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1.
Cell ; 155(4): 844-57, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24209622

RESUMO

Here, we show that a subset of breast cancers express high levels of the type 2 phosphatidylinositol-5-phosphate 4-kinases α and/or ß (PI5P4Kα and ß) and provide evidence that these kinases are essential for growth in the absence of p53. Knocking down PI5P4Kα and ß in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K ß and deficient for p53 impaired growth on plastic and in xenografts. This growth phenotype was accompanied by enhanced levels of reactive oxygen species (ROS) leading to senescence. Mice with homozygous deletion of both TP53 and PIP4K2B were not viable, indicating a synthetic lethality for loss of these two genes. Importantly however, PIP4K2A(-/-), PIP4K2B(+/-), and TP53(-/-) mice were viable and had a dramatic reduction in tumor formation compared to TP53(-/-) littermates. These results indicate that inhibitors of PI5P4Ks could be effective in preventing or treating cancers with mutations in TP53.


Assuntos
Neoplasias da Mama/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Respiração Celular , Senescência Celular , Embrião de Mamíferos/metabolismo , Técnicas de Silenciamento de Genes , Genes Letais , Xenoenxertos , Humanos , Camundongos , Transplante de Neoplasias , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
2.
Cell ; 155(7): 1624-38, 2013 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-24360282

RESUMO

Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/ß-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/ß-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.


Assuntos
Envelhecimento/patologia , Núcleo Celular/metabolismo , Mitocôndrias/metabolismo , NAD/metabolismo , Fosforilação Oxidativa , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Fatores de Transcrição/metabolismo
3.
Cell ; 147(7): 1459-72, 2011 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-22169038

RESUMO

SIRT1 is a NAD(+)-dependent deacetylase that governs a number of genetic programs to cope with changes in the nutritional status of cells and organisms. Behavioral responses to food abundance are important for the survival of higher animals. Here we used mice with increased or decreased brain SIRT1 to show that this sirtuin regulates anxiety and exploratory drive by activating transcription of the gene encoding the monoamine oxidase A (MAO-A) to reduce serotonin levels in the brain. Indeed, treating animals with MAO-A inhibitors or selective serotonin reuptake inhibitors (SSRIs) normalized anxiety differences between wild-type and mutant animals. SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter. Both common and rare variations in the SIRT1 gene were shown to be associated with risk of anxiety in human population samples. Together these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.


Assuntos
Ansiedade/genética , Encéfalo/metabolismo , Comportamento Exploratório , Monoaminoxidase/genética , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sequência de Aminoácidos , Animais , Comportamento Animal , Impulso (Psicologia) , Regulação da Expressão Gênica , Humanos , Camundongos , Dados de Sequência Molecular , Monoaminoxidase/química , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fatores de Transcrição/genética
4.
Genes Dev ; 28(10): 1054-67, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24788094

RESUMO

MicroRNAs delicately regulate the balance of angiogenesis. Here we show that depletion of all microRNAs suppresses tumor angiogenesis. We generated microRNA-deficient tumors by knocking out Dicer1. These tumors are highly hypoxic but poorly vascularized, suggestive of deficient angiogenesis signaling. Expression profiling revealed that angiogenesis genes were significantly down-regulated as a result of the microRNA deficiency. Factor inhibiting hypoxia-inducible factor 1 (HIF-1), FIH1, is derepressed under these conditions and suppresses HIF transcription. Knocking out FIH1 using CRISPR/Cas9-mediated genome engineering reversed the phenotypes of microRNA-deficient cells in HIF transcriptional activity, VEGF production, tumor hypoxia, and tumor angiogenesis. Using multiplexed CRISPR/Cas9, we deleted regions in FIH1 3' untranslated regions (UTRs) that contain microRNA-binding sites, which derepresses FIH1 protein and represses hypoxia response. These data suggest that microRNAs promote tumor responses to hypoxia and angiogenesis by repressing FIH1.


