Glucocorticoids downregulate Fyn and inhibit IP(3)-mediated calcium signaling to promote autophagy in T lymphocytes.
Autophagy
; 6(7): 912-21, 2010 Oct.
Article
em En
| MEDLINE
| ID: mdl-20814235
ABSTRACT
T cell receptor activation induces inositol 1,4,5 trisphosphate (IP(3))-mediated calcium signaling that is essential for cell metabolism and survival. Moreover, inhibitors of IP(3) or pharmacological agents that disrupt calcium homeostasis readily induce autophagy. Using a glucocorticoid-sensitive CD4/CD8 positive T cell line, we found that dexamethasone prevented both IP(3)-mediated and spontaneous calcium signals within a timeframe that correlated with the induction of autophagy. We determined that this loss in IP(3)-mediated calcium signaling was dependent upon the downregulation of the Src kinase Fyn at the mRNA and protein level. Because it has previously been shown that Fyn positively regulates IP(3)-mediated calcium release by phosphorylating Type I IP(3) receptors (IP(3)R1), we investigated the effect of glucocorticoids on IP(3)R1 phosphorylation at Tyr353. Accordingly, glucocorticoid-mediated downregulation of Fyn prevented IP(3)R1 phosphorylation at Tyr353. Moreover, selective knockdown of Fyn or treatment with a Src inhibitor also attenuated IP(3)-mediated calcium release and induced autophagy. Collectively, these data indicate that glucocorticoids promote autophagy by inhibiting IP(3)-dependent calcium signals. These findings carry important therapeutic implications given the widespread use of dexamethasone as both a chemotherapeutic and immunosuppressive agent.
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Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Dexametasona
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Linfócitos T
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Regulação para Baixo
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Inositol 1,4,5-Trifosfato
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Sinalização do Cálcio
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Proteínas Proto-Oncogênicas c-fyn
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Glucocorticoides
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article