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Pesquisa : D05.500.356.500 [Categoria DeCS]
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[PMID]:28986255
[Au] Autor:Olson DH; Burrill JS; Kuzmicic J; Hahn WS; Park JM; Kim DH; Bernlohr DA
[Ad] Endereço:Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
[Ti] Título:Down regulation of Peroxiredoxin-3 in 3T3-L1 adipocytes leads to oxidation of Rictor in the mammalian-target of rapamycin complex 2 (mTORC2).
[So] Source:Biochem Biophys Res Commun;493(3):1311-1317, 2017 Nov 25.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitochondrially-derived oxidative stress has been implicated in the development of obesity-induced insulin resistance and is correlated with down regulation of Peroxiredoxin-3 (Prdx3). Prdx3 knockout mice exhibit whole-body insulin resistance, while Prdx3 transgenic animals remain insulin sensitive when placed on a high fat diet. To define the molecular events linking mitochondrial oxidative stress to insulin action, Prdx3 was silenced in 3T3-L1 adipocytes (Prdx3 KD) and the resultant cells evaluated for mitochondrial function, endoplasmic reticulum stress (ER stress), mitochondrial unfolded protein response (mtUPR) and insulin signaling. Prdx3 KD cells exhibit a two-fold increase in H O , reduced insulin-stimulated glucose transport and attenuated S phosphorylation of the mTORC2 substrate, Akt. Importantly, the decrease in glucose uptake can be rescued by pre-treatment with the antioxidant N-acetyl-cysteine (NAC). The changes in insulin sensitivity occur independently from activation of the ER stress or mtUPR pathways. Analysis of mTORC2, the complex responsible for phosphorylating Akt at S , reveals increased cysteine oxidation of Rictor in Prdx3 KD cells that can be rescued with NAC. Taken together, these data suggest mitochondrial dysfunction in adipocytes may attenuate insulin signaling via oxidation of the mammalian-target of rapamycin complex 2 (mTORC2).
[Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo
Complexos Multiproteicos/metabolismo
Peroxirredoxina III/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Células 3T3-L1
Acetilcisteína/farmacologia
Adipócitos/metabolismo
Animais
Transporte Biológico/efeitos dos fármacos
Regulação para Baixo
Glucose/metabolismo
Insulina/farmacologia
Resistência à Insulina
Alvo Mecanístico do Complexo 2 de Rapamicina
Camundongos
Camundongos Endogâmicos C57BL
Mitocôndrias/metabolismo
Oxirredução
Estresse Oxidativo/efeitos dos fármacos
Peroxirredoxina III/genética
Fosforilação
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteína Companheira de mTOR Insensível à Rapamicina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Insulin); 0 (Multiprotein Complexes); 0 (Prdx3 protein, mouse); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (rictor protein, mouse); EC 1.11.1.15 (Peroxiredoxin III); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); IY9XDZ35W2 (Glucose); WYQ7N0BPYC (Acetylcysteine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171008
[St] Status:MEDLINE


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[PMID]:28821013
[Au] Autor:Huang L; Zhang Y; Xu C; Gu X; Niu L; Wang J; Sun X; Bai X; Xuan X; Li Q; Shi C; Yu B; Miller H; Yang G; Westerberg LS; Liu W; Song W; Zhao X; Liu C
[Ad] Endereço:Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.
[Ti] Título:Rictor positively regulates B cell receptor signaling by modulating actin reorganization via ezrin.
[So] Source:PLoS Biol;15(8):e2001750, 2017 Aug.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling. We found that the key positive and negative BCR signaling molecules, phosphorylated Brutons tyrosine kinase (pBtk) and phosphorylated SH2-containing inositol phosphatase (pSHIP), are reduced and enhanced, respectively, in Rictor KO B cells. This suggests that Rictor positively regulates the early events of BCR signaling. We found that the cellular filamentous actin (F-actin) is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration is associated with a decreased humoral immune response in Rictor KO mice. The inhibition of actin polymerization with latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, in which Rictor regulates BCR signaling via actin reorganization.