Assuntos
RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Neovascularização Patológica/genética , Ribonuclease III/genética , Ribonuclease III/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Genótipo , Camundongos , Camundongos Nus , Neovascularização Patológica/metabolismo , Transcriptoma
5.
Mol Cell ; 42(5): 561-8, 2011 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-21658599

RESUMO

Sirtuins are NAD(+) dependent deacetylases that counter aging and diseases of aging. Sirtuin research has focused on SirT1, which deacetylates transcription factors and cofactors in the nucleus. More recent findings highlight SirT3 as a mitochondrial sirtuin that regulates metabolism and oxidative stress. This review focuses on new data linking SirT3 to management of reactive oxygen species from mitochondria, which may have profound implications for aging and late-onset diseases.


Assuntos
Estresse Oxidativo , Sirtuína 3/fisiologia , Animais , Restrição Calórica , Linhagem Celular , Perda Auditiva/etiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/fisiologia
6.
Development ; 141(18): 3495-504, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25142464

RESUMO

Sirtuins are NAD(+)-dependent deacylases that regulate numerous biological processes in response to the environment. SirT1 is the mammalian ortholog of yeast Sir2, and is involved in many metabolic pathways in somatic tissues. Whole body deletion of SirT1 alters reproductive function in oocytes and the testes, in part caused by defects in central neuro-endocrine control. To study the function of SirT1 specifically in the male germ line, we deleted this sirtuin in male germ cells and found that mutant mice had smaller testes, a delay in differentiation of pre-meiotic germ cells, decreased spermatozoa number, an increased proportion of abnormal spermatozoa and reduced fertility. At the molecular level, mutants do not have the characteristic increase in acetylation of histone H4 at residues K5, K8 and K12 during spermiogenesis and demonstrate corresponding defects in the histone to protamine transition. Our findings thus reveal a germ cell-autonomous role of SirT1 in spermatogenesis.


Assuntos
Diferenciação Celular/genética , Fertilidade/genética , Células Germinativas/fisiologia , Sirtuína 1/metabolismo , Espermatogênese/genética , Acetilação , Animais , Diferenciação Celular/fisiologia , Montagem e Desmontagem da Cromatina/genética , Cromatografia Líquida , Feminino , Fertilidade/fisiologia , Imunofluorescência , Histonas/metabolismo , Immunoblotting , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Processamento de Proteína Pós-Traducional/genética , Sirtuína 1/deficiência , Espectrometria de Massas em Tandem , Testículo/metabolismo
7.
Nature ; 481(7381): 380-4, 2011 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-22101433

RESUMO

Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.


Assuntos
Hipóxia Celular , Glutamina/metabolismo , Isocitrato Desidrogenase/metabolismo , Lipogênese , Acetilcoenzima A/biossíntese , Acetilcoenzima A/metabolismo , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linfócitos T CD8-Positivos/citologia , Carbono/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Células Cultivadas , Ciclo do Ácido Cítrico , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isocitrato Desidrogenase/deficiência , Isocitrato Desidrogenase/genética , Ácidos Cetoglutáricos/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Oxirredução , Oxigênio/metabolismo , Ácido Palmítico/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
8.
Proc Natl Acad Sci U S A ; 110(9): 3483-8, 2013 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-23378636

RESUMO

CUB domain-containing protein 1 (CDCP1) is a transmembrane protein that is highly expressed in stem cells and frequently overexpressed and tyrosine-phosphorylated in cancer. CDCP1 promotes cancer cell metastasis. However, the mechanisms that regulate CDCP1 are not well-defined. Here we show that hypoxia induces CDCP1 expression and tyrosine phosphorylation in hypoxia-inducible factor (HIF)-2α-, but not HIF-1α-, dependent fashion. shRNA knockdown of CDCP1 impairs cancer cell migration under hypoxic conditions, whereas overexpression of HIF-2α promotes the growth of tumor xenografts in association with enhanced CDCP1 expression and tyrosine phosphorylation. Immunohistochemistry analysis of tissue microarray samples from tumors of patients with clear cell renal cell carcinoma shows that increased CDCP1 expression correlates with decreased overall survival. Together, these data support a critical role for CDCP1 as a unique HIF-2α target gene involved in the regulation of cancer metastasis, and suggest that CDCP1 is a biomarker and potential therapeutic target for metastatic cancers.


