Lysine demethylase inhibition protects pancreatic ß cells from apoptosis and improves ß-cell function.
Mol Cell Endocrinol
; 460: 47-56, 2018 01 15.
Article
em En
| MEDLINE
| ID: mdl-28684291
ABSTRACT
Transcriptional changes control ß-cell survival in response to inflammatory stress. Posttranslational modifications of histone and non-histone transcriptional regulators activate or repress gene transcription, but the link to cell-fate signaling is unclear. Inhibition of lysine deacetylases (KDACs) protects ß cells from cytokine-induced apoptosis and reduces type 1 diabetes incidence in animals. We hypothesized that also lysine demethylases (KDMs) regulate ß-cell fate in response to inflammatory stress. Expression of the demethylase Kdm6B was upregulated by proinflammatory cytokines suggesting a possible role in inflammation-induced ß-cell destruction. Inhibition of KDM6 demethylases using the selective inhibitor GSK-J4 protected insulin-producing cells and human and mouse islets from cytokine-induced apoptosis by blunting nuclear factor (NF)-κB signaling and endoplasmic reticulum (ER) stress response gene expression. GSK-J4 furthermore increased expression of insulin gene and glucose-stimulated insulin secretion. Expression of genes regulating purinergic and cytokine ligand-receptor interactions was downregulated following GSK-J4 exposure, while expression of genes involved in cell maintenance and survival was upregulated. These data suggest that KDMs are important regulators of inflammation-induced ß-cell dysfunction and death.
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MEDLINE
Assunto principal:
Pirimidinas
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Benzazepinas
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Apoptose
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Citoproteção
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Células Secretoras de Insulina
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Histona Desmetilases com o Domínio Jumonji
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article