[Mh] Termos MeSH primário: Actinas/metabolismo
Linfócitos B/metabolismo
Proteínas de Transporte/metabolismo
Proteínas do Citoesqueleto/metabolismo
Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo
Proteínas Tirosina Quinases/metabolismo
[Mh] Termos MeSH secundário: Animais
Compostos Bicíclicos Heterocíclicos com Pontes
Membrana Celular/metabolismo
Imunidade Humoral
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Polimerização
Proteína Companheira de mTOR Insensível à Rapamicina
Tiazolidinas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Carrier Proteins); 0 (Cytoskeletal Proteins); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (Thiazolidines); 0 (ezrin); 0 (rictor protein, mouse); EC 2.7.10.1 (Agammaglobulinaemia tyrosine kinase); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 3.1.3.86 (Inpp5d protein, mouse); EC 3.1.3.86 (Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases); LW7U308U7U (latrunculin B)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2001750


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[PMID]:28789972
[Au] Autor:Zhao Y; He L; Zhang Y; Zhao J; Liu Z; Xing F; Liu M; Feng Z; Li W; Zhang J
[Ad] Endereço:Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
[Ti] Título:Estrogen receptor alpha and beta regulate actin polymerization and spatial memory through an SRC-1/mTORC2-dependent pathway in the hippocampus of female mice.
[So] Source:J Steroid Biochem Mol Biol;174:96-113, 2017 Nov.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aging-related decline of estrogens, especially 17ß-estradiol (E2), has been shown to play an important role in the impairment of learning and memory in dementias, such as Alzheimer's disease (AD), but the underlying molecular mechanisms are poorly understood. In this study, we first demonstrated decreases in E2 signaling (aromatase, classic estrogen receptor ERα and ERß and their coactivator SRC-1), mTORC2 signaling (Rictor and phospho-AKTser473) and actin polymerization (phospho-Cofilin, Profilin-1 and the F-actin/G-actin ratio) in the hippocampus of old female mice compared with those levels detected in the adult hippocampus. We then showed that ERα and ERß antagonists induced a significant decrease in SRC-1, mTORC2 signaling, actin polymerization, and CA1 spine density, as well as impairments of learning and memory; however, ovariectomy-induced changes of these parameters could be significantly reversed by treatment with ER agonists. We further showed that expression of SRC-1, mTORC2 signaling and actin polymerization could be upregulated by E2 treatment, and the effects of E2 were blocked by the ER antagonists but mimicked by the agonists. We also showed that the lentivirus-mediated SRC-1 knockdown significantly inhibited the agonist-activated mTORC2 signaling and actin polymerization, and the lentivirus-mediated Rictor knockdown also significantly inhibited the agonist-activated actin polymerization. Finally, we demonstrated that the ERα and ERß antagonists induced a disruption in actin polymerization and an impairment of spatial memory, which were rescued by activation of mTORC2. Taken together, the above results clearly demonstrated an mTORC2-dependent regulation of actin polymerization that contributed to the effects of ERα and ERß on spatial learning, which may provide a novel target for the prevention and treatment of E2-related dementia in the aged population.
[Mh] Termos MeSH primário: Actinas/metabolismo
Receptor alfa de Estrogênio/metabolismo
Receptor beta de Estrogênio/metabolismo
Hipocampo/metabolismo
Complexos Multiproteicos/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Fatores de Despolimerização de Actina/metabolismo
Animais
Aromatase/metabolismo
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Linhagem Celular
Estradiol/farmacologia
Estrogênios/farmacologia
Feminino
Alvo Mecanístico do Complexo 2 de Rapamicina
Camundongos Endogâmicos C57BL
Coativador 1 de Receptor Nuclear/genética
Coativador 1 de Receptor Nuclear/metabolismo
Ovariectomia
Polimerização
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteína Companheira de mTOR Insensível à Rapamicina
Memória Espacial/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actin Depolymerizing Factors); 0 (Actins); 0 (Carrier Proteins); 0 (Estrogen Receptor alpha); 0 (Estrogen Receptor beta); 0 (Estrogens); 0 (Multiprotein Complexes); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (rictor protein, mouse); 4TI98Z838E (Estradiol); EC 1.14.14.1 (Aromatase); EC 2.3.1.48 (Ncoa1 protein, mouse); EC 2.3.1.48 (Nuclear Receptor Coactivator 1); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE


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[PMID]:28784627
[Au] Autor:Karmaus PWF; Herrada AA; Guy C; Neale G; Dhungana Y; Long L; Vogel P; Avila J; Clish CB; Chi H
[Ad] Endereço:Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN.
