RESUMO
O-linked beta-N-acetylglucosamine (O-GlcNAc) modification of nuclear and cytoplasmic proteins is important for many cellular processes, and the number of proteins that contain this modification is steadily increasing. This modification is dynamic and reversible, and in some cases competes for phosphorylation of the same residues. O-GlcNAc modification of proteins is regulated by cell cycle, nutrient metabolism, and other extracellular signals. Compared to protein phosphorylation, which is mediated by a large number of kinases, O-GlcNAc modification is catalyzed only by one enzyme called O-linked N-acetylglucosaminyl transferase or OGT. Removal of O-GlcNAc from proteins is catalyzed by the enzyme beta-N-acetylglucosaminidase (O-GlcNAcase or OGA). Altered O-linked GlcNAc modification levels contribute to the establishment of many diseases, such as cancer, diabetes, cardiovascular disease, and neurodegeneration. Many transcription factors have been shown to be modified by O-linked GlcNAc modification, which can influence their transcriptional activity, DNA binding, localization, stability, and interaction with other co-factors. This review focuses on modulation of transcription factor function by O-linked GlcNAc modification.
Assuntos
Acetilglucosamina/química , Acetilglucosamina/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Glicosilação , Humanos , Modelos Biológicos , N-Acetilglucosaminiltransferases/metabolismo , NF-kappa B/química , NF-kappa B/metabolismo , Domínios e Motivos de Interação entre Proteínas , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Receptores de Estrogênio/química , Receptores de Estrogênio/metabolismo , Fator de Transcrição STAT5/química , Fator de Transcrição STAT5/metabolismo , Transativadores/química , Transativadores/metabolismo , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo , Fator de Transcrição YY1/química , Fator de Transcrição YY1/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
The establishment of surrogate islet beta cells is important for the treatment of diabetes. Hepatocytes have a similar glucose sensing system as beta cells and have the potential to serve as surrogate beta cells. In this report, we demonstrate that infection of Hepa1-6 liver cells with a lentivirus expressing the human insulin cDNA results in expression and secretion of human insulin. Furthermore, we show that l-arginine at low levels of glucose significantly stimulates the release of insulin from these cells, compared to exposure to high concentration of glucose. The arginine-induced insulin release is via the production of nitric oxide, since treatment with N(G)-nitro-l-arginine, an inhibitor of nitric oxide synthase, blocks insulin secretion induced by l-arginine. These results indicate that nitric oxide plays a role in l-arginine-stimulated insulin release in hepatocytes expressing the human insulin gene, and provides a new strategy to induce insulin secretion from engineered non-beta cells.