Assuntos
Antígenos CD/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Moléculas de Adesão Celular/genética , Genes Neoplásicos/genética , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Proteínas de Neoplasias/genética , Animais , Antígenos CD/metabolismo , Antígenos de Neoplasias , Carcinoma de Células Renais/patologia , Moléculas de Adesão Celular/metabolismo , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/metabolismo
9.
Trends Mol Med ; 29(2): 152-172, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36503994

RESUMO

Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are a 48-member superfamily of membrane proteins that actively transport a variety of biological substrates across lipid membranes. Their functional diversity defines an expansive involvement in myriad aspects of human biology. At least 21 ABC transporters underlie rare monogenic disorders, with even more implicated in the predisposition to and symptomology of common and complex diseases. Such broad (patho)physiological relevance places this class of proteins at the intersection of disease causation and therapeutic potential, underlining them as promising targets for drug discovery, as exemplified by the transformative CFTR (ABCC7) modulator therapies for cystic fibrosis. This review will explore the growing relevance of ABC transporters to human disease and their potential as small-molecule drug targets.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Fibrose Cística , Humanos , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Fibrose Cística/metabolismo , Trifosfato de Adenosina/metabolismo
10.
J Cell Biol ; 177(6): 1029-36, 2007 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-17562787

RESUMO

Mammalian cells increase transcription of genes for adaptation to hypoxia through the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) protein. How cells transduce hypoxic signals to stabilize the HIF-1alpha protein remains unresolved. We demonstrate that cells deficient in the complex III subunit cytochrome b, which are respiratory incompetent, increase ROS levels and stabilize the HIF-1alpha protein during hypoxia. RNA interference of the complex III subunit Rieske iron sulfur protein in the cytochrome b-null cells and treatment of wild-type cells with stigmatellin abolished reactive oxygen species (ROS) generation at the Qo site of complex III. These interventions maintained hydroxylation of HIF-1alpha protein and prevented stabilization of HIF-1alpha protein during hypoxia. Antioxidants maintained hydroxylation of HIF-1alpha protein and prevented stabilization of HIF-1alpha protein during hypoxia. Exogenous hydrogen peroxide under normoxia prevented hydroxylation of HIF-1alpha protein and stabilized HIF-1alpha protein. These results provide genetic and pharmacologic evidence that the Qo site of complex III is required for the transduction of hypoxic signal by releasing ROS to stabilize the HIF-1alpha protein.


Assuntos
Hipóxia Celular , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Citocromos b , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Mitocondriais/metabolismo
11.
Cell Metab ; 1(6): 409-14, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16054090

RESUMO

Mammalian cells detect decreases in oxygen concentrations to activate a variety of responses that help cells adapt to low oxygen levels (hypoxia). One such response is stabilization of the protein HIF-1 alpha, a component of the transcription factor HIF-1. Here we show that a small interfering RNA (siRNA) against the Rieske iron-sulfur protein of mitochondrial complex III prevents the hypoxic stabilization of HIF-1 alpha protein. Fibroblasts from a patient with Leigh's syndrome, which display residual levels of electron transport activity and are incompetent in oxidative phosphorylation, stabilize HIF-1 alpha during hypoxia. The expression of glutathione peroxidase or catalase, but not superoxide dismutase 1 or 2, prevents the hypoxic stabilization of HIF-1 alpha. These findings provide genetic evidence that oxygen sensing is dependent on mitochondrial-generated reactive oxygen species (ROS) but independent of oxidative phosphorylation.


