Vitamin D3-retinoid X receptor dimerization, DNA binding, and transactivation are differentially affected by analogs of 1,25-dihydroxyvitamin D3

Molecular Endocrinology
B CheskisL P Freedman

Abstract

A number of analogs of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] have been synthesized that act as more potent inducers of cellular differentiation and inhibitors of cell growth than the natural ligand; at the same time, many of the analogs have reduced hypercalcemic properties. This combination makes these compounds attractive candidates for clinical use. The mechanism by which the analogs act, however, is unclear. Potentially, the analogs could be taken up more readily, be more slowly catabolized, or have higher binding affinities for the vitamin D receptor (VDR). Analogs of 1,25-(OH)2D3 could also differentially modulate one or more of the activities of VDR, namely dimerization, DNA binding, and/or transcriptional regulation. To directly examine this latter possibility, we used a sensitive assay for the kinetics of dimerization and DNA binding, surface plasmon resonance, and report here that three 1,25-(OH)2D3 analogs, 1,25-(OH)2-16-ene-23-yne-D3, 1,25-(OH)2-16-ene-23-yne-26,27-di home-D3, and 1,25-(OH)2-26,27-hexafluoro-16-ene-23-yne-D3, all confer distinct rate and equilibrium constants for VDR-retinoid X receptor heterodimerization and DNA binding to a specific vitamin D response element relative to the natural ligand. In r...Continue Reading

Citations

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