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  • Title: Transcriptional activity of a fluorinated vitamin D analog on VDR-RXR-mediated gene expression.
    Author: Sasaki H, Harada H, Handa Y, Morino H, Suzawa M, Shimpo E, Katsumata T, Masuhiro Y, Matsuda K, Ebihara K.
    Journal: Biochemistry; 1995 Jan 10; 34(1):370-7. PubMed ID: 7819220.
    Abstract:
    The transcriptional activity of the hexafluorinated derivative of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 [F6-1,25-(OH)2D3], was examined in cultured cells by a transient expression assay (CAT assay) using expression vectors for the rat nuclear vitamin D3 receptor (VDR) and the rat 9-cis-retinoic acid receptor (RXR beta), and a reporter plasmid containing a consensus vitamin D3 response element (VDRE) consisting of two directly repeated AGGTCA motifs spaced by 3 bp (DR3). At physiological concentrations, the transcriptional activity of F6-1,25-(OH)2D3 was 2-4 times more potent than that of 1,25-(OH)2D3 in both nontarget (HeLa) and target (UMR106) cells for 1,25-(OH)2D3. The transcriptional activity of F6-1,25-(OH)2D3 was also higher when the endogenous target gene (osteopontin), which has a VDRE related to the DR3 in its promoter, was induced. A gel-shift assay using DR3 as a probe and in vitro synthesized receptors showed that the ligand-induced DNA binding of VDR required RXR to form a heterodimer. Moreover, in this assay we found that F6-1,25-(OH)2D3 induced the receptor-DNA complex at a 10-fold lower concentration than 1,25-(OH)2D3 without influencing the dissociation kinetics. However, the binding affinity of F6-1,25-(OH)2D3 for VDR was slightly lower than that of 1,25-(OH)2D3. The increased DNA binding of ligand-bound VDR by introducing hexafluorines into 1,25-(OH)2D3 may potentiate the transcriptional activity. Thus, the higher biological activity of F6-1,25-(OH)2D3 may be exerted at least in part by enhanced transcriptional activity.
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