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J. Biol. Chem., Vol. 277, Issue 17, 14539-14546, April 26, 2002

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A Central Dinucleotide within Vitamin D Response Elements Modulates DNA Binding and Transactivation by the Vitamin D Receptor in Cellular Response to Natural and Synthetic Ligands^*

Gert-Jan C. M. van den Bemd^§, Mila Jhamai^§, Ada Staal^¶, André J. van Wijnen^¶, Jane B. Lian^¶, Gary S. Stein^¶, Huibert A. P. Pols, and Johannes P. T. M. van Leeuwen

From the  Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands and the ^¶ Department of Cell Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655

There is considerable divergence in the sequences of steroid receptor response elements, including the vitamin D response elements (VDREs). Two major VDRE-containing and thus 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃)-regulated genes are the two non-collagenous, osteoblast-derived bone matrix proteins osteocalcin and osteopontin. We observed a stronger induction of osteopontin than osteocalcin mRNA expression by 1,25-(OH)₂D₃. Subsequently, we have shown that vitamin D receptor/retinoid X receptor  (VDR/RXR) heterodimers bind more tightly to the osteopontin VDRE than to the osteocalcin VDRE. Studies using point mutants revealed that the internal dinucleotide at positions 3 and 4 of the proximal steroid half-element are most important for modulating the strength of receptor binding. In addition, studies with VDRE-driven luciferase reporter gene constructs revealed that the central dinucleotide influences the transactivation potential of VDR/RXR with the same order of magnitude as that observed in the DNA binding studies. The synthetic vitamin D analog KH1060 is a more potent stimulator of transcription and inducer of VDRE binding of VDR/RXR in the presence of nuclear factors isolated from ROS 17/2.8 osteoblast-like cells than the natural ligand 1,25-(OH)₂D₃. Interestingly, however, KH1060 is comparable or even less potent than 1,25-(OH)₂D₃ in stimulating VDRE binding of in vitro synthesized VDR/RXR. Thus, the extent of 1,25-(OH)₂D₃- and KH1060-dependent binding of VDR/RXR is specified by a central dinucleotide in the VDRE, and the ligand-induced effects on DNA binding are in part controlled by the cellular context of nuclear proteins.

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