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J. Biol. Chem., Vol. 278, Issue 34, 31756-31765, August 22, 2003
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2-Methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 Potently Stimulates Gene-specific DNA Binding of the Vitamin D Receptor in Osteoblasts*
From the Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706
2-Methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 (2MD)
is a highly potent analog of 1,25-dihydroxyvitamin D3
(1,25(OH)2D3) whose actions are mediated through the
vitamin D receptor (VDR). In this report, we have replicated this increased
potency of 2MD in vitro using osteoblastic cells and explored its
underlying molecular mechanism. 2MD stimulates the expression of several
vitamin D-sensitive genes including 25-hydroxyvitamin D3-24
hydroxylase (Cyp24), osteopontin and receptor activator of NF
B ligand
and suppresses osteoprotegerin at concentrations two logs lower than that for
1,25(OH)2D3. 2MD is also more potent in stimulating
transfected chimeric reporter genes under either Cyp24 or the osteocalcin
promoter control. Enhanced potency is retained regardless of medium serum
content. Interestingly, the uptake of both 1,25(OH)2D3
and 2MD into cells is similar, as is their rapid association with the VDR.
This indicates that comparable levels of occupied VDR do not elicit equivalent
levels of transactivation. Using chromatin immunoprecipitation (ChIP),
however, we observed a strong correlation between DNA-bound receptor and the
level of induced transcription suggesting a 2MD-induced increase in affinity
of the VDR for DNA. Additional studies using a mammalian two-hybrid system and
ChIP indicate that 2MD is also more potent in promoting interaction with RXR
and the coactivators SRC-1 and DRIP205. Finally, protease digestion studies
revealed a unique VDR conformation in the presence of 2MD. These studies
suggest that the molecular mechanism of 2MD potency is due to its ability to
promote enhanced levels of specific DNA binding by the VDR and could suggest
possible explanations for the tissue- and gene-selective actions of 2MD.
Received for publication, May 6, 2003 , and in revised form, June 6, 2003.
* This work was supported by National Institutes of Health Grant DK-52453 (to J. W. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Present address: Dept. of Clinical Nutrition, School of Medicine,
University of Tokushima, Tokushima 770-8503, Japan.
To whom correspondence should be addressed: Dept. of Biochemistry, University
of Wisconsin-Madison, 433 Babcock Dr., Madison, WI 53706. Tel.: 608-262-8229;
Fax: 608-263-7609; E-mail:
pike{at}biochem.wisc.edu.
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