Activation of orphan receptor-mediated transcription by Ca2+/calmodulin-dependent protein kinase IV

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Abstract
Retinoid‐related receptor α (RORα) is an orphan nuclear receptor that constitutively activates transcription from its cognate response element. We show that RORα is Ca2+ responsive, and a Ca2+/calmodulin‐independent form of Ca2+/calmodulin‐dependent protein kinase IV (CaMKIV) potentiates RORα‐dependent transcription 20‐ to 30‐fold. Other orphan receptors including RORα2, RORγ and COUP‐TFI are also potentiated by CaMKIV. Transcriptional activation by CaMKIV is orphan receptor selective and does not occur with either the thyroid hormone or estrogen receptor. CaMKIV does not phosphorylate RORα or its ligand‐binding domain (LBD) in vitro, although the LBD is essential for transactivation. Therefore, the RORα LBD was used in the mammalian two‐hybrid assay to identify a single class of small peptide molecules containing LXXLL motifs that interacted with greater affinity in the presence of CaMKIV. This class of peptides antagonized activation of orphan receptor‐mediated transcription by CaMKIV. These studies demonstrate a pivotal role for CaMKIV in the regulation of orphan receptor‐mediated transcription.