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1.
Nature ; 576(7786): 301-305, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31801997

RESUMO

A central aspect of aging research concerns the question of when individuality in lifespan arises1. Here we show that a transient increase in reactive oxygen species (ROS), which occurs naturally during early development in a subpopulation of synchronized Caenorhabditis elegans, sets processes in motion that increase stress resistance, improve redox homeostasis and ultimately prolong lifespan in those animals. We find that these effects are linked to the global ROS-mediated decrease in developmental histone H3K4me3 levels. Studies in HeLa cells confirmed that global H3K4me3 levels are ROS-sensitive and that depletion of H3K4me3 levels increases stress resistance in mammalian cell cultures. In vitro studies identified SET1/MLL histone methyltransferases as redox sensitive units of the H3K4-trimethylating complex of proteins (COMPASS). Our findings implicate a link between early-life events, ROS-sensitive epigenetic marks, stress resistance and lifespan.


Assuntos
Longevidade , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Animais , Caenorhabditis elegans , Regulação para Baixo , Histonas/metabolismo , Larva
2.
Cell Physiol Biochem ; 33(5): 1411-25, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24853800

RESUMO

UNLABELLED: BACKGOUND/AIMS: The injection of cerulein, an analogue of the pancreatic secretagogue cholecystokinin (CCK), induces acute pancreatitis in mice that is accompanied by the synthesis of the transcription factor Egr-1. The signaling cascade that connects cerulein stimulation with enhanced Egr-1 biosynthesis was analyzed. METHODS: AR42J rat pancreatic acinar cells were used as a model system to measure cerulein-induced Egr-1 biosynthesis. For comparison, the signaling cascade induced by activation of Gαq-coupled designer receptors with the designer drug clozapine-N-oxide (CNO) was investigated. RESULTS: Stimulation of AR42J cells with cerulein induced a robust and transient biosynthesis of Egr-1. The signaling cascade connecting cerulein stimulation with Egr-1 gene expression required elevated levels of cytosolic Ca(2+) and the activation of the protein kinases PKC, Raf and ERK, while expression of MKP-1 prevented Egr-1 biosynthesis in cerulein-stimulated AR42J cells. In addition, ternary complex factors are required to connect cerulein stimulation with enhanced transcription of the Egr-1 gene. Egr-1 biosynthesis induced in CNO-stimulated AR42J pancreatic acinar cells expressing Gαq-coupled designer receptors required identical signaling molecules, although subtle differences were observed in comparison to cerulein/CCK receptor signaling. CONCLUSION: We propose that overstimulation of the canonical Gαq-induced signaling pathway may be crucial for inducing acute pancreatitis.


Assuntos
Células Acinares/efeitos dos fármacos , Células Acinares/metabolismo , Ceruletídeo/farmacologia , Colecistocinina/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Pâncreas/citologia , Pâncreas/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Animais , Células Cultivadas , Ceruletídeo/administração & dosagem , Pâncreas/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
3.
J Cell Biochem ; 114(3): 681-96, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23059951

RESUMO

G-protein coupled designer receptors that are specifically activated by designer drugs have been developed. Here, we have analyzed the regulation of gene transcription following activation of Gα(q)-coupled designer receptor (Rα(q)). Stimulation of human embryonic kidney (HEK) 293 cells expressing Rα(q) with clozapine-N-oxide (CNO), a pharmacologically inert compound, induced the expression of biologically active Egr-1, a zinc finger transcription factor. Expression of a dominant-negative mutant of the ternary complex factor (TCF) Elk-1, a key transcriptional regulator of serum response element (SRE)-driven gene transcription, prevented Egr-1 expression. Stimulation of Rα(q) with CNO increased the transcriptional activation potential of Elk-1 and enhanced transcription of an SRE regulated reporter gene. In addition, AP-1 transcriptional activity was significantly elevated. AP-1 activity was controlled by TCFs and c-Jun in cells expressing an activated Gα(q)-coupled designer receptor. CNO stimulation did not increase Egr-1 and AP-1 activity in neuroblastoma cells expressing endogenous M3 muscarinic acetylcholine receptors, indicating that CNO did not function as a ligand for these receptors. Rα(q) stimulation also increased the transcriptional activation potential of CREB and cAMP response controlled gene transcription. Pharmacological and genetic experiments revealed that the protein kinases Raf and ERK were essential to connect Rα(q) stimulation with enhanced Egr-1 and AP-1 controlled transcription. In contrast, MAP kinase phosphatase-1 functioned as a nuclear shut-off device of stimulus-transcription coupling. The fact that Rα(q) stimulation activates the transcription factors Egr-1, Elk-1, AP-1, and CREB indicates that regulation of gene transcription is an integral part of Gα(q)-coupled receptor signaling.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Genes Precoces/genética , Sistema de Sinalização das MAP Quinases/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteína de Ligação a CREB/genética , Linhagem Celular Tumoral , Clozapina/análogos & derivados , Clozapina/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/genética , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mutação , Neuroblastoma/genética , Neuroblastoma/metabolismo , Receptor Muscarínico M3/biossíntese , Elemento de Resposta Sérica , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Transcrição Gênica , Ativação Transcricional , Quinases raf/metabolismo
4.
Biol Chem ; 394(12): 1615-22, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23893685

RESUMO

G-protein-coupled receptors (GPCRs) are the largest group of plasma membrane receptors in nature and are activated by a variety of different ligands. The biological outcome of GPCR stimulation is complex, as a plethora of signaling pathways are activated upon stimulation. These complexity and diversity of GPCR signaling make it difficult to manipulate the signaling pathway of a specific GPCR by natural ligands. To reduce the complexity in experimental settings, specific pharmacological ligands that preferentially activate one signaling pathway have been developed. In addition, G-protein-coupled designer receptors that are unresponsive to endogenous ligands but can be activated by otherwise pharmacologically inert compounds have been designed. These receptors have been termed designer receptors exclusively activated by designer drugs. The lack of constitutive activity of these designer receptors allows their use for in vitro and in vivo studies of GPCR-mediated signal transduction. The analysis of recently generated transgenic mice showed that the expression of G-protein-coupled designer receptors represents a powerful chemical-genetic tool to investigate GPCR signaling and function.


Assuntos
Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia , Animais , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Ligantes , Camundongos , Camundongos Transgênicos , Engenharia de Proteínas/métodos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores
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