[Ti] Título:Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF-mediated myelopoiesis.
[So] Source:J Exp Med;214(9):2629-2647, 2017 Sep 04.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Myelopoiesis is necessary for the generation of mature myeloid cells during homeostatic turnover and immunological insults; however, the metabolic requirements for this process remain poorly defined. Here, we demonstrate that myelopoiesis, including monocyte and macrophage differentiation, requires mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic metabolism. Loss of mTORC1 impaired myelopoiesis under steady state and dampened innate immune responses against infection. Stimulation of hematopoietic progenitors with macrophage colony-stimulating factor (M-CSF) resulted in mTORC1-dependent anabolic metabolism, which in turn promoted expression of M-CSF receptor and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Mechanistically, mTORC1 engaged glucose metabolism and initiated a transcriptional program involving Myc activation and sterol biosynthesis after M-CSF stimulation. Perturbation of glucose metabolism or disruption of Myc function or sterol biosynthesis impaired myeloid differentiation. Integrative metabolomic and genomic profiling further identified one-carbon metabolism as a central node in mTORC1-dependent myelopoiesis. Therefore, the interplay between mTORC1 signaling and metabolic reprogramming underlies M-CSF-induced myelopoiesis.
[Mh] Termos MeSH primário: Fator Estimulador de Colônias de Macrófagos/fisiologia
Complexos Multiproteicos/fisiologia
Mielopoese/fisiologia
Serina-Treonina Quinases TOR/fisiologia
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/fisiologia
Animais
Proteínas de Transporte/fisiologia
Técnicas de Introdução de Genes
Glucose/metabolismo
Alvo Mecanístico do Complexo 1 de Rapamicina
Metabolômica
Camundongos
Camundongos Endogâmicos C57BL
Proteína Companheira de mTOR Insensível à Rapamicina
Proteína Associada Regulatória a mTOR
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Carrier Proteins); 0 (Multiprotein Complexes); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (Regulatory-Associated Protein of mTOR); 0 (Rptor protein, mouse); 0 (rictor protein, mouse); 81627-83-0 (Macrophage Colony-Stimulating Factor); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20161855


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[PMID]:28585302
[Au] Autor:Ren J; Li J; Feng Y; Shu B; Gui Y; Wei W; He W; Yang J; Dai C
[Ad] Endereço:Centre for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China.
[Ti] Título:Rictor/mammalian target of rapamycin complex 2 promotes macrophage activation and kidney fibrosis.
[So] Source:J Pathol;242(4):488-499, 2017 Aug.