Assuntos
Mitocôndrias/metabolismo , Fosforilação Oxidativa , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Peróxido de Hidrogênio/metabolismo , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo
12.
FASEB J ; 23(3): 783-94, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18948382

RESUMO

Senescence is a potential tumor-suppressing mechanism and a commonly used model of cellular aging. One current hypothesis to explain senescence, based in part on the correlation of oxygen with senescence, postulates that it is caused by oxidative damage from reactive oxygen species (ROS). Here, we further test this theory by determining the mechanisms of hyperoxia-induced senescence. Exposure to 70% O(2) led to stress-induced, telomere-independent senescence. Although hyperoxia elevated mitochondrial ROS production, overexpression of antioxidant proteins was not sufficient to prevent hyperoxia-induced senescence. Hyperoxia activated AMPK; however, overexpression of a kinase-dead mutant of LKB1, which prevented AMPK activation, did not prevent hyperoxia-induced senescence. Knocking down p21 via shRNA, or suppression of the p16/pRb pathway by either BMI1 or HPV16-E7 overexpression, was also insufficient to prevent hyperoxia-induced senescence. However, suppressing p53 function resulted in partial rescue from senescence, suggesting that hyperoxia-induced senescence involves p53. Suppressing both the p53 and pRb pathways resulted in almost complete protection, indicating that both pathways cooperate in hyperoxia-induced senescence. Collectively, these results indicate a ROS-independent but p53/pRb-dependent senescence mechanism during hyperoxia.


Assuntos
Senescência Celular/fisiologia , Hiperóxia , Mitocôndrias/metabolismo , Proteína do Retinoblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Células Cultivadas , Citosol/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Pulmão/citologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Complexo Repressor Polycomb 1 , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína do Retinoblastoma/genética , Ribonucleotídeos , Telomerase/genética , Telomerase/metabolismo , Proteína Supressora de Tumor p53/genética
13.
Mol Cell Biol ; 27(16): 5737-45, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17562866

RESUMO

Physiological hypoxia extends the replicative life span of human cells in culture. Here, we report that hypoxic extension of replicative life span is associated with an increase in mitochondrial reactive oxygen species (ROS) in primary human lung fibroblasts. The generation of mitochondrial ROS is necessary for hypoxic activation of the transcription factor hypoxia-inducible factor (HIF). The hypoxic extension of replicative life span is ablated by a dominant negative HIF. HIF is sufficient to induce telomerase reverse transcriptase mRNA and telomerase activity and to extend replicative life span. Furthermore, the down-regulation of the von Hippel-Lindau tumor suppressor protein by RNA interference increases HIF activity and extends replicative life span under normoxia. These findings provide genetic evidence that hypoxia utilizes mitochondrial ROS as signaling molecules to activate HIF-dependent extension of replicative life span.


Assuntos
Senescência Celular , Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Citosol/efeitos dos fármacos , Dano ao DNA , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Humanos , Fator 1 Induzível por Hipóxia/genética , Mitocôndrias/efeitos dos fármacos , Oxigênio/farmacologia , Telomerase/genética , Termodinâmica , Transcrição Gênica/efeitos dos fármacos , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
14.
Mitochondrion ; 46: 51-58, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29458111

RESUMO

Duchenne muscular dystrophy (DMD) is a recessive, fatal X-linked disease that is characterized by progressive skeletal muscle wasting due to the absence of dystrophin, which is an a essential protein that bridges the inner cytoskeleton and extra-cellular matrix. This study set out to characterize the mitochondria in primary muscle satellite cell derived myoblasts from mdx mice and wild type control mice. Compared to wild type derived cells the mdx derived cells have reduced mitochondrial bioenergetics and have fewer mitochondria. Here, we demonstrate that a novel PPARδ modulator improves mitochondrial function in the mdx mice, which supports that modulating PPARδ may be therapeutically beneficial in DMD patients.


Assuntos
Ácidos Graxos/metabolismo , Mitocôndrias/patologia , Distrofia Muscular de Duchenne/patologia , Mioblastos/patologia , PPAR delta/metabolismo , Animais , Modelos Animais de Doenças , Metabolismo Energético , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Oxirredução
16.
Antioxid Redox Signal ; 10(3): 635-40, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17999628

RESUMO

As tumors develop, they outgrow the vascular network that supplies cells with oxygen and nutrients needed for survival. In response to decreased oxygen levels, the tumor cells initiate a program of adaptation by inducing the transcription of multiple genes via the activation of the transcription factor hypoxia-inducible factor (HIF). Proteins encoded by a subset of genes induced by HIF promote tumorigenesis by acting directly on both the tumor cells and the microenvironment in which the tumor cells reside. The mechanism(s) by which hypoxia activates HIF is a subject of intensive research. Understanding how hypoxia activates HIF will provide targets for the development of therapies that could specifically target growing tumors by not allowing adequate adaptation to hypoxia, which is necessary for cancer progression. Here we outline how mitochondria regulate the activity of HIF during hypoxia.


