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Pesquisa : D08.811.277.352.650.625.725 [Categoria DeCS]
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[PMID]:29357290
[Au] Autor:Fujimoto N; Kitamura S; Uramaru N; Miyagawa S; Iguchi T
[Ad] Endereço:Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Electronic address: nfjm@hiroshima-u.ac.jp.
[Ti] Título:Identification of hepatic thyroid hormone-responsive genes in neonatal rats: Potential targets for thyroid hormone-disrupting chemicals.
[So] Source:Toxicol Lett;286:48-53, 2018 Apr.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:There have been many concerns about the possible adverse effects of thyroid hormone-disrupting chemicals in the environment. Because thyroid hormones are essential for regulating the growth and differentiation of many tissues, disruption of thyroid hormones during the neonatal period of an organism might lead to permanent effects on that organism. We postulated that there are target genes that are sensitive to thyroid hormones particularly during the neonatal period and that would thus be susceptible to thyroid hormone-disrupting chemicals. Global gene expression analysis was used to identify these genes in the liver of rat neonates. The changes in hepatic gene expression were examined 24 h after administering 1.0, 10, and 100 ng/g body weight (bw) triiodothyronine (T3) to male rats on postnatal day 3. Thirteen upregulated and four downregulated genes were identified in the neonatal liver. Among these, Pdp2 and Slc25a25 were found to be upregulated and more sensitive to T3 than the others, whereas Cyp7b1 and Hdc were found to be downregulated even at the lowest dose of 1.0 ng/g bw T3. Interestingly, when the responses of gene expression to T3 were examined in adult rats (8-week old), one-third of them did not respond to T3. The environmental chemicals with thyroid hormone-like activity, hydroxylated polybrominated diphenyl ethers, were then administered to neonatal rats to examine the effects on expression of the identified genes. The results showed that these chemicals were indeed capable of changing the expression of Slc25a25 and Hdc. Our results demonstrated a series of hepatic T3-responsive genes that are more sensitive to hormones during the neonatal period than during adulthood. These genes might be the potential targets of thyroid hormone-disrupting chemicals in newborns.
[Mh] Termos MeSH primário: Disruptores Endócrinos/toxicidade
Regulação da Expressão Gênica/efeitos dos fármacos
Fígado/efeitos dos fármacos
Tri-Iodotironina/farmacologia
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Família 7 do Citocromo P450/genética
Família 7 do Citocromo P450/metabolismo
Relação Dose-Resposta a Droga
Perfilação da Expressão Gênica/métodos
Histidina Descarboxilase/genética
Histidina Descarboxilase/metabolismo
Fígado/metabolismo
Masculino
Proteínas de Transporte da Membrana Mitocondrial/genética
Proteínas de Transporte da Membrana Mitocondrial/metabolismo
Análise de Sequência com Séries de Oligonucleotídeos
Piruvato Desidrogenase (Lipoamida)-Fosfatase/genética
Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
Ratos Endogâmicos F344
Medição de Risco
Esteroide Hidroxilases/genética
Esteroide Hidroxilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endocrine Disruptors); 0 (Mitochondrial Membrane Transport Proteins); 0 (Slc25a25 protein, rat); 06LU7C9H1V (Triiodothyronine); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (Cyp7b1 protein, rat); EC 1.14.14.23 (Cytochrome P450 Family 7); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase); EC 4.1.1.22 (Histidine Decarboxylase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:28235541
[Au] Autor:Gutteridge RE; Singh CK; Ndiaye MA; Ahmad N
[Ad] Endereço:Department of Dermatology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
[Ti] Título:Targeted knockdown of polo-like kinase 1 alters metabolic regulation in melanoma.
[So] Source:Cancer Lett;394:13-21, 2017 May 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:A limited number of studies have indicated an association of the mitotic kinase polo-like kinase 1 (PLK1) and cellular metabolism. Here, employing an inducible RNA interference approach in A375 melanoma cells coupled with a PCR array and multiple validation approaches, we demonstrated that PLK1 alters a number of genes associated with cellular metabolism. PLK1 knockdown resulted in a significant downregulation of IDH1, PDP2 and PCK1 and upregulation of FBP1. Ingenuity Pathway Analysis (IPA) identified that 1) glycolysis and the pentose phosphate pathway are major canonical pathways associated with PLK1, and 2) PLK1 inhibition-modulated genes were largely associated with cellular proliferation, with FBP1 being the key modulator. Further, BI 6727-mediated inhibition of PLK1 caused a decrease in PCK1 and increase in FBP1 in A375 melanoma cell implanted xenografts in vivo. Furthermore, an inverse correlation between PLK1 and FBP1 was found in melanoma cells, with FBP1 expression significantly downregulated in a panel of melanoma cells. In addition, BI 6727 treatment resulted in an upregulation in FBP1 in A375, Hs294T and G361 melanoma cells. Overall, our study suggests that PLK1 may be an important regulator of metabolism maintenance in melanoma cells.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo
Metabolismo Energético
Técnicas de Silenciamento de Genes
Melanoma/enzimologia
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
Interferência de RNA
Neoplasias Cutâneas/enzimologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Ciclo Celular/genética
Linhagem Celular Tumoral
Proliferação Celular
Regulação para Baixo
Frutose-Bifosfatase/genética
Frutose-Bifosfatase/metabolismo
Regulação Enzimológica da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Redes Reguladoras de Genes
Células HEK293
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/genética
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Isocitrato Desidrogenase/genética
Isocitrato Desidrogenase/metabolismo
Melanoma/genética
Melanoma/patologia
Camundongos
Fosfoenolpiruvato Carboxiquinase (GTP)/genética
Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo
Proteínas Serina-Treonina Quinases/genética
Proteínas Proto-Oncogênicas/genética
Piruvato Desidrogenase (Lipoamida)-Fosfatase/genética
Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
Transdução de Sinais
Neoplasias Cutâneas/genética
Neoplasias Cutâneas/patologia
Transfecção
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (Intracellular Signaling Peptides and Proteins); 0 (Proto-Oncogene Proteins); EC 1.1.1.41 (Isocitrate Dehydrogenase); EC 1.1.1.42. (IDH1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (polo-like kinase 1); EC 3.1.3.11 (Fructose-Bisphosphatase); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase); EC 4.1.1.32 (PCK1 protein, human); EC 4.1.1.32 (Phosphoenolpyruvate Carboxykinase (GTP))
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170226
[St] Status:MEDLINE


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[PMID]:27846149
[Au] Autor:Barberio MD; Huffman KM; Giri M; Hoffman EP; Kraus WE; Hubal MJ
[Ad] Endereço:1Research Center for Genetic Medicine, Children's National Medical Center, Durham, NC; 2Division of Rheumatology, Department of Medicine, Duke University School of Medicine, Durham, NC; 3Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC; 4Department of Exercise and Nutrition Sciences, George Washington University, WASHINGTON, DC; 5Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC; and 6Department of Integrative Systems Biology, George Washington University, Washington, DC.
[Ti] Título:Pyruvate Dehydrogenase Phosphatase Regulatory Gene Expression Correlates with Exercise Training Insulin Sensitivity Changes.
[So] Source:Med Sci Sports Exerc;48(12):2387-2397, 2016 Dec.
