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

Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706

Address all correspondence and requests for reprints to: Dr. J. W. Pike, Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, Wisconsin 53706. E-mail: pike{at}biochem.wisc.edu.

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 D₃ [1,25-(OH)₂D₃], 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)₂D₃ 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 transcription 3, in contrast, was associated with only a subset. Interestingly, only the most distal of these regions demonstrated CREB- and oncostatin M-regulated transcriptional activity in a heterologous transfection system. Mapping studies pointed to two highly conserved cAMP response elements as well as an adjacent regulatory site that bound Runt transcription factor 2 and was able to influence both basal as well as hormone-inducible RankL activity. Surprisingly, PKA and gp130 activation prompted recruitment of RNA polymerase II to the five distal enhancers as well as to the RankL transcriptional start site. Activation was also accompanied by a significant and location-selective rise in histone 4 acetylation. This study demonstrates that the activation of RankL gene expression by PKA- and gp130-inducers is mediated via common regulatory domains that also served to facilitate the activity of 1,25-(OH)₂D₃.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR

Ligands:   Calcitriol

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