Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity
Identifieur interne : 000C53 ( Main/Exploration ); précédent : 000C52; suivant : 000C54Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity
Auteurs : Marcus Quack [Allemagne] ; Andreas Clarin [Allemagne] ; Ernst Binderup [Danemark] ; Fredrik Björkling [Danemark] ; Christina M Rk Hansen [Danemark] ; Carsten Carlberg [Allemagne]Source :
- Journal of Cellular Biochemistry [ 0730-2312 ] ; 1998-12-01.
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Abstract
The nuclear hormone 1α,25‐dihydroxyvitamin D3 (VD) has important cell‐regulatory functions but also a strong calcemic effect. Therefore, various VD analogues have been synthesized and screened for their biological profile. In order to gain more insight into the molecular basis of the high antiproliferative but low calcemic action of the VD analogue EB1089, we characterized this compound in comparison to five structurally related VD analogues. The activities of the six VD analogues in in vitro assays (limited protease digestion assays for determining interaction with monomeric vitamin D receptor (VDR), ligand‐dependent gel shift assays for showing the increase of DNA binding of VDR‐retinoid X receptor (RXR) heterodimers, and reporter gene assays on different types of VD response elements for demonstrating the efficacy in nuclear VD signalling) were found to represent their biological potency (antiproliferative effect on different malignant cell lines). In this series, EB1089 proved to be the most potent VD analogue; that is, every structural modification (20‐epi configuration, cis‐configuration at position C24, or changes at the ethyl groups at position C25) appeared to reduce the determined activities mediated through the VDR of these analogues. Moreover, the modifications of EB1089 resulted in a loss of VD response element selectivity, suggesting that this parameter is very critical for the biological profile of this VD analogue. J. Cell. Biochem. 71:340–350, 1998. © 1998 Wiley‐Liss, Inc.
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DOI: 10.1002/(SICI)1097-4644(19981201)71:3<340::AID-JCB3>3.0.CO;2-C
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Biochem.</title><idno type="ISSN">0730-2312</idno><idno type="eISSN">1097-4644</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="1998-12-01">1998-12-01</date><biblScope unit="volume">71</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="340">340</biblScope><biblScope unit="page" to="350">350</biblScope></imprint><idno type="ISSN">0730-2312</idno></series><idno type="istex">4A664E6AEFAC67319B0747E9A3F4D6B00A7FCC1E</idno><idno type="DOI">10.1002/(SICI)1097-4644(19981201)71:3<340::AID-JCB3>3.0.CO;2-C</idno><idno type="ArticleID">JCB3</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0730-2312</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>gene regulation</term><term>ligand binding</term><term>ligand‐dependent gel shift assay</term><term>limited protease digestion</term><term>vitamin D analogues</term><term>vitamin D receptor</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The nuclear hormone 1α,25‐dihydroxyvitamin D3 (VD) has important cell‐regulatory functions but also a strong calcemic effect. Therefore, various VD analogues have been synthesized and screened for their biological profile. In order to gain more insight into the molecular basis of the high antiproliferative but low calcemic action of the VD analogue EB1089, we characterized this compound in comparison to five structurally related VD analogues. The activities of the six VD analogues in in vitro assays (limited protease digestion assays for determining interaction with monomeric vitamin D receptor (VDR), ligand‐dependent gel shift assays for showing the increase of DNA binding of VDR‐retinoid X receptor (RXR) heterodimers, and reporter gene assays on different types of VD response elements for demonstrating the efficacy in nuclear VD signalling) were found to represent their biological potency (antiproliferative effect on different malignant cell lines). In this series, EB1089 proved to be the most potent VD analogue; that is, every structural modification (20‐epi configuration, cis‐configuration at position C24, or changes at the ethyl groups at position C25) appeared to reduce the determined activities mediated through the VDR of these analogues. Moreover, the modifications of EB1089 resulted in a loss of VD response element selectivity, suggesting that this parameter is very critical for the biological profile of this VD analogue. J. Cell. Biochem. 71:340–350, 1998. © 1998 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Danemark</li></country><region><li>District de Düsseldorf</li><li>Rhénanie-du-Nord-Westphalie</li></region><settlement><li>Düsseldorf</li></settlement></list><tree><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Quack, Marcus" sort="Quack, Marcus" uniqKey="Quack M" first="Marcus" last="Quack">Marcus Quack</name></region><name sortKey="Carlberg, Carsten" sort="Carlberg, Carsten" uniqKey="Carlberg C" first="Carsten" last="Carlberg">Carsten Carlberg</name><name sortKey="Clarin, Andreas" sort="Clarin, Andreas" uniqKey="Clarin A" first="Andreas" last="Clarin">Andreas Clarin</name></country><country name="Danemark"><noRegion><name sortKey="Binderup, Ernst" sort="Binderup, Ernst" uniqKey="Binderup E" first="Ernst" last="Binderup">Ernst Binderup</name></noRegion><name sortKey="Bjorkling, Fredrik" sort="Bjorkling, Fredrik" uniqKey="Bjorkling F" first="Fredrik" last="Björkling">Fredrik Björkling</name><name sortKey="Hansen, Christina M Rk" sort="Hansen, Christina M Rk" uniqKey="Hansen C" first="Christina M Rk" last="Hansen">Christina M Rk Hansen</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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