[Is] ISSN:1530-0315
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Whole body insulin sensitivity (Si) typically improves after aerobic exercise training; however, individual responses can be highly variable. The purpose of this study was to use global gene expression to identify skeletal muscle genes that correlate with exercise-induced Si changes. METHODS: Longitudinal cohorts from the Studies of Targeted Risk Reduction Intervention through Defined Exercise were used as Discovery (Affymetrix) and Confirmation (Illumina) of vastus lateralis gene expression profiles. Discovery (n = 39; 21 men) and Confirmation (n = 42; 19 men) cohorts were matched for age (52 ± 8 vs 51 ± 10 yr), body mass index (30.4 ± 2.8 vs 29.7 ± 2.8 kg·m), and VË™O2max (30.4 ± 2.8 vs 29.7 ± 2.8 mL·kg·min). Si was determined via intravenous glucose tolerance test pretraining and posttraining. Pearson product-moment correlation coefficients determined relationships between a) baseline and b) training-induced changes in gene expression and %ΔSi after training. RESULTS: Expression of 2454 (Discovery) and 1778 genes (Confirmation) at baseline were significantly (P < 0.05) correlated to %ΔSi; 112 genes overlapped. Pathway analyses identified Ca signaling-related transcripts in this 112-gene list. Expression changes of 1384 (Discovery) and 1288 genes (Confirmation) after training were significantly (P < 0.05) correlated to %ΔSi; 33 genes overlapped, representing contractile apparatus of skeletal and smooth muscle genes. Pyruvate dehydrogenase phosphatase regulatory subunit expression at baseline (P = 0.01, r = 0.41) and posttraining (P = 0.01, r = 0.43) were both correlated with %ΔSi. CONCLUSIONS: Exercise-induced adaptations in skeletal muscle Si are related to baseline levels of Ca-regulating transcripts, which may prime the muscle for adaptation. Relationships between %ΔSi and pyruvate dehydrogenase phosphatase regulatory, a regulatory subunit of the pyruvate dehydrogenase complex, indicate that the Si response is strongly related to key steps in metabolic regulation.
[Mh] Termos MeSH primário: Exercício/fisiologia
Expressão Gênica
Resistência à Insulina/fisiologia
Músculo Esquelético/enzimologia
Piruvato Desidrogenase (Lipoamida)-Fosfatase/genética
[Mh] Termos MeSH secundário: Sinalização do Cálcio
Doenças Cardiovasculares/prevenção & controle
Feminino
Seres Humanos
Estudos Longitudinais
Masculino
Meia-Idade
Músculo Esquelético/metabolismo
Obesidade/metabolismo
Fatores de Risco
Estilo de Vida Sedentário
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161116
[St] Status:MEDLINE


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[PMID]:26601949
[Au] Autor:Ryan ZC; Craig TA; Folmes CD; Wang X; Lanza IR; Schaible NS; Salisbury JL; Nair KS; Terzic A; Sieck GC; Kumar R
[Ad] Endereço:From the Departments of Medicine.
[Ti] Título:1α,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells.
[So] Source:J Biol Chem;291(3):1514-28, 2016 Jan 15.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Muscle weakness and myopathy are observed in vitamin D deficiency and chronic renal failure, where concentrations of the active vitamin D3 metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are low. To evaluate the mechanism of action of 1α,25(OH)2D3 in skeletal muscle, we examined mitochondrial oxygen consumption, dynamics, and biogenesis and changes in expression of nuclear genes encoding mitochondrial proteins in human skeletal muscle cells following treatment with 1α,25(OH)2D3. The mitochondrial oxygen consumption rate (OCR) increased in 1α,25(OH)2D3-treated cells. Vitamin D3 metabolites lacking a 1α-hydroxyl group (vitamin D3, 25-hydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3) decreased or failed to increase OCR. 1α-Hydroxyvitamin D3 did not increase OCR. In 1α,25(OH)2D3-treated cells, mitochondrial volume and branching and expression of the pro-fusion protein OPA1 (optic atrophy 1) increased, whereas expression of the pro-fission proteins Fis1 (fission 1) and Drp1 (dynamin 1-like) decreased. Phosphorylated pyruvate dehydrogenase (PDH) (Ser-293) and PDH kinase 4 (PDK4) decreased in 1α,25(OH)2D3-treated cells. There was a trend to increased PDH activity in 1α,25(OH)2D3-treated cells (p = 0.09). 83 nuclear mRNAs encoding mitochondrial proteins were changed following 1α,25(OH)2D3 treatment; notably, PDK4 mRNA decreased, and PDP2 mRNA increased. MYC, MAPK13, and EPAS1 mRNAs, which encode proteins that regulate mitochondrial biogenesis, were increased following 1α,25(OH)2D3 treatment. Vitamin D receptor-dependent changes in the expression of 1947 mRNAs encoding proteins involved in muscle contraction, focal adhesion, integrin, JAK/STAT, MAPK, growth factor, and p53 signaling pathways were observed following 1α,25(OH)2D3 treatment. Five micro-RNAs were induced or repressed by 1α,25(OH)2D3. 1α,25(OH)2D3 regulates mitochondrial function, dynamics, and enzyme function, which are likely to influence muscle strength.
