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[PMID]:28460466
[Au] Autor:Mesclon F; Lambert-Langlais S; Carraro V; Parry L; Hainault I; Jousse C; Maurin AC; Bruhat A; Fafournoux P; Averous J
[Ad] Endereço:Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
[Ti] Título:Decreased ATF4 expression as a mechanism of acquired resistance to long-term amino acid limitation in cancer cells.
[So] Source:Oncotarget;8(16):27440-27453, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The uncontrolled growth of tumor can lead to the formation of area deprived in nutrients. Due to their high genetic instability, tumor cells can adapt and develop resistance to this pro-apoptotic environment. Among the resistance mechanisms, those involved in the resistance to long-term amino acid restriction are not elucidated. A long-term amino acid restriction is particularly deleterious since nine of them cannot be synthetized by the cells. In order to determine how cancer cells face a long-term amino acid deprivation, we developed a cell model selected for its capacity to resist a long-term amino acid limitation. We exerted a selection pressure on mouse embryonic fibroblast to isolate clones able to survive with low amino acid concentration. The study of several clones revealed an alteration of the eiF2α/ATF4 pathway. Compared to the parental cells, the clones exhibited a decreased expression of the transcription factor ATF4 and its target genes. Likewise, the knock-down of ATF4 in parental cells renders them resistant to amino acid deprivation. Moreover, this association between a low level of ATF4 protein and the resistance to amino acid deprivation was also observed in the cancer cell line BxPC-3. This resistance was abolished when ATF4 was overexpressed. Therefore, decreasing ATF4 expression may be one important mechanism for cancer cells to survive under prolonged amino acid deprivation.
[Mh] Termos MeSH primário: Fator 4 Ativador da Transcrição/genética
Aminoácidos/metabolismo
Regulação Neoplásica da Expressão Gênica
[Mh] Termos MeSH secundário: Fator 4 Ativador da Transcrição/metabolismo
Animais
Apoptose/genética
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Perfilação da Expressão Gênica
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
Camundongos
Modelos Biológicos
Neoplasias/genética
Neoplasias/metabolismo
Ligação Proteica
Proteínas Serina-Treonina Quinases/metabolismo
Interferência de RNA
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 145891-90-3 (Activating Transcription Factor 4); EC 2.7.11.1 (EIF2AK4 protein, human); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15828


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[PMID]:29233869
[Au] Autor:Rabanal-Ruiz Y; Otten EG; Korolchuk VI
[Ad] Endereço:Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE4 5PL, U.K.
[Ti] Título:mTORC1 as the main gateway to autophagy.
[So] Source:Essays Biochem;61(6):565-584, 2017 12 12.
[Is] ISSN:1744-1358
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cells and organisms must coordinate their metabolic activity with changes in their environment to ensure their growth only when conditions are favourable. In order to maintain cellular homoeostasis, a tight regulation between the synthesis and degradation of cellular components is essential. At the epicentre of the cellular nutrient sensing is the mechanistic target of rapamycin complex 1 (mTORC1) which connects environmental cues, including nutrient and growth factor availability as well as stress, to metabolic processes in order to preserve cellular homoeostasis. Under nutrient-rich conditions mTORC1 promotes cell growth by stimulating biosynthetic pathways, including synthesis of proteins, lipids and nucleotides, and by inhibiting cellular catabolism through repression of the autophagic pathway. Its close signalling interplay with the energy sensor AMP-activated protein kinase (AMPK) dictates whether the cell actively favours anabolic or catabolic processes. Underlining the role of mTORC1 in the coordination of cellular metabolism, its deregulation is linked to numerous human diseases ranging from metabolic disorders to many cancers. Although mTORC1 can be modulated by a number of different inputs, amino acids represent primordial cues that cannot be compensated for by any other stimuli. The understanding of how amino acids signal to mTORC1 has increased considerably in the last years; however this area of research remains a hot topic in biomedical sciences. The current ideas and models proposed to explain the interrelationship between amino acid sensing, mTORC1 signalling and autophagy is the subject of the present review.
[Mh] Termos MeSH primário: Autofagia/fisiologia
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
[Mh] Termos MeSH secundário: Aminoácidos/metabolismo
Animais
Autofagia/genética
Seres Humanos
Lisossomos/metabolismo
Alvo Mecanístico do Complexo 1 de Rapamicina/genética
Transdução de Sinais/genética
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acids); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1042/EBC20170027


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[PMID]:28455969
[Au] Autor:Wang MH; Zhou XM; Zhang MY; Shi L; Xiao RW; Zeng LS; Yang XZ; Zheng XFS; Wang HY; Mai SJ
[Ad] Endereço:State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.
[Ti] Título:BMP2 promotes proliferation and invasion of nasopharyngeal carcinoma cells via mTORC1 pathway.
[So] Source:Aging (Albany NY);9(4):1326-1340, 2017 Apr.
[Is] ISSN:1945-4589
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bone morphogenetic protein-2 (BMP2) is a secreted protein that highly expressed in a variety of cancers and contributes to cell proliferation, migration, invasiveness, mobility, metastasis and EMT. However, its clinical significance and biological function in nasopharyngeal carcinoma (NPC) remain unknown up to now. Up-regulation of BMP2 was first observed in NPC cell lines by a genome-wide transcriptome analysis in our previous study. In this study, BMP2 mRNA was detected by qRT-PCR and data showed that it was upregulated in NPC compared with non-cancerous nasopharynx samples. Immunohistochemistry (IHC) analysis in NPC specimens revealed that high BMP2 expression was significantly associated with clinical stage, distant metastasis and shorter survival of NPC patients. Moreover, overexpression of BMP2 in NPC cells promoted cell proliferation, migration, invasiveness and epithelial-mesenchymal transition (EMT). Mechanistically, BMP2 overexpression increase phosphorylated protein level of mTOR, S6K and 4EBP1. Correspondingly, mTORC1 inhibitor rapamycin blocked the effect of BMP2 on NPC cell proliferation and invasion. In conclusion, our results suggest that BMP2 overexpression in NPC enhances proliferation, invasion and EMT of tumor cells through the mTORC1 signaling pathway.
[Mh] Termos MeSH primário: Proteína Morfogenética Óssea 2/farmacologia
Proliferação Celular/efeitos dos fármacos
Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos
Neoplasias Nasofaríngeas/patologia
Invasividade Neoplásica/patologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica
Estudo de Associação Genômica Ampla
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina/genética
Neoplasias Nasofaríngeas/genética
Metástase Neoplásica
RNA Mensageiro/biossíntese
RNA Mensageiro/genética
Receptores da Colecistocinina/biossíntese
Transdução de Sinais/efeitos dos fármacos
Transcriptoma/genética
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bone Morphogenetic Protein 2); 0 (RNA, Messenger); 0 (Receptors, Cholecystokinin); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.18632/aging.101230


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[PMID]:29233655
[Au] Autor:Li Q; Han Y; Du J; Jin H; Zhang J; Niu M; Qin J
[Ad] Endereço:Department of Pediatrics, Peking University First Hospital, No. 1, Xi-An Men Street, Beijing 100034, PR China.
[Ti] Título:Recombinant human erythropoietin protects against brain injury through blunting the mTORC1 pathway in the developing brains of rats with seizures.
[So] Source:Life Sci;194:15-25, 2018 Feb 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Recurrent seizures can result in neuronal death, cognitive deficits and intellectual disability, which causes devastating damage in children. Recombinant human erythropoietin (rhEPO) is considered a neuroprotective factor in many nervous system diseases. However, the precise mechanisms through which rhEPO exerts its neuroprotective effects on epilepsy remain unknown. Thus, in this study, we determined whether rhEPO protects against brain injury by inducing cortical neuronal autophagy through blunting the mammalian target of rapamycin complex 1 (mTORC1) pathway in the developing brains of rats with seizures. MAIN METHODS: We used kainic acid to induce recurrent seizures in rats. Nissl staining and TUNEL analysis were used to evaluate the neuronal damage and apoptotic cells. Western blot analysis was employed to evaluate the phospho-mammalian target of rapamycin (p-mTOR)/mTOR protein ratio, the phospho-ribosomal protein S6 (S6)/S6 protein ratio, the microtubule-associated protein light chain 3 (LC3) II/I protein ratio and sequestosome 1 (P62/SQSTM1) protein expression levels. KEY FINDINGS: rhEPO reversed the decrease in the number of Nissl-positive neurons and the increase in the number of apoptotic cells in the kainic acid group. Notably, rhEPO induced autophagy and inhibited the mTORC1 pathway to protect against brain injury in rats with seizures. Treating rats with rapamycin blocked the mTORC1 pathway and masked the abovementioned effects of rhEPO. SIGNIFICANCE: Based on these results, rhEPO protects against brain injury by activating autophagy through blunting the mTORC1 pathway in developing rats with seizures.
[Mh] Termos MeSH primário: Lesões Encefálicas/prevenção & controle
Encéfalo/efeitos dos fármacos
Eritropoetina/uso terapêutico
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
Fármacos Neuroprotetores/uso terapêutico
Convulsões/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Autofagia/efeitos dos fármacos
Encéfalo/metabolismo
Encéfalo/patologia
Lesões Encefálicas/etiologia
Lesões Encefálicas/metabolismo
Lesões Encefálicas/patologia
Epilepsia/complicações
Epilepsia/tratamento farmacológico
Epilepsia/metabolismo
Epilepsia/patologia
Eritropoetina/farmacologia
Seres Humanos
Masculino
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Neurônios/patologia
Neuroproteção/efeitos dos fármacos
Fármacos Neuroprotetores/farmacologia
Ratos Sprague-Dawley
Proteínas Recombinantes/farmacologia
Proteínas Recombinantes/uso terapêutico
Convulsões/complicações
Convulsões/metabolismo
Convulsões/patologia
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neuroprotective Agents); 0 (Recombinant Proteins); 11096-26-7 (Erythropoietin); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE


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[PMID]:29357370
[Au] Autor:Sathe A; Chalaud G; Oppolzer I; Wong KY; von Busch M; Schmid SC; Tong Z; Retz M; Gschwend JE; Schulz WA; Nawroth R
[Ad] Endereço:Department of Urology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
[Ti] Título:Parallel PI3K, AKT and mTOR inhibition is required to control feedback loops that limit tumor therapy.
[So] Source:PLoS One;13(1):e0190854, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Targeting the PI3K pathway has achieved limited success in cancer therapy. One reason for the disappointing activity of drugs that interfere with molecules that are important player in this pathway is the induction of multiple feedback loops that have been only partially understood. To understand these limitations and develop improved treatment strategies, we comprehensively characterized molecular mechanisms of PI3K pathway signaling in bladder cancer cell lines upon using small molecule inhibitors and RNAi technologies against all key molecules and protein complexes within the pathway and analyzed functional and molecular consequences. When targeting either mTORC1, mTOR, AKT or PI3K, only S6K1 phosphorylation was affected in most cell lines examined. Dephosphorylation of 4E-BP1 required combined inhibition of PI3K and mTORC1, independent from AKT, and resulted in a robust reduction in cell viability. Long-term inhibition of PI3K however resulted in a PDK1-dependent, PIP3 and mTORC2 independent rephosphorylation of AKT. AKT rephosphorylation could also be induced by mTOR or PDK1 inhibition. Combining PI3K/mTOR inhibitors with AKT or PDK1 inhibitors suppressed this rephosphorylation, induced apoptosis, decreased colony formation, cell viability and growth of tumor xenografts. Our findings reveal novel molecular mechanisms that explain the requirement for simultaneous targeting of PI3K, AKT and mTORC1 to achieve effective tumor growth inhibition.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Inibidores Enzimáticos/administração & dosagem
Fosfatidilinositol 3-Quinase/antagonistas & inibidores
Inibidores de Proteínas Quinases/administração & dosagem
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Serina-Treonina Quinases TOR/antagonistas & inibidores
Neoplasias da Bexiga Urinária/tratamento farmacológico
Neoplasias da Bexiga Urinária/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Protocolos de Quimioterapia Combinada Antineoplásica
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Embrião de Galinha
Retroalimentação Fisiológica/efeitos dos fármacos
Compostos Heterocíclicos com 3 Anéis/administração & dosagem
Seres Humanos
Imidazóis/administração & dosagem
Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores
Fosfoproteínas/metabolismo
Fosforilação/efeitos dos fármacos
Quinolinas/administração & dosagem
Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
Transdução de Sinais/efeitos dos fármacos
Neoplasias da Bexiga Urinária/patologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents); 0 (EIF4EBP1 protein, human); 0 (Enzyme Inhibitors); 0 (Heterocyclic Compounds, 3-Ring); 0 (Imidazoles); 0 (MK 2206); 0 (Phosphoproteins); 0 (Protein Kinase Inhibitors); 0 (Quinolines); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1); RUJ6Z9Y0DT (dactolisib)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190854


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[PMID]:29269484
[Au] Autor:Geter PA; Ernlund AW; Bakogianni S; Alard A; Arju R; Giashuddin S; Gadi A; Bromberg J; Schneider RJ
[Ad] Endereço:Department of Microbiology, Alexandria Center for Life Science, New York University School of Medicine, New York, New York 10016, USA.
[Ti] Título:Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming.
[So] Source:Genes Dev;31(22):2235-2249, 2017 11 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The majority of breast cancers expresses the estrogen receptor (ER ) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen-resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include , which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER breast cancer through selective mRNA translational reprogramming.
[Mh] Termos MeSH primário: Antineoplásicos Hormonais/farmacologia
Neoplasias da Mama/metabolismo
Antagonistas de Estrogênios/farmacologia
Fator de Iniciação 4E em Eucariotos/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
Biossíntese de Proteínas
Proteínas Serina-Treonina Quinases/metabolismo
Tamoxifeno/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Fosforilação
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents, Hormonal); 0 (Estrogen Antagonists); 0 (Eukaryotic Initiation Factor-4E); 0 (Intracellular Signaling Peptides and Proteins); 0 (RNA, Messenger); 094ZI81Y45 (Tamoxifen); EC 2.7.1.- (MKNK1 protein, human); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE
[do] DOI:10.1101/gad.305631.117


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[PMID]:28450306
[Au] Autor:Xiao M; Wang Y; Tao C; Wang Z; Yang J; Chen Z; Zou Z; Li M; Liu A; Jia C; Huang B; Yan B; Lai P; Ding C; Cai D; Xiao G; Jiang Y; Bai X
[Ad] Endereço:State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences and.
[Ti] Título:Osteoblasts support megakaryopoiesis through production of interleukin-9.
[So] Source:Blood;129(24):3196-3209, 2017 06 15.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Severe thrombocytopenia is a significant challenge in patients undergoing myelosuppressive chemotherapy for malignancies. Understanding the biology of platelet-producing megakaryocytes development in the bone marrow microenvironment may facilitate the development of novel therapies to stimulate platelet production and prevent thrombocytopenia. We report here that osteoblasts supported megakaryopoiesis by secreting interleukin-9 (IL-9), which stimulated IL-9 receptor (IL-9R)/Stat3 signaling in promoting megakaryopoiesis. IL-9 production in osteoblasts was negatively regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signaling in a NF-κB-dependent manner. Constitutive activation of mTORC1 inhibited IL-9 production in osteoblasts and suppressed megakaryocytic cells expansion, whereas mTORC1 inactivation increased IL-9 production and enhanced megakaryocyte and platelet numbers in mice. In mouse models, we showed that IL-9 administration stimulated megakaryopoiesis, whereas neutralizing endogenous IL-9 or IL-9R depletion inhibited the process. Importantly, we found that low doses of IL-9 efficiently prevented chemotherapy-induced thrombocytopenia (CIT) and accelerated platelet recovery after CIT. These data indicate that IL-9 is an essential regulator of megakaryopoiesis and a promising therapeutic agent for treatment of thrombocytopenia such as CIT.
[Mh] Termos MeSH primário: Interleucina-9/metabolismo
Megacariócitos/metabolismo
Osteoblastos/metabolismo
Transdução de Sinais/fisiologia
Trombopoese/fisiologia
[Mh] Termos MeSH secundário: Animais
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina
Megacariócitos/citologia
Camundongos
Complexos Multiproteicos/metabolismo
Osteoblastos/citologia
Células RAW 264.7
Receptores de Interleucina-9/metabolismo
Fator de Transcrição STAT3/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (IL9 protein, human); 0 (IL9R protein, human); 0 (Il9r protein, mouse); 0 (Interleukin-9); 0 (Multiprotein Complexes); 0 (Receptors, Interleukin-9); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human); 0 (Stat3 protein, mouse); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180113
[Lr] Data última revisão:
180113
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-11-749838


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[PMID]:29175333
[Au] Autor:Peng H; Kasada A; Ueno M; Hoshii T; Tadokoro Y; Nomura N; Ito C; Takase Y; Vu HT; Kobayashi M; Xiao B; Worley PF; Hirao A
[Ad] Endereço:Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
[Ti] Título:Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells.
[So] Source:Biochem Biophys Res Commun;495(1):1129-1135, 2018 01 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) senses a cell's energy status and environmental levels of nutrients and growth factors. In response, mTORC1 mediates signaling that controls protein translation and cellular metabolism. Although mTORC1 plays a critical role in hematopoiesis, it remains unclear which upstream stimuli regulate mTORC1 activity in the context of hematopoietic stem cells (HSC) maintenance in vivo. In this study, we investigated the function of Rheb, a critical regulator of mTORC1 activity controlled by the PI3K-AKT-TSC axis, both in HSC maintenance in mice at steady-state and in HSC-derived hematopoiesis post-transplantation. In contrast to the severe hematopoietic dysfunction caused by Raptor deletion, which completely inactivates mTORC1, Rheb deficiency in adult mice did not show remarkable hematopoietic failure. Lack of Rheb caused abnormalities in myeloid cells but did not have impact on hematopoietic regeneration in mice subjected to injury by irradiation. As previously reported, Rheb deficiency resulted in defective HSC-derived hematopoiesis post-transplantation. However, while Raptor is essential for HSC competitiveness in vivo, Rheb is dispensable for HSC maintenance under physiological conditions, indicating that the PI3K-AKT-TSC pathway does not contribute to mTORC1 activity for sustaining HSC self-renewal activity at steady-state. Thus, the various regulatory elements that impinge upstream of mTORC1 activation pathways are differentially required for HSC homeostasis in vivo.
[Mh] Termos MeSH primário: Autorrenovação Celular/fisiologia
Transplante de Células-Tronco Hematopoéticas
Células-Tronco Hematopoéticas/citologia
Células-Tronco Hematopoéticas/fisiologia
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo
Proteína Associada Regulatória a mTOR/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ras Homolog Enriched in Brain Protein); 0 (Regulatory-Associated Protein of mTOR); 0 (Rheb protein, mouse); 0 (Rptor protein, mouse); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


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[PMID]:28468873
[Au] Autor:Vink EI; Smiley JR; Mohr I
[Ad] Endereço:Department of Microbiology, New York University School of Medicine, New York, New York, USA.
[Ti] Título:Subversion of Host Responses to Energy Insufficiency by Us3 Supports Herpes Simplex Virus 1 Replication during Stress.
[So] Source:J Virol;91(14), 2017 Jul 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cellular stress responses to energy insufficiency can impact virus reproduction. In particular, activation of the host AMP-activated protein kinase (AMPK) by low energy could limit protein synthesis by inhibiting mTORC1. Although many herpesviruses, including herpes simplex virus 1 (HSV-1), stimulate mTORC1, how HSV-1-infected cells respond to energy availability, a physiological indicator regulating mTORC1, has not been investigated. In addition, the impact of low-energy stress on productive HSV-1 growth and viral genetic determinants potentially enabling replication under physiological stress remains undefined. Here, we demonstrate that mTORC1 activity in HSV-1-infected cells is largely insensitive to stress induced by simulated energy insufficiency. Furthermore, resistance of mTORC1 activity to low-energy-induced stress, while not significantly influenced by the HSV-1 UL46-encoded phosphatidylinositol 3-kinase (PI3K)-Akt activator, was dependent upon the Ser/Thr kinase activity of Us3. A Us3-deficient virus was hypersensitive to low-energy-induced stress as infected cell protein synthesis and productive replication were reduced compared to levels in cells infected with a Us3-expressing virus. Although Us3 did not detectably prevent energy stress-induced AMPK activation, it enforced mTORC1 activation despite the presence of activated AMPK. In the absence of applied low-energy stress, AMPK activity in infected cells was restricted in a Us3-dependent manner. This establishes that the Us3 kinase not only activated mTORC1 but also enabled sustained mTORC1 signaling during simulated energy insufficiency that would otherwise restrict protein synthesis and virus replication. Moreover, it identifies the alphaherpesvirus-specific Us3 kinase as an mTORC1 activator that subverts the host cell energy-sensing program to support viral productive growth irrespective of physiological stress. Like all viruses, herpes simplex virus type 1 (HSV-1) reproduction relies upon numerous host energy-intensive processes, the most demanding of which is protein synthesis. In response to low energy, the cellular AMP-activated protein kinase (AMPK) triggers a physiological stress response that antagonizes mTORC1, a multisubunit host kinase that controls protein synthesis. This could restrict virus protein production and growth. Here, we establish that the HSV-1 Us3 protein kinase subverts the normal response to low-energy-induced stress. While Us3 does not prevent AMPK activation by low energy, it enforces mTORC1 activation and overrides a physiological response that couples energy availability and protein synthesis. These results help explain how reproduction of HSV-1, a ubiquitous, medically significant human pathogen causing a spectrum of diseases ranging from the benign to the life threatening, occurs during physiological stress. This is important because HSV-1 reproduction triggered by physiological stress is characteristic of reactivation of lifelong latent infections.
