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 reported [Schräder 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 on established VDREs from the rat osteocalcin (rOC) and mouse osteopontin (mOP) genes, plus the thyroid hormone response element (TRE) from the rat myosin heavy chain (rMHC) gene. In gel mobility shift assays, we found no evidence for VDR-TR heterodimer interaction with any tested element. Further, employing these hormone response elements linked to reporter genes in transfected cells, VDR and TR mediated responses to their cognate ligands only from the rOC/mOP and rMHC elements, respectively, while the CaBP elements were unresponsive to any combination of ligand(s). Utilizing the rOC and mOP VDREs, two distinct repressive actions of TR on VDR-mediated signaling were demonstrated: a T(3)-independent action, presumably via direct TR-RXR competition for DNA binding, and a T(3)-dependent repression, likely by diversion of limiting RXR from VDR-RXR toward the formation of TR-RXR heterodimers. The relative importance of these two mechanisms differed in a response element-specific manner. These results may provide a partial explanation for the observed association between hyperthyroidism and bone demineralization/osteoporosis.

Thompson PD ，Hsieh JC ，Whitfield GK ，Haussler CA ，Jurutka PW ，Galligan MA ，Tillman JB ，Spindler SR ，Haussler MR ... -  《JOURNAL OF CELLULAR BIOCHEMISTRY》

Thyroid hormone receptor does not heterodimerize with the vitamin D receptor but represses vitamin D receptor-mediated transactivation.

Raval-Pandya M ，Freedman LP ，Li H ，Christakos S ... -  《molecular endocrinology》

Ligand-triggered stabilization of vitamin D receptor/retinoid X receptor heterodimer conformations on DR4-type response elements.

Nuclear receptors integrate an incoming signal in the form of a nuclear hormone by undergoing a conformational change that results via co-activator proteins in an activation of the basal transcriptional machinery. The vitamin D(3) receptor is the nuclear receptor for 1alpha,25-dihydroxyvitamin D(3 )(1alpha,25(OH)(2)D(3)) and is known to function as a heterodimer with the retinoid X receptor on DR3-type 1alpha,25(OH)(2)D(3) response elements. Here, it could be demonstrated that DR4-type response elements are at least as effective as DR3-type 1alpha,25(OH)(2)D(3) response elements. Gel shift clipping analysis showed that vitamin D(3) receptor-retinoid X receptor heterodimers form in response to 1alpha, 25(OH)(2)D(3) and retinoid X receptor ligands, the pan-agonist 9-cis retinoic acid (9cRA) and the retinoid X receptor-selective retinoid CD2425, different conformations on the DR4-type element of the rat Pit-1 gene. Interestingly, on this response element the heterodimeric complexes of retinoid X receptor with the thyroid hormone receptor, the retinoic acid receptor and the benzoate ester receptor also displayed characteristic individual ligand-dependent complex formation. On the level of complex formation, utilizing DNA affinity and functional assays, only vitamin D(3) receptor-retinoid X receptor heterodimers showed a synergistic interaction of both ligands. However, the sensitivity of vitamin D(3) receptor-retinoid X receptor heterodimers to 1alpha,25(OH)(2)D(3) was found to be much higher than to retinoid X receptor ligands. Taken together, this study demonstrates a unique interaction potential of vitamin D(3) receptor and retinoid X receptor but also establishes DR4-type response elements as multi-functional DNA binding sites with a potential to integrate various hormone signalling pathways.

Quack M ，Carlberg C 《JOURNAL OF MOLECULAR BIOLOGY》

DNA bending is induced by binding of vitamin D receptor-retinoid X receptor heterodimers to vitamin D response elements.

Kimmel-Jehan C ，Darwish HM ，Strugnell SA ，Jehan F ，Wiefling B ，DeLuca HF ... -  《JOURNAL OF CELLULAR BIOCHEMISTRY》

The vitamin D hormone and its nuclear receptor: molecular actions and disease states.

Haussler MR ，Haussler CA ，Jurutka PW ，Thompson PD ，Hsieh JC ，Remus LS ，Selznick SH ，Whitfield GK ... -  《JOURNAL OF ENDOCRINOLOGY》