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Coactivation of the Human Vitamin D Receptor by the Peroxisome Proliferator-Activated Receptor Coactivator-1

Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana (R.S.S., K.S.B., K.R.S., S.N., T.P.B.); and Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana (K.S.B., T.P.B.)

The vitamin D Receptor (VDR) belongs to the superfamily of steroid/thyroid hormone receptors that is activated by 1,25-dihydroxyvitamin D₃. Traditional targets for 1,25-dihydroxyvitamin D₃ action include tissues involved in the maintenance of calcium homeostasis and bone development and remodeling. Peroxisome proliferator-activated receptor coactivator-1 (PGC-1), a transcriptional coactivator that plays a role in mitochondrial biogenesis and energy metabolism, is predominantly expressed in kidney, heart, liver, and skeletal muscle. Because VDR and PGC-1 display an overlapping pattern of expression, we investigated the possibility that PGC-1 could serve as a coactivator for VDR. Transient cotransfection assays demonstrate that PGC-1 augments ligand-dependent VDR transcription when either full-length VDR or Gal4 DNA binding domain-VDR-ligand binding domain chimeras were analyzed. Furthermore, mammalian two-hybrid assays, coimmunoprecipitation analyses, and biochemical coactivator recruitment assays demonstrate a ligand-dependent interaction between the two proteins both in cells and in vitro. The coactivation potential of PGC-1 requires an intact AF-2 domain of VDR and the LXXLL motif in PGC-1. Taken together, these results indicate that PGC-1 serves as a coactivator for VDR.

Address correspondence to: Dr. Thomas P. Burris, Eli Lilly and Company, DC0434, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: burris_thomas_p{at}lilly.com

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