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Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis
Author(s) -
MonteserinGarcia Jose,
AlMassadi Omar,
Seoane Luisa M.,
Alvarez Clara V.,
Shan Bing,
Stalla Johanna,
PaezPereda Marcelo,
Casanueva Felipe F.,
Stalla Günter K.,
Theodoropoulou Marily
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-220129
Subject(s) - creb , transcription factor , growth hormone , chemistry , microbiology and biotechnology , medicine , endocrinology , hormone , biology , biochemistry , gene
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 50 =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.—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. FASEB J. 27, 1561–1571 (2013). www.fasebj.org