Abstract

Retinoid-related receptor (ROR) is an orphan nuclear receptor that constitutively activates transcription from its cognate response element. We show that ROR is Ca²⁺ responsive, and a Ca²⁺/calmodulin-independent form of Ca²⁺/calmodulin-dependent protein kinase IV (CaMKIV) potentiates ROR-dependent transcription 20- to 30-fold. Other orphan receptors including ROR2, ROR 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 ROR or its ligand-binding domain (LBD) in vitro, although the LBD is essential for transactivation. Therefore, the ROR 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.