Transcriptional Control of Receptor Activator of Nuclear Factor-κB Ligand by the Protein Kinase A Activator Forskolin and the Transmembrane Glycoprotein 130-Activating Cytokine, Oncostatin M, Is Exerted through Multiple Distal Enhancers

Abstract

Receptor activator of nuclear factor-B ligand (RankL) is a potent osteoclastogenic cytokine the expression of which is regulated at the transcriptional level by 1,25-dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ], protein kinase A (PKA) activators such as PTH and transmembrane glycoprotein 130 (gp130)activating cytokines such as oncostatin M. We recently identified five highly conserved chromatin domains located significant distances upstream of the RankL transcriptional start site that contribute to the ability of 1,25-(OH) 2 D 3 and its receptor to enhance RankL gene output. We therefore screened these five common regulatory regions for their potential ability to mediate the actions of PKA-and gp130-activators using a directed chromatin immunoprecipitation approach employing antibodies to the PKA target cAMP response element-binding protein (CREB) and the gp130 target signal transducer and activator of transcription 3. CREB was identified at each of the upstream regulatory regions; signal transducer and activator of