Vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor

The vitamin D receptor (VDR) is a transcription factor believed to function as a heterodimer with the retinoid X receptor (RXR). However, it was repor ted [Schrader et al., 1994] that, on putative vitamin D response elements ( VDREs) within the rat 9k and mouse 28k calcium binding protein genes (rCaBP 9k and mCaBP 28k), VDR and thyroid hormone receptor (TR) form heterodimers that transactivate in response to both 1,25-dihydroxyvitamin D-3 (1,25(OH) (2)D-3) and triiodothyronine (T-3). We, therefore, examined associations of these receptors on the putative rCaBP 9k and mCaBP 28k VDREs, as well as o n established VDREs from the rat osteocalcin (rOC) and mouse osteopontin (m OP) genes, plus the thyroid hormone response clement (TRE) from the rat myo sin heavy chain (rMHC) gene. In gel mobility shift assays, we found no evid ence for VDR-TR heterodimer interaction with any tested element. Further, e mploying these hormone response elements linked to reporter genes in transf ected cells, VDR and TR mediated responses to their cognate ligands only fr on 1 the rOC/mOP and rMHC elements, respectively, while the CaBP elements w ere unresponsive to any combination of ligand(s). Utilizing the rOC and mOP VDREs, two distinct repressive actions of TR on VDR-mediated signaling wer e demonstrated: a T-3-independent action, presumably via direct TR-RXR comp etition for DNA binding, and a T-3-dependent repression, likely by diversio n of limiting RXR from VDR-RXR toward the formation of TR-RXR heterodimers. The relative importance of these two mechanisms differed in a response ele ment-specific manner. These results may provide a partial explanation for t he observed association between hyperthyroidism and bone demineralization/o steoporosis. J. Cell. Biochem. 75:462-480, 1999. (C) 1999 Wiley-Liss, Inc.