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Inhibition of 1,25-dihydroxyvitamin D3-dependent transcription by synthetic LXXLL peptide antagonists that target the activation domains of the vitamin D and retinoid X receptors.

Publication ,  Journal Article
Pathrose, P; Barmina, O; Chang, C-Y; McDonnell, DP; Shevde, NK; Pike, JW
Published in: J Bone Miner Res
December 2002

The vitamin D receptor (VDR) is known to mediate the biological actions of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] through its ability to regulate cellular programs of gene expression. Although RXR appears to participate as a heterodimeric partner with the VDR, absolute evidence for its role remains equivocal in vivo. To test this role and to investigate the requirement for comodulator interaction, we identified VDR- and retinoid X receptor (RXR)-interacting LXXLL peptides and examined whether these molecules could block vitamin D and 9-cis retinoic acid (9-cis RA) response. We used a mammalian cell two-hybrid system to screen a series of nuclear receptor (NR)-reactive LXXLL peptides previously identified through phage display screening for hormone-dependent reactivity with either VDR or RXR. Three categories of peptides were identified: those reactive with both VDR and RXR, those selective for RXR, and those unreactive to either receptor. Peptide fusion proteins were then examined in MC3T3-E1 cells for their ability to block induction of the osteocalcin (OC) promoter by 1,25(OH)2D3 or stimulation of a retinoic acid response element-thymidine kinase (RARE-TK) reporter by 9-cis-RA. Peptides that interacted with both VDR and RXR blocked 1,25(OH)2D3-dependent transcription by up to 75%. Control LXXLL sequences derived from Src-1 and Grip also suppressed 1,25(OH)2D3-induced transactivation; peptides that interacted with RXR blocked 9-cis-RA-induced transcription. Interestingly, two RXR-interacting peptides were also found to block 1,25(OH)2D3 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)2D3-induced OC gene transcription. This approach may represent a novel means of assessing the contribution of RXR in various endogenous biological responses to 1,25(OH)2D3.

Duke Scholars

Published In

J Bone Miner Res

DOI

ISSN

0884-0431

Publication Date

December 2002

Volume

17

Issue

12

Start / End Page

2196 / 2205

Location

England

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factors
  • Retinoid X Receptors
  • Receptors, Retinoic Acid
  • Receptors, Calcitriol
  • Precipitin Tests
  • Oligopeptides
  • Mice
  • Calcitriol
  • COS Cells
 

Citation

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MLA
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Pathrose, P., Barmina, O., Chang, C.-Y., McDonnell, D. P., Shevde, N. K., & Pike, J. W. (2002). Inhibition of 1,25-dihydroxyvitamin D3-dependent transcription by synthetic LXXLL peptide antagonists that target the activation domains of the vitamin D and retinoid X receptors. J Bone Miner Res, 17(12), 2196–2205. https://doi.org/10.1359/jbmr.2002.17.12.2196
Pathrose, Peterson, Olga Barmina, Ching-Yi Chang, Donald P. McDonnell, Nirupama K. Shevde, and J Wesley Pike. “Inhibition of 1,25-dihydroxyvitamin D3-dependent transcription by synthetic LXXLL peptide antagonists that target the activation domains of the vitamin D and retinoid X receptors.J Bone Miner Res 17, no. 12 (December 2002): 2196–2205. https://doi.org/10.1359/jbmr.2002.17.12.2196.
Pathrose, Peterson, et al. “Inhibition of 1,25-dihydroxyvitamin D3-dependent transcription by synthetic LXXLL peptide antagonists that target the activation domains of the vitamin D and retinoid X receptors.J Bone Miner Res, vol. 17, no. 12, Dec. 2002, pp. 2196–205. Pubmed, doi:10.1359/jbmr.2002.17.12.2196.
Journal cover image

Published In

J Bone Miner Res

DOI

ISSN

0884-0431

Publication Date

December 2002

Volume

17

Issue

12

Start / End Page

2196 / 2205

Location

England

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factors
  • Retinoid X Receptors
  • Receptors, Retinoic Acid
  • Receptors, Calcitriol
  • Precipitin Tests
  • Oligopeptides
  • Mice
  • Calcitriol
  • COS Cells