The thyroid hormone receptor antagonizes CREB-mediated transcription

Combinatorial regulation of transcription involves binding of transcription factors to DNA as well as protein–protein interactions between them. In this paper, we demonstrate the existence of a mutual transcriptional antagonism between the thyroid hormone receptor (TR) and the cyclic AMP response element binding protein (CREB), which involves a direct association of both transcription factors. TR inhibits transcriptional activity of CREB and represses activation of cAMP response element (CRE)‐containing promoters. TR does not bind to the CRE in vitro , but in vivo the liganded receptor is tethered to the promoter through protein–protein interactions. In turn, expression of CREB reduces TR‐dependent transcriptional responses. The association of TR with CREB inhibits the ability of protein kinase A to phosphorylate CREB at Ser133, and leads to a reduction in the ligand‐dependent recruitment of the p160 coactivators by TR. These results indicate the existence of a transcriptional cross‐talk between CREB and TR signalling pathways, which can have important functional consequences.