The vitamin D receptor binds in a transcriptionally inactive form and without a defined polarity on a retinoic acid response element.
Heterodimers of the vitamin D receptor (VDR) with the retinoid X receptor (RXR) bind in a transcriptionally unproductive manner to the retinoic acid response element present in the retinoic acid receptor-beta2 promoter. This element is composed of a direct repeat (DR) of the sequence PuGTTCA spaced by five nucleotides. However, the same sequence separated by three nucleotides (DR3) acts as a strong vitamin D response element. Here we show that the polarity of binding of the heterodimers to the DR3 was 5'-RXR-VDR-3', whereas on the DR5, both heterodimeric partners bind indistinctly to the 5' or 3' hemi-sites. These results suggest that the response elements can allosterically regulate the conformation of the receptors to determine positive or negative regulation of gene expression. Despite the altered polarity, the DR5-bound heterodimer was able to recruit the nuclear receptor coactivator ACTR in a vitamin D-dependent fashion. Furthermore, binding of the corepressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) to the RXR/VDR heterodimer on a DR5 was not observed. Binding of RXR/VDR heterodimers to DRs with different transcriptional outcomes may generate selectivity and provide a greater complexity and flexibility to the vitamin D responses.
Jimenez-Lara
A M
AM
Instituto de Investigaciones Biomédicas. CSIC-UAM, Madrid, Spain.
Aranda
A
A
D000494:Allosteric Regulation; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D005786:Gene Expression Regulation; D056985:Nuclear Receptor Co-Repressor 2; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D056985:Nuclear Receptor Co-Repressor 2; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors