The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor - Potential clinical implications

Glucocorticoids play pivotal roles in the maintenance of homeostasis but, when dysregulated, may also have deleterious effects. Smad6, one of the transforming growth factor beta ( TGF beta) family downstream transcription factors, interacts with the N-terminal domain of the glucocorticoid receptor ( GR) through its Mad homology 2 domain and suppresses GR-mediated transcriptional activity in vitro. Adenovirus-mediated Smad6 overexpression inhibits glucocorticoid action in rat liver in vivo, preventing dexamethasone-induced elevation of blood glucose levels and hepatic mRNA expression of phosphoenolpyruvate carboxykinase, a well known rate-limiting enzyme of liver gluconeogenesis. Smad6 suppresses GR-induced transactivation by attracting histone deacetylase 3 to DNA-bound GR and by antagonizing acetylation of histone H3 and H4 induced by p160 histone acetyltransferase. These results indicate that Smad6 regulates glucocorticoid actions as a corepressor of the GR. From our results and known cross-talks between glucocorticoids and TGF beta family molecules, it appears that the anti-glucocorticoid actions of Smad6 may contribute to the neuroprotective, anticatabolic and pro-wound healing properties of the TGF beta family of proteins.