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Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis.

Authors: Monteserin-Garcia, J  Al-Massadi, O  Seoane, LM  Alvarez, CV  Shan, B  Stalla, J  Paez-Pereda, M  Casanueva, FF  Stalla, GK  Theodoropoulou, M 
Citation: Monteserin-Garcia J, etal., FASEB J. 2013 Apr;27(4):1561-71. doi: 10.1096/fj.12-220129. Epub 2013 Jan 4.
Pubmed: (View Article at PubMed) PMID:23292070
DOI: Full-text: DOI:10.1096/fj.12-220129

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 (IC(5)(0)=87 muM) 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-Ser(133) phosphorylation by keeping protein phosphatase protein phosphatase 1 activity low. Sirt1 activation suppressed glycogen synthase kinase 3 beta acetylation, and a mutation on the GSK3beta-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.

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CRRD Object Information
CRRD ID: 9585999
Created: 2014-09-24
Species: All species
Last Modified: 2014-09-24
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.