[Mh] Termos MeSH primário: Calcitriol/metabolismo
Regulação da Expressão Gênica
Mitocôndrias Musculares/metabolismo
Dinâmica Mitocondrial
Músculo Esquelético/metabolismo
Fosforilação Oxidativa
Receptores de Calcitriol/agonistas
[Mh] Termos MeSH secundário: Calcitriol/análogos & derivados
Células Cultivadas
GTP Fosfo-Hidrolases/genética
GTP Fosfo-Hidrolases/metabolismo
Perfilação da Expressão Gênica
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Seres Humanos
MicroRNAs/agonistas
MicroRNAs/antagonistas & inibidores
MicroRNAs/metabolismo
Mitocôndrias Musculares/enzimologia
Músculo Esquelético/citologia
Músculo Esquelético/enzimologia
Fosforilação
Processamento de Proteína Pós-Traducional
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Piruvato Desidrogenase (Lipoamida)-Fosfatase/genética
Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
Interferência de RNA
Receptores de Calcitriol/antagonistas & inibidores
Receptores de Calcitriol/genética
Receptores de Calcitriol/metabolismo
Proteínas Recombinantes de Fusão/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (MicroRNAs); 0 (Receptors, Calcitriol); 0 (Recombinant Fusion Proteins); 0 (VDR protein, human); 0 (enhanced green fluorescent protein); 147336-22-9 (Green Fluorescent Proteins); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.1.- (OPA1 protein, human); FXC9231JVH (Calcitriol)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170418
[Lr] Data última revisão:
170418
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151126
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.684399


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[PMID]:25798621
[Au] Autor:Xu J; Chi F; Guo T; Punj V; Lee WN; French SW; Tsukamoto H
[Ti] Título:NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation.
[So] Source:J Clin Invest;125(4):1579-90, 2015 Apr.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metabolic reprogramming is implicated in macrophage activation, but the underlying mechanisms are poorly understood. Here, we demonstrate that the NOTCH1 pathway dictates activation of M1 phenotypes in isolated mouse hepatic macrophages (HMacs) and in a murine macrophage cell line by coupling transcriptional upregulation of M1 genes with metabolic upregulation of mitochondrial oxidative phosphorylation and ROS (mtROS) to augment induction of M1 genes. Enhanced mitochondrial glucose oxidation was achieved by increased recruitment of the NOTCH1 intracellular domain (NICD1) to nuclear and mitochondrial genes that encode respiratory chain components and by NOTCH-dependent induction of pyruvate dehydrogenase phosphatase 1 (Pdp1) expression, pyruvate dehydrogenase activity, and glucose flux to the TCA cycle. As such, inhibition of the NOTCH pathway or Pdp1 knockdown abrogated glucose oxidation, mtROS, and M1 gene expression. Conditional NOTCH1 deficiency in the myeloid lineage attenuated HMac M1 activation and inflammation in a murine model of alcoholic steatohepatitis and markedly reduced lethality following endotoxin-mediated fulminant hepatitis in mice. In vivo monocyte tracking further demonstrated the requirement of NOTCH1 for the migration of blood monocytes into the liver and subsequent M1 differentiation. Together, these results reveal that NOTCH1 promotes reprogramming of mitochondrial metabolism for M1 macrophage activation.