[Is] ISSN:1096-9896
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mammalian target of rapamycin (mTOR) signalling controls many essential cellular functions. However, the role of Rictor/mTOR complex 2 (mTORC2) in regulating macrophage activation and kidney fibrosis remains largely unknown. We report here that Rictor/mTORC2 was activated in macrophages from the fibrotic kidneys of mice. Ablation of Rictor in macrophages reduced kidney fibrosis, inflammatory cell accumulation, macrophage proliferation and polarization after unilateral ureter obstruction or ischaemia/reperfusion injury. In bone marrow-derived macrophages (BMMs), deletion of Rictor or blockade of protein kinase Cα inhibited cell migration. Additionally, deletion of Rictor or blockade of Akt abolished interleukin-4-stimulated or transforming growth factor (TGF)-ß1-stimulated macrophage M2 polarization. Furthermore, deletion of Rictor downregulated TGF-ß1-stimulated upregulation of multiple profibrotic cytokines, including platelet-derived growth factor, vascular endothelial growth factor and connective tissue growth factor, in BMMs. Conditioned medium from TGF-ß1-pretreated Rictor macrophages stimulated fibroblast activation less efficiently than that from TGF-ß1-pretreated Rictor macrophages. These results demonstrate that Rictor/mTORC2 signalling can promote macrophage activation and kidney fibrosis. Targeting this signalling pathway in macrophages may shine light on ways to protect against kidney fibrosis in patients with chronic kidney diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Proteínas de Transporte/fisiologia
Rim/patologia
Ativação de Macrófagos/fisiologia
Complexos Multiproteicos/fisiologia
Serina-Treonina Quinases TOR/fisiologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/metabolismo
Movimento Celular/fisiologia
Polaridade Celular/fisiologia
Células Cultivadas
Citocinas/biossíntese
Modelos Animais de Doenças
Fibrose
Rim/metabolismo
Macrófagos/metabolismo
Masculino
Alvo Mecanístico do Complexo 2 de Rapamicina
Camundongos Endogâmicos C57BL
Proteína Companheira de mTOR Insensível à Rapamicina
Transdução de Sinais/fisiologia
Regulação para Cima/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Cytokines); 0 (Multiprotein Complexes); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (rictor protein, mouse); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170607
[St] Status:MEDLINE
[do] DOI:10.1002/path.4921


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[PMID]:28319045
[Au] Autor:Li N; Xue W; Yuan H; Dong B; Ding Y; Liu Y; Jiang M; Kan S; Sun T; Ren J; Pan Q; Li X; Zhang P; Hu G; Wang Y; Wang X; Li Q; Qin J
[Ti] Título:AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis.
[So] Source:J Clin Invest;127(4):1284-1302, 2017 Apr 03.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4Cdt2 E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis.
[Mh] Termos MeSH primário: Movimento Celular
Histona-Lisina N-Metiltransferase/metabolismo
Neoplasias da Próstata/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/biossíntese
Proteínas de Transporte/genética
Estabilidade Enzimática/genética
Epigênese Genética
Regulação Neoplásica da Expressão Gênica
Histona-Lisina N-Metiltransferase/genética
Masculino
Alvo Mecanístico do Complexo 2 de Rapamicina
Camundongos
Camundongos Transgênicos
Complexos Multiproteicos/genética
Complexos Multiproteicos/metabolismo
Metástase Neoplásica
Neuropeptídeos/genética
Neuropeptídeos/metabolismo
PTEN Fosfo-Hidrolase/genética
PTEN Fosfo-Hidrolase/metabolismo
Fosfatidilinositol 3-Quinases/genética
Fosfatidilinositol 3-Quinases/metabolismo
Fosforilação/genética
Neoplasias da Próstata/genética
Neoplasias da Próstata/patologia
Proteínas Proto-Oncogênicas c-akt/genética
Proteína Companheira de mTOR Insensível à Rapamicina
Serina-Treonina Quinases TOR/genética
Serina-Treonina Quinases TOR/metabolismo
Transcrição Genética
Proteínas rac1 de Ligação ao GTP/genética
Proteínas rac1 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Multiprotein Complexes); 0 (Neuropeptides); 0 (Rac1 protein, mouse); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (rictor protein, mouse); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); EC 2.1.1.43 (WHSC1 protein, mouse); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (Pten protein, mouse); EC 3.6.5.2 (rac1 GTP-Binding Protein)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170321
[St] Status:MEDLINE


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[PMID]:28288859
[Au] Autor:Tang LL; Wang JD; Xu TT; Zhao Z; Zheng JJ; Ge RS; Zhu DY
[Ad] Endereço:Institute of Pharmacology and Toxicology, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China; Department of Pharmacy, Xiaoshan Hospital, Hangzhou 311200, China.
