Activation of orphan receptor-mediated transcription by Ca(2+)/calmodulin-dependent protein kinase IV.
Retinoid-related receptor alpha (RORalpha) is an orphan nuclear receptor that constitutively activates transcription from its cognate response element. We show that RORalpha is Ca(2+ )responsive, and a Ca(2+)/calmodulin-independent form of Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) potentiates RORalpha-dependent transcription 20- to 30-fold. Other orphan receptors including RORalpha2, RORgamma 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 RORalpha or its ligand-binding domain (LBD) in vitro, although the LBD is essential for transactivation. Therefore, the RORalpha 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.
Kane
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Department of Pharmacology and Cancer Biology, Duke University Medical Center, PO Box 3813, Durham, NC 27710, USA.
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D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008024:Ligands; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
D008024:Ligands; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D010455:Peptides; C539738:RORA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; C517596:CAMK1 protein, human; C517683:CAMK4 protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases