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Effect of Cellular Environment on the Selective Activation of the Vitamin D Receptor by 1,25-Dihydroxyvitamin D₃ and Its Analog 1-Fluoro-16-Ene-20-Epi-23-Ene-26,27-Bishomo-25-Hydroxyvitamin D₃ (Ro-26-9228)

Department of Endocrine Neoplasia and Hormonal Disorders (A.I., C.V.N., S.P.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Muscoloskeletal Research (A.A., M.R.U.), Roche Bioscience, Palo Alto, California 94305; and Department of Foods and Nutrition (J.C.F.), Purdue University, West Lafayette, Indiana 47907-1264

Address all correspondence and requests for reprints to: Sara Peleg, Ph.D., Department of Endocrine Neoplasia and Hormonal Disorders, Unit 435, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail: speleg{at}mail.mdanderson.org.

The vitamin D analog, 1-fluoro-16-ene-20-epi-23-ene-26,27-bishomo-25-hydroxyvitamin D₃ (Ro-26-9228) is tissue selective, with a gene regulation preference for bone over duodenum in vivo. In the human osteoblast-like cells, hFOB, the vitamin D receptor (VDR)-mediated transcriptional potencies of Ro-26-9228 and 1,25-dihydroxyvitamin D₃ (1,25D₃) were similar, but in the intestinal cells, Caco-2, transcriptional potency of Ro-26-9228 was 10–50 times lower. We hypothesized that transcriptional activation of the VDR by Ro-26-9228 in the two cell types is regulated differently, and compared VDR extracted from hFOB or Caco-2 cells for their abilities to interact with a p160 coactivator [glucocorticoid receptor-interacting protein (GRIP)] and with retinoid X receptor (RXR) by pull-down assays. 1,25D₃ had similar potencies to induce interactions of VDR from the two cell types with these partners of transcription. In contrast, Ro-26-9228 induced interaction of osteoblastic VDR with RXR and GRIP but did not induce these interactions with VDR from Caco-2 cells. Further studies revealed that in hFOB cells the unoccupied VDR was cytoplasmic and proteasome sensitive, and that ligand treatment caused a rapid accumulation of the VDR in the chromatin. Both cytoplasmic and chromatin-associated ligand-bound VDR from hFOB cells had the abilities to interact with GRIP. In contrast, in Caco-2 cells, unoccupied VDR was localized in both the cytoplasm (70%) and the chromatin (30%). In Caco-2 cells, the cytoplasmic VDR was proteasome resistant, and neither 1,25D₃ nor Ro-26-9228 induced its binding to GRIP. Only a small fraction of the chromatin-associated VDR was proteasome sensitive, and this fraction was distinguishable by a faster electrophoretic mobility. 1,25D₃ induced an accumulation of the proteasome-sensitive VDR in the chromatin of Caco-2 cells and binding to GRIP. Ro-26-9228 failed to induce accumulation of the proteasome-sensitive VDR in the chromatin or binding to GRIP, but a coincubation of Caco-2 cells with the analog and a proteasome inhibitor restored these abilities. These results suggest that Ro-26-9228 has poor ability to promote the accumulation of a proteasome-sensitive, transcriptionally active VDR isoform in Caco-2 cells, whereas it does not have this limitation in hFOB cells.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR  |  RXRα

Coregulators:   GRIP1

Ligands:   Calcitriol

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