[Ti] Título:Mitochondrial toxicity of perfluorooctane sulfonate in mouse embryonic stem cell-derived cardiomyocytes.
[So] Source:Toxicology;382:108-116, 2017 May 01.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Perfluorooctane sulfonate (PFOS) is a persistent organic contaminant that may cause cardiotoxicity in animals and humans. However, little is known about the underlying mechanism by which it affects the organelle toxicity in cardiomyocytes during the cardiogenesis. Our previous proteomic study showed that differences of protein expression mainly existed in mitochondria of cardiomyocytes differentiated from embryonic stem (ES) cells after exposure to PFOS. Here, we focused on mitochondrial toxicity of PFOS in ES cell-derived cardiomyocytes. The cardiomyogenesis from ES cells in vitro was inhibited, and the expression of L-type Ca channel (LTCC) was decreased to interrupt [Ca ] transient amplitude in cardiomyocytes after PFOS treatment. Transmission electron microscope revealed that swollen mitochondrion with vacuole in PFOS-treated cells. Meanwhile, mitochondrial transmembrane potential (ΔΨm) was declined and ATP production was lowered. These changes were related to the increased EGFR phosphorylation, activated Rictor signaling, then mediated HK2 binding to mitochondrial membrane. Furthermore, PFOS reduced the interaction of IP3R-Grp75-VDAC and accumulated intracellular fatty acids by activating Rictor, thereby attenuating PGC-1α and Mfn2 expressions, then destroying mitochondria-associated endoplasmic reticulum membrane (MAM), which resulted in the decrease of [Ca ] transient amplitude triggered by ATP. In conclusion, mitochondrial structure damages and abnormal Ca shuttle were the important aspects in PFOS-induced cardiomyocytes toxicity from ES cells by activating Rictor signaling pathway.
[Mh] Termos MeSH primário: Ácidos Alcanossulfônicos/toxicidade
Poluentes Ambientais/toxicidade
Fluorcarbonetos/toxicidade
Mitocôndrias Cardíacas/efeitos dos fármacos
Células-Tronco Embrionárias Murinas/citologia
Miócitos Cardíacos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Animais
Cálcio/metabolismo
Cálcio/fisiologia
Proteínas de Transporte/metabolismo
Diferenciação Celular/efeitos dos fármacos
Linhagem Celular
Ácido Láctico/metabolismo
Alvo Mecanístico do Complexo 2 de Rapamicina
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Camundongos
Mitocôndrias Cardíacas/fisiologia
Complexos Multiproteicos/metabolismo
Miócitos Cardíacos/citologia
Miócitos Cardíacos/metabolismo
Proteína Companheira de mTOR Insensível à Rapamicina
Receptor do Fator de Crescimento Epidérmico/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkanesulfonic Acids); 0 (Carrier Proteins); 0 (Environmental Pollutants); 0 (Fluorocarbons); 0 (Multiprotein Complexes); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (rictor protein, mouse); 33X04XA5AT (Lactic Acid); 8L70Q75FXE (Adenosine Triphosphate); 9H2MAI21CL (perfluorooctane sulfonic acid); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.10.1 (EGFR protein, mouse); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170315
[St] Status:MEDLINE


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[PMID]:28167137
[Au] Autor:Kaska S; Brunk R; Bali V; Kechner M; Mazei-Robison MS
[Ad] Endereço:Dept. of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, United States.
[Ti] Título:Deletion of Rictor in catecholaminergic neurons alters locomotor activity and ingestive behavior.
