Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis
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Identificadores
URI: http://hdl.handle.net/20.500.11940/3991
PMID: 23292070
DOI: 10.1096/fj.12-220129
ISSN: 0892-6638
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Fecha de publicación
2013Título de revista
FASEB JOURNAL
Tipo de contenido
Artigo
MeSH
Animals | Colforsin | Cyclic AMP Response Element-Binding Protein | Gene Expression | Gene Knockdown Techniques | Glycogen Synthase Kinase 3 | Glycogen Synthase Kinase 3 beta | Growth Hormone | Growth Hormone-Releasing Hormone | Male | Pituitary Gland, Anterior | Rats | Rats, Sprague-Dawley | Receptors, Pituitary Hormone-Regulating Hormone | Sirtuin 1 | Transcription Factors | Transcriptional ActivationResumen
Growth hormone (GH) is a major anabolic hormone and the primary regulator of organism growth. Its transcription is triggered by GH-releasing hormone (GHRH) through the transcription factor cAMP response element-binding protein (CREB) and by caloric intake. In contrast, the deacetylase Sirt1 is activated by caloric restriction. Therefore, the present study investigates how Sirt1 affects CREB function and GH synthesis. Sirt1 pharmacological activation with resveratrol (IC50 =87 mu M) suppressed GHRH-induced GH secretion from rat anterior pituitary cells in vivo and in vitro, while vehicle controls showed no effect. Resveratrol's effects were abolished after knocking down Sirt1 with RNA interference, but not in control scrambled siRNA-transfected rat somatotrophs, confirming the Sirt1 specificity. Sirt1 activation and overexpression suppressed forskolin-induced CREB-Ser(133) phosphorylation, but no effect was seen with vehicle and empty plasmid controls. The deacetylase-dead mutant Sirt1 retained CREB-Ser133 phosphorylation by keeping protein phosphatase protein phosphatase 1 activity low. Sirt1 activation suppressed glycogen synthase kinase 3 beta acetylation, and a mutation on the GSK3 beta-Lys(205) residue mimicking a hypoacetylated form revealed increased activity. In summary, this is a novel mechanism through which Sirt1 intercepts the cAMP pathway by suppressing CREB transcriptional activation, resulting in decreased GH synthesis.-Monteserin-Garcia, J., Al-Massadi, O., Seoane, L. M., Alvarez, C. V., Shan, B., Stalla, J., Paez-Pereda, M., Casanueva, F. F., Stalla, G. K., Theodoropoulou, M. Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis.
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