Inhibition of ERK1/2 Restores GSK3ß Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis.
Sci Rep
; 7(1): 4174, 2017 06 23.
Article
em En
| MEDLINE
| ID: mdl-28646232
Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decreased glycogen synthase kinase 3ß (GSK3ß) activity, activation of the mammalian target of rapamycin complex 1 (mTORC1), and subsequent increase in protein synthesis. Here, we show that extracellular signal-regulated kinases (ERK1/2) respond to insulin stimulation and integrate insulin signaling to phosphorylate and thus inactivate GSK3ß, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity. Inhibition of ERK1/2 in Tsc2 -/- cells-a model of TS-rescues GSK3ß activity and protein synthesis levels, thus highlighting ERK1/2 as a potential therapeutic target for the treatment of TS.
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Base de dados:
MEDLINE
Assunto principal:
Biossíntese de Proteínas
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Esclerose Tuberosa
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MAP Quinases Reguladas por Sinal Extracelular
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Glicogênio Sintase Quinase 3 beta
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Modelos Biológicos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article