[So] Source:Neuropharmacology;117:158-170, 2017 May 01.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:While the etiology of depression is not fully understood, increasing evidence from animal models suggests a role for the ventral tegmental area (VTA) in pathogenesis. In this paper, we investigate the potential role of VTA mechanistic target of rapamycin 2 (TORC2) signaling in mediating susceptibility to chronic social defeat stress (CSDS), a well-established mouse model of depression. Utilizing genetic and viral knockout of Rictor (rapamycin-insensitive companion of target of rapamycin), a requisite component of TORC2, we demonstrate that decreasing Rictor-dependent TORC2 signaling in catecholaminergic neurons, or within the VTA specifically, does not alter susceptibility to CSDS. Opiate abuse and mood disorders are often comorbid, and previous data demonstrate a role for VTA TORC2 in mediating opiate reward. Thus, we also investigated its potential role in mediating changes in opiate reward following CSDS. Catecholaminergic deletion of Rictor increases water, sucrose, and morphine intake but not preference in a two-bottle choice assay in stress-naïve mice, and these effects are maintained after stress. VTA-specific knockout of Rictor increases water and sucrose intake after physical CSDS, but does not alter consummatory behavior in the absence of stress. These findings suggest a novel role for TORC2 in mediating stress-induced changes in consummatory behaviors that may contribute to some aspects of mood disorders.
[Mh] Termos MeSH primário: Proteínas de Transporte/fisiologia
Ingestão de Líquidos/efeitos dos fármacos
Comportamento Alimentar/fisiologia
Locomoção/fisiologia
Complexos Multiproteicos/fisiologia
Neurônios/fisiologia
Sacarose/farmacologia
Serina-Treonina Quinases TOR/fisiologia
Tirosina 3-Mono-Oxigenase/metabolismo
Área Tegmentar Ventral/fisiologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/genética
Comportamento de Escolha/efeitos dos fármacos
Comportamento Alimentar/efeitos dos fármacos
Feminino
Masculino
Alvo Mecanístico do Complexo 2 de Rapamicina
Camundongos
Camundongos Knockout
Morfina/farmacologia
Proteína Companheira de mTOR Insensível à Rapamicina
Comportamento Social
Estresse Psicológico/metabolismo
Estresse Psicológico/psicologia
Área Tegmentar Ventral/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Multiprotein Complexes); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (rictor protein, mouse); 57-50-1 (Sucrose); 76I7G6D29C (Morphine); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170208
[St] Status:MEDLINE


  9 / 293 MEDLINE  
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[PMID]:28132115
[Au] Autor:Jiang WJ; Feng RX; Liu JT; Fan LL; Wang H; Sun GP
[Ad] Endereço:Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China.
[Ti] Título:RICTOR expression in esophageal squamous cell carcinoma and its clinical significance.
[So] Source:Med Oncol;34(3):32, 2017 Mar.
[Is] ISSN:1559-131X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Esophageal cancer is one of the most common malignant tumors in the world, and its incidence is the eighth highest; meanwhile, its fatality rate is the sixth highest. The PI3K/Akt/mTOR signaling pathway plays a required role in human cancer, including cell survival, metabolism and migration. As a kind of important scaffold protein in mTORC2, RICTOR has showed over-expression in several malignancies like melanoma and endometrial cancer. In this research, we selected 201 cases of paraffin specimens from patients diagnosed as esophageal squamous cell carcinoma after surgical treatment and then estimated the RICTOR expression in each esophageal squamous cell carcinoma tissue by using the immunohistochemical streptavidin-peroxidase technique. Then, we analyzed the association among the clinicopathological parameters, the prognosis and the expression of RICTOR. Eventually, we found that the percentage of RICTOR-positive expression in 201 ESCC samples is 70.6% (142/201) and the figure for RICTOR-negative or RICTOR-doubtful-positive expression is 29.4% (59/201). RICTOR expression positively correlated with ESCC patients' AJCC stage (P = 0.011) and showed an opposite trend with survival (P = 0.007). Based on univariate and multivariate Cox proportional hazards regression analysis, RICTOR-positive expression, AJCC staging III or IV and nodal metastasis are prognostic factors and the former two are independent risk factors for ESCC. In conclusion, our study showed potential that targeting RICTOR may represent new effective inhibitors for treating ESCC.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/metabolismo
Proteínas de Transporte/biossíntese
Neoplasias Esofágicas/metabolismo
[Mh] Termos MeSH secundário: Biomarcadores Tumorais/biossíntese
Carcinoma de Células Escamosas/patologia
Neoplasias Esofágicas/patologia
Feminino
Seres Humanos
Imuno-Histoquímica
Masculino
Meia-Idade
Estadiamento de Neoplasias
Prognóstico
Proteína Companheira de mTOR Insensível à Rapamicina
Taxa de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Carrier Proteins); 0 (RICTOR protein, human); 0 (Rapamycin-Insensitive Companion of mTOR Protein)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170130
[St] Status:MEDLINE
[do] DOI:10.1007/s12032-017-0894-5


  10 / 293 MEDLINE  
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[PMID]:28123351
[Au] Autor:Zheng B; Wang J; Tang L; Tan C; Zhao Z; Xiao Y; Ge R; Zhu D
[Ad] Endereço:Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou 310058, CHINA.
