Identification of DNA sequences that bind retinoid X receptor-1,25(OH)2D3-receptor heterodimers with high affinity.
Vitamin D3 receptors (VDR) bind as heterodimers with retinoid X receptors (RXR) to vitamin D response elements (VDRE) and transactivate gene expression in a 1,25(OH)2D3-dependent manner. These elements are tandem direct repeats (DRs) of the hexamer RGGTCA separated by three nucleotides ( DR3). We determined whether this DR3 was the optimal and/or only recognition sequence, by PCR-mediated binding site selection with reticulocyte lysate-expressed hVDR and mRXRalpha, and a pool of random sequences. We derived a consensus binding site for RXR-VDR heterodimers, RGGTCANN RRGTTCAB, and analyzed 10 of the 45 sequences slected by EMSA, methylation interference and transfection experiments: all the sequences were specific and acted as positive VDREs; the underlined purine of the spacer interacted with the heterodimer; the mutation of the third T in the second motif to a G did not influence VDRE activity. Thus, the selectivity of vitamin D pathway involving heterodimerization rather than VDR-homodimerization is not due to internal sequence variations. Except for mouse osteopontin VDRE, the natural VDREs would be efficient, only when helped by adjacent sequences and/or transactivators other than VDR and RXR.[1]References
- Identification of DNA sequences that bind retinoid X receptor-1,25(OH)2D3-receptor heterodimers with high affinity. Colnot, S., Lambert, M., Blin, C., Thomasset, M., Perret, C. Mol. Cell. Endocrinol. (1995) [Pubmed]
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