[Mh] Termos MeSH primário: Herpesvirus Humano 1/fisiologia
Interações Hospedeiro-Patógeno
Complexos Multiproteicos/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Serina-Treonina Quinases TOR/metabolismo
Proteínas Virais/metabolismo
Replicação Viral
[Mh] Termos MeSH secundário: Células Cultivadas
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Multiprotein Complexes); 0 (Viral Proteins); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (US3 protein, Human herpesvirus 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


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[PMID]:29203562
[Au] Autor:Hartupee J; Szalai GD; Wang W; Ma X; Diwan A; Mann DL
[Ad] Endereço:From the Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO (J.H., X.M., A.D., D.L.M.); John Cochran VA Medical Center, St. Louis, MO (A.D.); and Winters Center for Heart Failure Research, Section of Cardiology, Department of Medicine, Baylor Col
[Ti] Título:Impaired Protein Quality Control During Left Ventricular Remodeling in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor.
[So] Source:Circ Heart Fail;10(12), 2017 Dec.
[Is] ISSN:1941-3297
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Sustained inflammation in the heart is sufficient to provoke left ventricular dysfunction and left ventricular remodeling. Although inflammation has been linked to many of the biological changes responsible for adverse left ventricular remodeling, the relationship between inflammation and protein quality control in the heart is not well understood. METHODS AND RESULTS: To study the relationship between chronic inflammation and protein quality control, we used a mouse model of dilated cardiomyopathy driven by cardiac restricted overexpression of TNF (tumor necrosis factor; -sTNF). -sTNF mice develop protein aggregates containing ubiquitin-tagged proteins within cardiac myocytes related to proteasome dysfunction and impaired autophagy. The 26S proteasome was dysfunctional despite normal function of the core 20S subunit. We found an accumulation of autophagy substrates in -sTNF mice, which were also seen in tissue from patients with end-stage heart failure. Moreover, there was evidence of impaired autophagosome clearance after chloroquine administration in these mice indicative of impaired autophagic flux. Finally, there was increased mammalian target of rapamycin complex 1 (mTORC1) activation, which has been linked to inhibition of both the proteasome and autophagy. CONCLUSIONS: -sTNF mice with sustained inflammatory signaling develop proteasome dysfunction and impaired autophagic flux that is associated with enhanced mTORC1 activation.
[Mh] Termos MeSH primário: Cardiomiopatia Dilatada/enzimologia
Ventrículos do Coração/enzimologia
Mediadores da Inflamação/metabolismo
Miócitos Cardíacos/enzimologia
Complexo de Endopeptidases do Proteassoma/metabolismo
Fator de Necrose Tumoral alfa/metabolismo
Disfunção Ventricular Esquerda/enzimologia
Função Ventricular Esquerda
Remodelação Ventricular
[Mh] Termos MeSH secundário: Animais
Autofagossomos/enzimologia
Autofagossomos/patologia
Autofagia
Cardiomiopatia Dilatada/genética
Cardiomiopatia Dilatada/patologia
Cardiomiopatia Dilatada/fisiopatologia
Modelos Animais de Doenças
Predisposição Genética para Doença
Insuficiência Cardíaca/enzimologia
Insuficiência Cardíaca/patologia
Ventrículos do Coração/patologia
Ventrículos do Coração/fisiopatologia
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
Camundongos Transgênicos
Miócitos Cardíacos/patologia
Cadeias Pesadas de Miosina/genética
Fenótipo
Regiões Promotoras Genéticas
Agregados Proteicos
Agregação Patológica de Proteínas
Fatores de Tempo
Fator de Necrose Tumoral alfa/genética
Ubiquitinação
Regulação para Cima
Disfunção Ventricular Esquerda/genética
Disfunção Ventricular Esquerda/patologia
Disfunção Ventricular Esquerda/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Inflammation Mediators); 0 (Myh6 protein, mouse); 0 (Protein Aggregates); 0 (Tumor Necrosis Factor-alpha); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 3.4.99.- (ATP dependent 26S protease); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE



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