[Ti] Título:Involvement of Rictor/mTORC2 in cardiomyocyte differentiation of mouse embryonic stem cells .
[So] Source:Int J Biol Sci;13(1):110-121, 2017.
[Is] ISSN:1449-2288
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:Rictor is a key regulatory/structural subunit of the mammalian target of rapamycin complex 2 (mTORC2) and is required for phosphorylation of Akt at serine 473. It plays an important role in cell survival, actin cytoskeleton organization and other processes in embryogenesis. However, the role of Rictor/mTORC2 in the embryonic cardiac differentiation has been uncovered. In the present study, we examined a possible link between Rictor expression and cardiomyocyte differentiation of the mouse embryonic stem (mES) cells. Knockdown of Rictor by shRNA significantly reduced the phosphorylation of Akt at serine 473 followed by a decrease in cardiomyocyte differentiation detected by beating embryoid bodies. The protein levels of brachyury (mesoderm protein), Nkx2.5 (cardiac progenitor cell protein) and α-Actinin (cardiomyocyte biomarker) decreased in Rictor knockdown group during cardiogenesis. Furthermore, knockdown of Rictor specifically inhibited the ventricular-like cells differentiation of mES cells with reduced level of ventricular-specific protein, MLC-2v. Meanwhile, patch-clamp analysis revealed that shRNA- significantly increased the number of cardiomyocytes with abnormal electrophysiology. In addition, the expressions and distribution patterns of cell-cell junction proteins (Cx43/Desmoplakin/N-cadherin) were also affected in shRNA- cardiomyocytes. Taken together, the results demonstrated that Rictor/mTORC2 might play an important role in the cardiomyocyte differentiation of mES cells. Knockdown of Rictor resulted in inhibiting ventricular-like myocytes differentiation and induced arrhythmias symptom, which was accompanied by interfering the expression and distribution patterns of cell-cell junction proteins. Rictor/mTORC2 might become a new target for regulating cardiomyocyte differentiation and a useful reference for application of the induced pluripotent stem cells.
[Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo
Células-Tronco Embrionárias Murinas/metabolismo
Complexos Multiproteicos/metabolismo
Miócitos Cardíacos/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Animais
Western Blotting
Proteínas de Transporte/genética
Diferenciação Celular/genética
Diferenciação Celular/fisiologia
Proliferação Celular
Eletrofisiologia
Citometria de Fluxo
Alvo Mecanístico do Complexo 2 de Rapamicina
Camundongos
Células-Tronco Embrionárias Murinas/fisiologia
Complexos Multiproteicos/genética
Miócitos Cardíacos/fisiologia
Fosforilação/genética
Fosforilação/fisiologia
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteína Companheira de mTOR Insensível à Rapamicina
Serina-Treonina Quinases TOR/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Multiprotein Complexes); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (rictor protein, mouse); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170127
[St] Status:MEDLINE
[do] DOI:10.7150/ijbs.16312



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