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1.
Cell ; 149(1): 49-62, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22401813

RESUMO

Decremental loss of PTEN results in cancer susceptibility and tumor progression. PTEN elevation might therefore be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with PTEN expression elevated to varying levels by taking advantage of bacterial artificial chromosome (BAC)-mediated transgenesis. The "Super-PTEN" mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake and increased mitochondrial oxidative phosphorylation and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and -independent pathways and negatively impacting two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect.


Assuntos
PTEN Fosfo-Hidrolase/metabolismo , Transdução de Sinais , Animais , Tamanho Corporal , Contagem de Células , Proliferação de Células , Respiração Celular , Metabolismo Energético , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo
2.
Mol Cell ; 63(6): 1006-20, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27635760

RESUMO

While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here, we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Ácidos Graxos/metabolismo , Regulação Neoplásica da Expressão Gênica , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Leucemia Mieloide Aguda/metabolismo , Prolina/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/química , Acetil-CoA Carboxilase/genética , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Hidroxilação , Prolina Dioxigenases do Fator Induzível por Hipóxia/química , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos NOD , Modelos Moleculares , Transplante de Neoplasias , Oxirredução , Prolina/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Homologia Estrutural de Proteína , Análise de Sobrevida
3.
Mol Cell ; 50(5): 686-98, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23746352

RESUMO

Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism, leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis.


Assuntos
Carboxiliases/metabolismo , Metabolismo dos Lipídeos , Proteínas Mitocondriais/metabolismo , Sirtuínas/metabolismo , Acetilação , Tecido Adiposo Branco/metabolismo , Animais , Dieta , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/genética , Lipídeos/biossíntese , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Obesidade/etiologia , Obesidade/metabolismo , Oxirredução , Sirtuínas/genética
4.
Proc Natl Acad Sci U S A ; 109(27): 10843-8, 2012 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-22711838

RESUMO

Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylation-mimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach.


Assuntos
Genes ras/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas ras/química , Proteínas ras/metabolismo , Acetilação , Animais , Células COS , Chlorocebus aethiops , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Guanosina Trifosfato/química , Guanosina Trifosfato/metabolismo , Células HEK293 , Células HeLa , Humanos , Lisina/metabolismo , Mutagênese Sítio-Dirigida , Prenilação/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína/fisiologia , Relação Estrutura-Atividade , Proteínas ras/genética
5.
Cell Metab ; 7(2): 113-24, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18249171

RESUMO

JunD, a transcription factor of the AP-1 family, protects cells against oxidative stress. Here, we show that junD(-/-) mice exhibit features of premature aging and shortened life span. They also display persistent hypoglycemia due to enhanced insulin secretion. Consequently, the insulin/IGF-1 signaling pathways are constitutively stimulated, leading to inactivation of FoxO1, a positive regulator of longevity. Hyperinsulinemia most likely results from enhanced pancreatic islet vascularization owing to chronic oxidative stress. Indeed, accumulation of free radicals in beta cells enhances VEGF-A transcription, which in turn increases pancreatic angiogenesis and insulin secretion. Accordingly, long-term treatment with an antioxidant rescues the phenotype of junD(-/-) mice. Indeed, dietary antioxidant supplementation was protective against pancreatic angiogenesis, hyperinsulinemia, and subsequent activation of insulin signaling cascades in peripheral tissues. Taken together, these data establish a pivotal role for oxidative stress in systemic regulation of insulin and define a key role for the JunD protein in longevity.


Assuntos
Envelhecimento/fisiologia , Insulina/metabolismo , Neovascularização Patológica/etiologia , Estresse Oxidativo/fisiologia , Pâncreas/irrigação sanguínea , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Hipoglicemia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-jun/genética , Transdução de Sinais
6.
Am J Pathol ; 179(1): 134-40, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21640331

RESUMO

Genetic investigation of crescentic glomerulonephritis (Crgn) susceptibility in the Wistar Kyoto rat, a strain uniquely susceptible to nephrotoxic nephritis (NTN), allowed us to positionally clone the activator protein-1 transcription factor Jund as a susceptibility gene associated with Crgn. To study the influence of Jund deficiency (Jund(-/-)) on immune-mediated renal disease, susceptibility to accelerated NTN was examined in Jund(-/-) mice and C57BL/6 wild-type (WT) controls. Jund(-/-) mice showed exacerbated glomerular crescent formation and macrophage infiltration, 10 days after NTN induction. Serum urea levels were also significantly increased in the Jund(-/-) mice compared with the WT controls. There was no evidence of immune response differences between Jund(-/-) and WT animals because the quantitative immunofluorescence for sheep and mouse IgG deposition in glomeruli was similar. Because murine Jund was inactivated by replacement with a bacterial LacZ reporter gene, we then investigated its glomerular expression by IHC and found that the Jund promoter is mainly active in Jund(-/-) podocytes. Furthermore, cultured glomeruli from Jund(-/-) mice showed relatively increased expression of vascular endothelial growth factor A (Vegfa), Cxcr4, and Cxcl12, well-known HIF target genes. Accordingly, small-interfering RNA-mediated JUND knockdown in conditionally immortalized human podocyte cell lines led to increased VEGFA and HIF1A expression. Our findings suggest that deficiency of Jund may cause increased oxidative stress in podocytes, leading to altered VEGFA expression and subsequent glomerular injury in Crgn.


