title: Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis.
abstract: 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 μM) 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 β acetylation, and a mutation on the GSK3β-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.
authors.affiliation: Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Jose
authors.initials: J
authors.lastname: Monteserin-Garcia
authors.forename: Omar
authors.initials: O
authors.lastname: Al-Massadi
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Seoane
authors.forename: Clara V
authors.initials: CV
authors.lastname: Alvarez
authors.forename: Bing
authors.initials: B
authors.lastname: Shan
authors.forename: Johanna
authors.initials: J
authors.lastname: Stalla
authors.forename: Marcelo
authors.initials: M
authors.lastname: Paez-Pereda
authors.forename: Felipe F
authors.initials: FF
authors.lastname: Casanueva
authors.forename: Günter K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
mesh_terms: D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D013006:Growth Hormone / Q000096:biosynthesis* / Q000235:genetics; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D008297:Male; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D014157:Transcription Factors; D005576:Colforsin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C488368:Sirt1 protein, rat; D056564:Sirtuin 1