Differential recruitment of coactivators to the vitamin D receptor transcriptional complex by 1alpha,25-dihydroxyvitamin D3 analogs.
To clarify the molecular mechanism for analog potency and selectivity, we investigated the ability of 1,25(OH)(2)D(3) analogs to recruit coactivators to the vitamin D receptor (VDR) transcriptional complex. Using a modified version of the avidin-biotin complex DNA binding assay, we discovered that 20S-analogs enhance the binding of specific coactivators to the transcriptional complex relative to natural hormone and that the enhanced binding occurs independently of vitamin D response element and cell type. With the exception of two of these coactivators, DRIP205 and DRIP240, all proteins were recruited to the transcriptional complex in a dose-dependent manner. While the results do not provide an explanation for tissue selectivity of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D(3) (2MD), they provide evidence that in the presence of a full-length side chain, the 20S configuration improves binding of specific proteins to the VDR transcriptional complex while modifications at carbon 2 do not.
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Marie K
MK
Schwinn
Hector F
HF
DeLuca
D000818:Animals; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D012516:Osteosarcoma / Q000378:metabolism*; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015533:Transcriptional Activation; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism
D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D