[Mh] Termos MeSH primário: Inflamação/imunologia
Ativação de Macrófagos/fisiologia
Mitocôndrias/metabolismo
Receptor Notch1/fisiologia
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Transporte de Elétrons/genética
Endotoxemia/complicações
Fígado Gorduroso Alcoólico/imunologia
Fígado Gorduroso Alcoólico/metabolismo
Fígado Gorduroso Alcoólico/patologia
Retroalimentação Fisiológica
Regulação da Expressão Gênica
Glucose/metabolismo
Inflamação/metabolismo
Falência Hepática Aguda/etiologia
Falência Hepática Aguda/imunologia
Falência Hepática Aguda/metabolismo
Falência Hepática Aguda/patologia
Ativação de Macrófagos/genética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Células Mieloides/metabolismo
Células Mieloides/patologia
Óxido Nítrico/metabolismo
Fosforilação Oxidativa
Estrutura Terciária de Proteína
Piruvato Desidrogenase (Lipoamida)-Fosfatase/antagonistas & inibidores
Piruvato Desidrogenase (Lipoamida)-Fosfatase/genética
Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
Complexo Piruvato Desidrogenase/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Receptor Notch1/deficiência
Transcrição Genética
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Notch1 protein, mouse); 0 (Pyruvate Dehydrogenase Complex); 0 (Reactive Oxygen Species); 0 (Receptor, Notch1); 31C4KY9ESH (Nitric Oxide); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150324
[St] Status:MEDLINE


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[PMID]:25712957
[Au] Autor:Prabhu A; Sarcar B; Miller CR; Kim SH; Nakano I; Forsyth P; Chinnaiyan P
[Ad] Endereço:Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.C.); Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (A.P., B.S., P.F., P.C.); Neuro-Oncology, H. Lee Moffitt Cancer Center and Research
[Ti] Título:Ras-mediated modulation of pyruvate dehydrogenase activity regulates mitochondrial reserve capacity and contributes to glioblastoma tumorigenesis.
[So] Source:Neuro Oncol;17(9):1220-30, 2015 Sep.
[Is] ISSN:1523-5866
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Even though altered metabolism representing a hallmark of cancer was proposed nearly a century ago, recent technological advances have allowed investigators to continue uncovering a previously unrecognized complexity of metabolic programs that drive tumorigenesis beyond that of aerobic glycolysis. METHODS: The bioenergetic state of a diverse panel of glioblastoma models, including isogenic lines derived from a genetically engineered adult astrocytic mouse model and patient-derived glioblastoma stem cells, was determined at baseline and in stressed conditions. Mechanisms contributing to the discovered metabolic phenotypes were determined through molecular and chemical perturbation, and their biological consequences were evaluated in vivo and in patient samples. RESULTS: Attenuated mitochondrial reserve capacity was identified as a common metabolic phenotype in glioblastoma lines. This phenotype was linked mechanistically with the capacity of Ras-mediated signaling to inhibit pyruvate dehydrogenase (PDH) activity through downregulation of PDH phosphatase (PDP) expression. PDP1 repression was validated clinically in patient-derived samples, suggesting that aberrant cellular signaling typical of glioblastoma actively modulates PDH activity. This phenotype was reversed through both chemical and molecular perturbation. Restoration of PDH activity through stable expression of PDP1-impaired tumorigenic potential. CONCLUSIONS: These findings support the central role that PDH regulation plays as a downstream consequence of aberrant signaling associated with gliomagenesis and the scientific rationale to continue to develop and test clinical strategies designed to activate PDH as a form of anticancer therapy in glioblastoma.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/metabolismo
Glioblastoma/metabolismo
Mitocôndrias/metabolismo
Complexo Piruvato Desidrogenase/metabolismo
Proteínas ras/metabolismo
[Mh] Termos MeSH secundário: Animais
Neoplasias Encefálicas/enzimologia
Linhagem Celular Tumoral
Metabolismo Energético
Glioblastoma/enzimologia
Seres Humanos
Camundongos
Mitocôndrias/enzimologia
Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Pyruvate Dehydrogenase Complex); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150226
[St] Status:MEDLINE
[do] DOI:10.1093/neuonc/nou369


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[PMID]:24962578
[Au] Autor:Shan C; Kang HB; Elf S; Xie J; Gu TL; Aguiar M; Lonning S; Hitosugi T; Chung TW; Arellano M; Khoury HJ; Shin DM; Khuri FR; Boggon TJ; Fan J
[Ad] Endereço:From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322.
