Augmentation of thyroid hormone receptor-mediated transcription by Ca2+/calmodulin-dependent protein kinase type IV

Thyroid hormone receptor (TR), a ligand-mediated transcription factor, binds to a DNA sequence known as a thyroid-hormone response element (TRE) to activate or repress transcription of target genes. Recently, studies have shown that Ca2+/calmodulin-dependent protein kinases (CaMKs) may be involved in regulating gene transcription via phosphorylation of specific transcription factors, including ROR alpha, a retinoic acid-related orphan nuclear hormone receptor. In this light, we examined the effect of CaMK type IV (CaMKIV) and ROR alpha, which also shown to influence thyroid hormone action, on TR-mediated transcription using a transient transfection assay. Expression vectors containing TR, vitamin D receptor (VDR), and estrogen receptor (ER) were cotransfected in CV-1 cells with ROR alpha and/or constitutively active CaMKIV and thymidine kinase promotor-luciferase reporter vector containing their cognate response elements. When CaMKIV or ROR alpha was co-transfected with TR, the T3-induced transcription was significantly augmented compared to that induced by TR alone. When both were co-transfected with TR, T3-induced transcription was augmented additively. In contrast, the augmentation by CaMKIV or ROR on ligand-induced transcription was not detected with VDR and ER. Hence, these results indicate that the augmentation mediated by CaMKIV and ROR alpha is specific for TR-mediated transcription on TRE. Our results suggest that CaMKIV, as well as ROR alpha, play important roles in TR-mediated transcription on TREs.