Coactivation of the human vitamin D receptor by the peroxisome proliferator-activated receptor gamma coactivator-1 alpha.
The vitamin D receptor (VDR) belongs to the superfamily of steroid/thyroid hormone receptors that is activated by 1alpha,25-dihydroxyvitamin D(3). Traditional targets for 1alpha,25-dihydroxyvitamin D(3) action include tissues involved in the maintenance of calcium homeostasis and bone development and remodeling. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), 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-1alpha display an overlapping pattern of expression, we investigated the possibility that PGC-1alpha could serve as a coactivator for VDR. Transient cotransfection assays demonstrate that PGC-1alpha 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-1alpha requires an intact AF-2 domain of VDR and the LXXLL motif in PGC-1alpha. Taken together, these results indicate that PGC-1alpha serves as a coactivator for VDR.
Savkur
Rajesh S
RS
Eli Lilly and Company, DC0434, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Bramlett
Kelli S
KS
Stayrook
Keith R
KR
Nagpal
Sunil
S
Burris
Thomas P
TP
D002460:Cell Line; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding / Q000502:physiology; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018167:Receptors, Calcitriol; D014157:Transcription Factors