[Ti] Título:Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth.
[So] Source:J Biol Chem;289(31):21413-22, 2014 Aug 01.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many cancer cells rely more on aerobic glycolysis (the Warburg effect) than mitochondrial oxidative phosphorylation and catabolize glucose at a high rate. Such a metabolic switch is suggested to be due in part to functional attenuation of mitochondria in cancer cells. However, how oncogenic signals attenuate mitochondrial function and promote the switch to glycolysis remains unclear. We previously reported that tyrosine phosphorylation activates and inhibits mitochondrial pyruvate dehydrogenase kinase (PDK) and phosphatase (PDP), respectively, leading to enhanced inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) and consequently inhibition of pyruvate dehydrogenase complex (PDC) in cancer cells. In particular, Tyr-381 phosphorylation of PDP1 dissociates deacetylase SIRT3 and recruits acetyltransferase ACAT1 to PDC, resulting in increased inhibitory lysine acetylation of PDHA1 and PDP1. Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients. Moreover, expression of a phosphorylation-deficient PDP1 Y94F mutant in cancer cells resulted in increased oxidative phosphorylation, decreased cell proliferation under hypoxia, and reduced tumor growth in mice. Together, our findings suggest that phosphorylation at different tyrosine residues inhibits PDP1 through independent mechanisms, which act in concert to regulate PDC activity and promote the Warburg effect.
[Mh] Termos MeSH primário: Divisão Celular
Neoplasias/patologia
Piruvato Desidrogenase (Lipoamida)-Fosfatase/antagonistas & inibidores
Tirosina/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Sequência de Aminoácidos
Animais
Sequência de Bases
Linhagem Celular Tumoral
Primers do DNA
Seres Humanos
Ácido Láctico/metabolismo
Dados de Sequência Molecular
Neoplasias/enzimologia
Consumo de Oxigênio
Fosforilação
Piruvato Desidrogenase (Lipoamida)-Fosfatase/química
Piruvato Desidrogenase (Lipoamida)-Fosfatase/genética
Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/fisiologia
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA Primers); 33X04XA5AT (Lactic Acid); 42HK56048U (Tyrosine); 8L70Q75FXE (Adenosine Triphosphate); EC 2.7.10.1 (FGFR1 protein, human); EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:161202
[Lr] Data última revisão:
161202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140626
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M114.581124


  8 / 137 MEDLINE  
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[PMID]:24486017
[Au] Autor:Fan J; Shan C; Kang HB; Elf S; Xie J; Tucker M; Gu TL; Aguiar M; Lonning S; Chen H; Mohammadi M; Britton LM; Garcia BA; Aleckovic M; Kang Y; Kaluz S; Devi N; Van Meir EG; Hitosugi T; Seo JH; Lonial S; Gaddh M; Arellano M; Khoury HJ; Khuri FR; Boggon TJ; Kang S; Chen J
[Ad] Endereço:Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
[Ti] Título:Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex.
[So] Source:Mol Cell;53(4):534-48, 2014 Feb 20.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDK), whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here, we report that lysine acetylation of PDHA1 and PDP1 is common in epidermal growth factor (EGF)-stimulated cells and diverse human cancer cells. K321 acetylation inhibits PDHA1 by recruiting PDK1, and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important in promoting glycolysis in cancer cells and consequent tumor growth. Moreover, we identified mitochondrial ACAT1 and SIRT3 as the upstream acetyltransferase and deacetylase, respectively, of PDHA1 and PDP1, while knockdown of ACAT1 attenuates tumor growth. Furthermore, Y381 phosphorylation of PDP1 dissociates SIRT3 and recruits ACAT1 to PDC. Together, hierarchical, distinct posttranslational modifications act in concert to control molecular composition of PDC and contribute to the Warburg effect.
