Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 88, Issue 2, Pages 252-258Publisher
WILEY
DOI: 10.1002/jcb.10336
Keywords
peptides; VDR; RXR; comodulators; transcription
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Funding
- NCI NIH HHS [CA90645] Funding Source: Medline
- NIDDK NIH HHS [DK-52453] Funding Source: Medline
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The vitamin D receptor (VDR) is known to mediate the biological actions of 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) through its ability to regulate cellular programs of gene expression. We identified VDR- and retinoid X receptor (RXR)-interacting LXXLL peptides using a mammalian two-hybrid system and examined whether these molecules could block vitamin D and 9-cis retinoic acid (9-cis RA) response. Peptides were identified that were reactive to RXR alone as well as to both VDR and RXR. Peptide fusion proteins were then examined in MC3T3 E1 cells for their ability to block induction of the osteocalcin promoter by 1,25(OH)(2)D-3 or stimulation of an RARE-TK reporter by 9-cis RA. Peptides that interacted with both VDR and RXR blocked 1,25(OH)(2)D-3-dependent transcription by up to 75%. Peptides that interacted with RXR blocked 9-cis RA induced transcription. Two RXR-interacting peptides, however, were also found to block 1,25(OH)(2)D-3 response effectively. These studies support the idea that comodulator recruitment is essential for VDR- and RXR-mediated gene expression and that RXR is required for 1,25(OH)(2)D-3-induced osteocalcin gene transcription. This approach may represent a novel means of assessing the contribution of RXR in various endogenous biological responses to 1,25(OH)(2)D-3. (C) 2002 Wiley-Liss, Inc.
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