20-epi analogues of 1,25-dihydroxyvitamin D(3) are highly potent inducers of DRIP coactivator complex binding to the vitamin D(3) receptor Journal Article

  


Authors: Yang, W.; Freedman, L. P.
Article Title: 20-epi analogues of 1,25-dihydroxyvitamin D(3) are highly potent inducers of DRIP coactivator complex binding to the vitamin D(3) receptor
Abstract: 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) plays a major role in the stimulation of bone growth, mineralization, and intestinal calcium and phosphate absorption; it also acts as a general inhibitor of cellular proliferation. Several new, clinically relevant compounds dissociate antiproliferative and calcemic activities of 1,25(OH)2D3, but the molecular basis for this has not been clearly elucidated. Here, we tested whether the potency of one class of compounds, 20-epi analogues, to induce myeloid cell differentiation, is because of direct molecular effects on vitamin D receptor (VDR). We report that two 20-epi analogues, MC1627 and MC1288, induced differentiation and transcription of p21(Waf1,Cip1), a key VDR target gene involved in growth inhibition, at a concentration 100-fold lower than that of 1,25(OH)2D3. We compared this sensitivity to analogue effects on VDR interacting proteins: RXR, GRIP-1, and DRIP205, a subunit of the DRIP coactivator complex. Compared with the interaction of VDR with RXR or GRIP- 1, the differentiation dose-response most closely correlated to the ligand- dependent recruitment of the DRIP coactivator complex to VDR and to the ability of the receptor to activate transcription in a cell-free system. These results provide compelling links between the efficiency of the 20-epi analogue in inducing VDR/DRIP interactions, transactivation in vitro, and its enhanced ability to induce cellular differentiation.
Keywords: nonhuman; animal cell; gene targeting; protein binding; cell differentiation; calcitriol; animalia; transcription factors; nuclear proteins; transcription regulation; recombinant fusion proteins; response elements; trans-activators; bone marrow cell; cyclin-dependent kinase inhibitor p21; monocytes; macrophages; cyclins; vitamin d receptor; receptor binding; nuclear receptor coactivator 2; growth inhibition; u937 cells; colecalciferol; receptors, retinoic acid; trans-activation (genetics); retinoid x receptors; receptors, calcitriol; humans; priority journal; article; calcitriol derivative
Journal Title: Journal of Biological Chemistry
Volume: 274
Issue: 24
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 1999-06-11
Start Page: 16838
End Page: 16845
Language: English
DOI: 10.1074/jbc.274.24.16838
PUBMED: 10358028
PROVIDER: scopus
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0033546407&partnerID=40&md5=60007513d4476cb5ab2a575a6d18d674
Notes: Article -- Export Date: 16 August 2016 -- Source: Scopus
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MSK Authors
  1. Leonard P Freedman
    80 Freedman
  2. Wen Yang
    2 Yang
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