Assuntos
Glomerulonefrite/metabolismo , Glomerulonefrite/prevenção & controle , Podócitos/metabolismo , Proteínas Proto-Oncogênicas c-jun/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Western Blotting , Células Cultivadas , Feminino , Imunofluorescência , Glomerulonefrite/etiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas Imunoenzimáticas , Imunoglobulina G/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Podócitos/citologia , Proteínas Proto-Oncogênicas c-jun/antagonistas & inibidores , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ovinos , Fator de Transcrição AP-1 , Fator A de Crescimento do Endotélio Vascular/genética
7.
Biochim Biophys Acta ; 1804(8): 1652-7, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19962456

RESUMO

Members of the sirtuin family of NAD(+)-dependent protein deacetylases are important regulators of longevity in yeast, worms, and flies. Mammals have seven sirtuins (SIRT1-7), each characterized by differences in subcellular localization, substrate preference, and biological function. While it is unclear whether sirtuins regulate aging in mammals, it is clear that sirtuins influence diverse aspects of their metabolism. Indeed, SIRT1 promotes oxidation of fatty acids in liver and skeletal muscle, cholesterol metabolism in liver, and lipid mobilization in white adipose tissue. Moreover, small-molecule activators of SIRT1 have recently been shown to protect mice from the negative effects of a high-fat diet. These findings suggest that sirtuins might provide important new targets for the treatment of obesity and related diseases. In this review, we discuss the major findings linking sirtuins with the regulation of lipid metabolism.


Assuntos
Metabolismo dos Lipídeos , Sirtuínas/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Restrição Calórica , Gorduras na Dieta/administração & dosagem , Ativação Enzimática/efeitos dos fármacos , Humanos , Insulina/metabolismo , Secreção de Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Modelos Biológicos , Músculo Esquelético/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Resveratrol , Estilbenos/farmacologia
8.
Cell Rep ; 36(2): 109345, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34260923

RESUMO

Upon nutrient stimulation, pre-adipocytes undergo differentiation to transform into mature adipocytes capable of storing nutrients as fat. We profiled cellular metabolite consumption to identify early metabolic drivers of adipocyte differentiation. We find that adipocyte differentiation raises the uptake and consumption of numerous amino acids. In particular, branched-chain amino acid (BCAA) catabolism precedes and promotes peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of adipogenesis. In early adipogenesis, the mitochondrial sirtuin SIRT4 elevates BCAA catabolism through the activation of methylcrotonyl-coenzyme A (CoA) carboxylase (MCCC). MCCC supports leucine oxidation by catalyzing the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA. Sirtuin 4 (SIRT4) expression is decreased in adipose tissue of numerous diabetic mouse models, and its expression is most correlated with BCAA enzymes, suggesting a potential role for SIRT4 in adipose pathology through the alteration of BCAA metabolism. In summary, this work provides a temporal analysis of adipocyte differentiation and uncovers early metabolic events that stimulate transcriptional reprogramming.


Assuntos
Adipogenia , Aminoácidos de Cadeia Ramificada/metabolismo , Proteínas Mitocondriais/metabolismo , Sirtuínas/metabolismo , Células 3T3-L1 , Tecido Adiposo/metabolismo , Animais , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/metabolismo
9.
Aging Cell ; 14(5): 818-25, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26109058

RESUMO

The mitochondrial deacetylase SIRT3 regulates several important metabolic processes. SIRT3 is transcriptionally upregulated in multiple tissues during nutrient stresses such as dietary restriction and fasting, but the molecular mechanism of this induction is unclear. We conducted a bioinformatic study to identify transcription factor(s) involved in SIRT3 induction. Our analysis identified an enrichment of binding sites for nuclear respiratory factor 2 (NRF-2), a transcription factor known to play a role in the expression of mitochondrial genes, in the DNA sequences of SIRT3 and genes with closely correlated expression patterns. In vitro, knockdown or overexpression of NRF-2 modulated SIRT3 levels, and the NRF-2α subunit directly bound to the SIRT3 promoter. Our results suggest that NRF-2 is a regulator of SIRT3 expression and may shed light on how SIRT3 is upregulated during nutrient stress.


