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A more recent version of this article appeared on May 26, 2000
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M910000199v1
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Papers In Press, published online ahead of print March 15, 2000
J. Biol. Chem, 10.1074/jbc.M910000199
Submitted on December 15, 1999
Revised on February 7, 2000
Accepted on March 13, 2000

Antagonistic action of a 25-carboxylic ester analogue of 1a,25-dihydroxyvitamin D3 is mediated by a lack of ligand-induced vitamin D receptor interaction with coactivators

Michaela Herdick, Andreas Steinmeyer, and Carsten Carlberg

Institut für Physiologische Chemie I, Heinrich-Heine-Universität Düsseldorf, Düsseldorf D-40001

Corresponding Author: carlberg{at}uni-duesseldorf.de

A 25-carboxylic ester analogue of 1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3), ZK159222, was described as a novel type of antagonist of 1a,25(OH)2D3 signalling. The ligand sensitivity of ZK159222, in facilitating complex formation between 1a,25(OH)2D3 receptor (VDR) and the retinoid X receptor (RXR) on a 1a,25(OH)2D3 response element (VDRE) was approximately 7-fold lower when compared to 1a,25(OH)2D3. However, ZK159222 was not able to promote a ligand-dependent interaction of the VDR with the coactivator proteins SRC-1, TIF2 and RAC3, neither in solution nor in a complex with RXR on DNA. Functional analysis in HeLa and Cos-7 cells demonstrated a 10- to 100-fold lower ligand sensitivity for ZK159222 than for 1a,25(OH)2D3 and most interestingly, a potency that was drastically reduced compared to 1a,25(OH)2D3. A cotreatment of 1a,25(OH)2D3 with a 100-fold higher concentration of ZK159222 resulted in a prominent antagonistic effect both in functional in vivo and in in vitro assays. These data suggest that the antagonistic action of ZK159222 is due to a lack of ligand-induced interaction of the VDR with coactivators with a parallel ligand sensitivity which is sufficient for competition with the natural hormone for VDR binding.


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