determines the localization and the function of the lipoproteins. Lipidated proteins participate in many essential biological processes in eukaryotic cells, including vesicular trafficking, signal transduction, and regulation of the immune response. Malfunction of these cellular processes usually leads to various diseases such as cancer. Understanding the mechanism of cellular signaling and identifying the protein-protein and protein-lipid interactions in which the lipoproteins are involved is a crucial task...
August 17, 2016: Bioconjugate Chemistry
Nishant Mohan, Yi Shen, Milos Dokmanovic, Yukinori Endo, Dianne S Hirsch, Wen Jin Wu
VPS34 is reported to activate S6K1 and is implicated in regulating cell growth, the mechanisms of which remain elusive. Here, we describe novel mechanisms by which VPS34 upregulates mTOR/S6K1 activity via downregulating TSC2 protein and activating RheB activity. Specifically, upregulation of VPS34 lipid kinase increases local production of ptdins(3)p in the plasma membrane, which recruits PIKFYVE, a FYVE domain containing protein, to ptdins(3)p enriched regions of the plasma membrane, where VPS34 forms a protein complex with PIKFYVE and TSC1...
July 7, 2016: Oncotarget
Y Wang, X Hong, J Wang, Y Yin, Y Zhang, Y Zhou, H-L Piao, Z Liang, L Zhang, G Li, G Xu, D J Kwiatkowski, Y Liu
Rheb is a Ras family GTPase, which binds to and activates mammalian target of rapamycin complex 1 (mTORC1) when GTP loaded. Recently, cancer genome sequencing efforts have identified recurrent Rheb Tyr35Asn mutations in kidney and endometrial carcinoma. Here we show that Rheb-Y35N causes not only constitutive mTORC1 activation, but sustained activation of the MEK-ERK pathway in a TSC1/TSC2/TBC1D7 protein complex and mTORC1-independent manner, contributing to intrinsic resistance to rapamycin. Rheb-Y35N transforms NIH3T3 cells, resulting in aggressive tumor formation in xenograft nude mice, which could be suppressed by combined treatment with rapamycin and an extracellular signal-regulated kinase (ERK) inhibitor...
July 11, 2016: Oncogene
Fan Diao, Chen Jiang, Xiu-Xing Wang, Rui-Lou Zhu, Qiang Wang, Bing Yao, Chao-Jun Li
Spermatogenesis in adulthood depends on the successful neonatal establishment of the spermatogonial stem cell (SSC) pool and gradual differentiation during puberty. The stage-dependent changes in protein prenylation in the seminiferous epithelium might be important during the first round of spermatogenesis before sexual maturation, but the mechanisms are unclear. We have previous found that altered prenylation in Sertoli cells induced spermatogonial apoptosis in the neonatal testis, resulting in adult infertility...
2016: Scientific Reports
William Apró, Marcus Moberg, Hans-Christer Holmberg, Eva Blomstrand
No abstract text is available yet for this article.
May 2016: Medicine and Science in Sports and Exercise
Xiao-Min Wang, Qiao-Zhu Xu, Ya-Nan Gao, Juan Gao, Ming-Hao Li, Wan-Zhu Yang, Jiang-Xiang Wang, Wei-Ping Yuan
OBJECTIVE: To investigate the role of Rheb (mTOR activator) in AML development by measuring Rheb expression in bone marrow of adult AML patients and in AML cell line HL-60. METHODS: Real-time PCR assay was used to measure the Rheb mRNA expression in 27 AML patients and 29 ITP patients as control. The relationship between Rheb mRNA expression and age, AML subtype, fusion gene, splenomegaly, hepatomegaly and survival of AML patients was analyzed and compared. In addition, HL-60 cell line over-expressing Rheb was established, and the HL-60 cells and HL-60 cells with overexpression of Rheb were treated with Ara-C of different concentrations, the proliferation level was detected by CCK-8 method, and the IC50 was calculated...
June 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
Vinod K Srivastava, Jill K Hiney, William L Dees
Low-dose administration of manganese chloride (MnCl2) causes release of hypothalamic LH-releasing hormone (LHRH) and advances puberty in rat. Recently, this element was shown to up-regulate mammalian target of rapamycin (mTOR), kisspeptin gene (KiSS-1), and LHRH gene expressions in the brain preoptic area (POA)/anteroventral periventricular (AVPV) nucleus. Because these genes are critical for puberty, this study was conducted to identify the upstream mechanism by which Mn activates the mTOR/KiSS-1 pathway. On day 12, immature female rats began receiving a daily supplemental dose of 10 mg/kg of MnCl2 or saline by gavage, and POA/AVPV tissues were collected on day 29 for specific protein assessments...
August 2016: Endocrinology
Yingpeng Liu, Lakshmi Kelamangalath, Hyukmin Kim, Seung Baek Han, Xiaoqing Tang, Jinbin Zhai, Jee W Hong, Shen Lin, Young-Jin Son, George M Smith
Although previous studies have identified several strategies to stimulate regeneration of CNS axons, extensive regeneration and functional recovery have remained a major challenge, particularly for large diameter myelinated axons. Within the CNS, myelin is thought to inhibit axon regeneration, while modulating activity of the mTOR pathway promotes regeneration of injured axons. In this study, we examined NT-3 mediated regeneration of sensory axons through the dorsal root entry zone in a triple knockout of myelin inhibitory proteins or after activation of mTOR using a constitutively active (ca) Rheb in DRG neurons to determine the influence of environmental inhibitory or activation of intrinsic growth pathways could enhance NT-3-mediate regeneration...
September 2016: Experimental Neurology
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