RESUMO
The general control nonderepressible 2 (GCN2) kinase is a nutrient-sensing pathway that responds to amino acids deficiency and induces a genetic program to effectively maintain cellular homeostasis. Here we established the conserved role of Caenorhabditis elegans GCN-2 under amino acid limitation as a translation initiation factor 2 (eIF2) kinase. Using a combination of genetic and molecular approaches, we showed that GCN-2 kinase activity plays a central role in survival under nutrient stress and mediates lifespan extension conferred by dietary restriction (DR) or inhibition of the major nutrient-sensing pathway, the target of rapamycin (TOR). We also demonstrated that the GCN-2 and TOR signaling pathways converge on the PHA-4/FoxA transcription factor and its downstream target genes to ensure survival of the whole organism under a multitude of stress conditions, such as nutrient scarcity or environmental stresses. This is one step forward in the understanding of evolutionary conserved mechanisms that confer longevity and healthspan.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Longevidade/fisiologia , Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fatores Ativadores da Transcrição/genética , Fatores Ativadores da Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Expressão Gênica , Longevidade/efeitos dos fármacos , Longevidade/genética , Masculino , Dados de Sequência Molecular , Fosforilação , Proteínas Quinases/genética , Transdução de Sinais , Estresse Fisiológico/fisiologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
The aim of the paper is to determine whether the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is associated with abdominal aortic aneurysm (AAA) and inguinal hernia. A case-control study was conducted in 264 subjects: 65 patients with AAA, 91 patients with inguinal hernia, 19 patients with both AAA and hernia, and 89 controls were investigated for the ACE I/D polymorphism. Genotype analysis was performed using a polymerase chain reaction technique. Significant differences in the genotype between the patient groups and controls were identified (aneurysm versus control, P = 0.011; aneurysm plus hernia versus control, P = 0.022; hernia versus control, P = 0.001), whereas no differences were found within patient groups. Patients with AAA and/or hernia had an increased prevalence of I/D heterozygosity, which persisted even after adjusting for differences in confounding clinical variables (aneurysm versus control, OR 0.3, 95% CI 0.2-0.8, P = 0.005; aneurysm plus hernia versus control, OR 0.3, 95% CI 0.1-0.9, P = 0.040; hernia versus control, OR 0.4, 95% CI 0.2-0.7, P = 0.004). In conclusion, an association between the heterozygote ACE I/D state and the presence of AAA and/or hernia was identified. The role of the ACE I/D polymorphism in aneurysm and hernia needs further investigation.