Assuntos
Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Oxigênio/metabolismo , Humanos , Mitocôndrias/metabolismo
17.
Essays Biochem ; 43: 17-27, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17705790

RESUMO

Decreased oxygen availability (hypoxia) promotes physiological processes such as energy metabolism, angiogenesis, cell proliferation and cell viability through the transcription factor HIF (hypoxia-inducible factor). Activation of HIF can also promote pathophysiological processes such as cancer and pulmonary hypertension. The mechanism(s) by which hypoxia activates HIF are the subject of intensive research. In this chapter we outline the model in which mitochondria regulate the stability of HIF through the increased production of ROS (reactive oxygen species) during hypoxia.


Assuntos
Regulação da Expressão Gênica , Mitocôndrias/fisiologia , Oxigênio/metabolismo , Espécies Reativas de Oxigênio , Animais , Transporte de Elétrons , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Modelos Biológicos
18.
ACS Med Chem Lett ; 9(9): 935-940, 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30258544

RESUMO

The X-ray structure of the previously reported PPARδ modulator 1 bound to the ligand binding domain (LBD) revealed that the amide moiety in 1 exists in the thermodynamically disfavored cis-amide orientation. Isosteric replacement of the cis-amide with five-membered heterocycles led to the identification of imidazole 17 (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested in vivo in mice and in vitro in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); 17 altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.

19.
Methods Enzymol ; 435: 447-61, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17998068

RESUMO

Oxygen is the terminal electron acceptor in the mitochondrial electron transport chain and therefore is required for the generation of energy through oxidative phosphorylation. In environments of decreased oxygen levels (hypoxia), organisms have developed an adaptive response through the activation of the hypoxia-inducible transcription factor (HIF) to maintain their energetic demand. In order to sense hypoxic environments, cells have developed oxygen-sensing machinery that allows for the activation of HIF. The mitochondrial electron transport chain is required for the oxygen-sensing pathway. This chapter outlines methods used to explore the role of the electron transport chain and a by-product of electron transport, reactive oxygen species, in oxygen sensing.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Mitocôndrias/metabolismo , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/análise , Animais , Linhagem Celular , Transporte de Elétrons/genética , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Ferro-Enxofre/metabolismo , Mitocôndrias/genética , Espécies Reativas de Oxigênio/metabolismo
20.
Cell Rep ; 17(3): 809-820, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27732856

RESUMO

The enhancer landscape is dramatically restructured as naive preimplantation epiblasts transition to the post-implantation state of primed pluripotency. A key factor in this process is Otx2, which is upregulated during the early stages of this transition and ultimately recruits Oct4 to a different set of enhancers. In this study, we discover that the acetylation status of Oct4 regulates the induction of the primed pluripotency gene network. Maintenance of the naive state requires the NAD-dependent deacetylase, SirT1, which deacetylates Oct4. The activity of SirT1 is reduced during the naive-to-primed transition; Oct4 becomes hyper-acetylated and binds to an Otx2 enhancer to induce Otx2 expression. Induction of Otx2 causes the reorganization of acetylated Oct4 and results in the induction of the primed pluripotency gene network. Regulation of Oct4 by SirT1 may link stem cell development to environmental conditions, and it may provide strategies to manipulate epiblast cell state.


Assuntos
Fator 3 de Transcrição de Octâmero/metabolismo , Células-Tronco Pluripotentes/metabolismo , Sirtuína 1/metabolismo , Acetilação , Animais , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Camadas Germinativas/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Células-Tronco Embrionárias Murinas , Fatores de Transcrição Otx/metabolismo , Células-Tronco Pluripotentes/citologia , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Gênica
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