Assuntos
Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Sirtuína 3/genética , Animais , Sítios de Ligação , Células Cultivadas , Biologia Computacional , Indução Enzimática/genética , Fator de Transcrição de Proteínas de Ligação GA/deficiência , Células HEK293 , Humanos , Regiões Promotoras Genéticas/genética , Sirtuína 3/biossíntese
10.
Cell Metab ; 22(1): 164-74, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26001423

RESUMO

Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-ß molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Diferenciação de Crescimento/metabolismo , Músculo Esquelético/fisiologia , Regeneração , Envelhecimento , Animais , Proteínas Morfogenéticas Ósseas/sangue , Proteínas Morfogenéticas Ósseas/genética , Diferenciação Celular , Linhagem Celular , Fatores de Diferenciação de Crescimento/sangue , Fatores de Diferenciação de Crescimento/genética , Humanos , Camundongos , Mioblastos/citologia , Mioblastos/metabolismo , Miostatina/metabolismo , Ratos , Transdução de Sinais , Regulação para Cima
11.
Mol Cancer Res ; 11(9): 1072-7, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23723075

RESUMO

UNLABELLED: Activating point mutations in K-RAS are extremely common in cancers of the lung, colon, and pancreas and are highly predictive of poor therapeutic response. One potential strategy for overcoming the deleterious effects of mutant K-RAS is to alter its posttranslational modification. Although therapies targeting farnesylation have been explored, and have ultimately failed, the therapeutic potential of targeting other modifications remains to be seen. Recently, it was shown that acetylation of lysine 104 attenuates K-RAS transforming activity by interfering with GEF-induced nucleotide exchange. Here, the deacetylases HDAC6 and SIRT2 were shown to regulate the acetylation state of K-RAS in cancer cells. By extension, inhibition of either of these enzymes has a dramatic impact on the growth properties of cancer cells expressing activation mutants of K-RAS. These results suggest that therapeutic targeting of HDAC6 and/or SIRT2 may represent a new way to treat cancers expressing mutant forms of K-RAS. IMPLICATIONS: This study suggests that altering K-RAS acetylation is a feasible approach to limiting tumorigenic potential.


Assuntos
Transformação Celular Neoplásica , Histona Desacetilases/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Sirtuína 2/metabolismo , Proteínas ras/metabolismo , Acetilação , Animais , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Desacetilase 6 de Histona , Histona Desacetilases/genética , Humanos , Camundongos , Terapia de Alvo Molecular , Células NIH 3T3 , Neoplasias/patologia , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Sirtuína 2/genética , Proteínas ras/genética
12.
Mol Cell Biol ; 33(22): 4552-61, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24043310

RESUMO

Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator-activated receptor α (PPARα) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism.


Assuntos
Ácidos Graxos/metabolismo , Fígado/metabolismo , Proteínas Mitocondriais/metabolismo , PPAR alfa/metabolismo , Sirtuínas/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Jejum , Ácidos Graxos/genética , Feminino , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/genética , NAD/metabolismo , Oxirredução , PPAR alfa/genética , Sirtuína 1/metabolismo , Sirtuínas/genética , Ativação Transcricional , Regulação para Cima
13.
Cancer Cell ; 23(4): 450-63, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23562301

RESUMO

DNA damage elicits a cellular signaling response that initiates cell cycle arrest and DNA repair. Here, we find that DNA damage triggers a critical block in glutamine metabolism, which is required for proper DNA damage responses. This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into tricarboxylic acid cycle. SIRT4 loss leads to both increased glutamine-dependent proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes. Moreover, SIRT4 knockout mice spontaneously develop lung tumors. Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest, and tumor suppression.


Assuntos
Dano ao DNA , Glutamina/antagonistas & inibidores , Glutamina/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Neoplasias Experimentais/genética , Sirtuínas/genética , Animais , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Reparo do DNA , Feminino , Glutamina/genética , Células HEK293 , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/enzimologia , Mitocôndrias/genética , Proteínas Mitocondriais/metabolismo , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Transdução de Sinais , Sirtuínas/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
14.
J Clin Invest ; 122(9): 3088-100, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22886304

RESUMO

Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted as both a negative regulator of PPARγ coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated strikingly with reduced time to recurrence, a gene signature of poor prognosis, and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Acetilação , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Dieta Hiperlipídica/efeitos adversos , Intervalo Livre de Doença , Ácidos Graxos/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Fígado/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Proteínas Nucleares/genética , Obesidade/etiologia , Obesidade/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Proteína da Leucemia Promielocítica , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Transativadores/metabolismo , Fatores de Transcrição/genética , Transcrição Gênica , Transcriptoma , Proteínas Supressoras de Tumor/genética
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