[Mh] Termos MeSH primário: Acetil-CoA C-Acetiltransferase/metabolismo
Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
Piruvato Desidrogenase (Lipoamida)/metabolismo
Sirtuína 3/metabolismo
Tirosina/química
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proliferação Celular
Regulação Enzimológica da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Glicólise
Seres Humanos
Lisina/química
Masculino
Camundongos
Camundongos Nus
Mitocôndrias/metabolismo
Transplante de Neoplasias
Neoplasias/metabolismo
Fosforilação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
42HK56048U (Tyrosine); EC 1.2.4.1 (Pyruvate Dehydrogenase (Lipoamide)); EC 1.2.4.1 (pyruvate dehydrogenase E1alpha subunit); EC 2.3.1.9 (ACAT1 protein, human); EC 2.3.1.9 (Acetyl-CoA C-Acetyltransferase); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase); EC 3.5.1.- (SIRT3 protein, human); EC 3.5.1.- (Sirtuin 3); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1404
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140204
[St] Status:MEDLINE


  9 / 137 MEDLINE  
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[PMID]:23685455
[Au] Autor:Kaplon J; Zheng L; Meissl K; Chaneton B; Selivanov VA; Mackay G; van der Burg SH; Verdegaal EM; Cascante M; Shlomi T; Gottlieb E; Peeper DS
[Ad] Endereço:Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
[Ti] Título:A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence.
[So] Source:Nature;498(7452):109-12, 2013 Jun 06.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In response to tenacious stress signals, such as the unscheduled activation of oncogenes, cells can mobilize tumour suppressor networks to avert the hazard of malignant transformation. A large body of evidence indicates that oncogene-induced senescence (OIS) acts as such a break, withdrawing cells from the proliferative pool almost irreversibly, thus crafting a vital pathophysiological mechanism that protects against cancer. Despite the widespread contribution of OIS to the cessation of tumorigenic expansion in animal models and humans, we have only just begun to define the underlying mechanism and identify key players. Although deregulation of metabolism is intimately linked to the proliferative capacity of cells, and senescent cells are thought to remain metabolically active, little has been investigated in detail about the role of cellular metabolism in OIS. Here we show, by metabolic profiling and functional perturbations, that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence was accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of OIS, a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. These results reveal a mechanistic relationship between OIS and a key metabolic signalling axis, which may be exploited therapeutically.
[Mh] Termos MeSH primário: Senescência Celular/genética
Mitocôndrias/enzimologia
Oncogenes/genética
Complexo Piruvato Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Ciclo do Ácido Cítrico
Modelos Animais de Doenças
Ativação Enzimática
Glicólise
Seres Humanos
Melanoma/tratamento farmacológico
Melanoma/enzimologia
Melanoma/genética
Melanoma/patologia
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Mitocôndrias/metabolismo
Terapia de Alvo Molecular
Fosforilação Oxidativa
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Proteínas Serina-Treonina Quinases/deficiência
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas B-raf/genética
Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Pyruvate Dehydrogenase Complex); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase)
[Em] Mês de entrada:1306
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130521
[St] Status:MEDLINE
[do] DOI:10.1038/nature12154


  10 / 137 MEDLINE  
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[PMID]:23263789
[Au] Autor:Luft FC
[Ad] Endereço:Experimental and Clinical Research Center, a Joint Cooperation Between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenbergerweg 80, 13125 Berlin, Germany. luft@mdc-berlin.de
[Ti] Título:Finding a job for dichloroacetate.
[So] Source:J Mol Med (Berl);91(3):329-31, 2013 Mar.
[Is] ISSN:1432-1440
[Cp] País de publicação:Germany
[La] Idioma:eng
[Mh] Termos MeSH primário: Ácido Dicloroacético/metabolismo
Redes e Vias Metabólicas
Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
Ácido Pirúvico/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Complexo Piruvato Desidrogenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pyruvate Dehydrogenase Complex); 8558G7RUTR (Pyruvic Acid); 9LSH52S3LQ (Dichloroacetic Acid); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:170916
[Lr] Data última revisão:
170916
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:121225
[St] Status:MEDLINE
[do] DOI:10.1007/s00109-012-0989-6



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