Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity
Identifieur interne : 000A44 ( Main/Corpus ); précédent : 000A43; suivant : 000A45Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity
Auteurs : Marcus Quack ; Andreas Clarin ; Ernst Binderup ; Fredrik Björkling ; Christina M Rk Hansen ; Carsten CarlbergSource :
- 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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Cell. 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><istex><corpusName>wiley</corpusName><author><json:item><name>Marcus Quack</name><affiliations><json:string>Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität, D‐40001 Düsseldorf, Germany</json:string></affiliations></json:item><json:item><name>Andreas Clarin</name><affiliations><json:string>Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität, D‐40001 Düsseldorf, Germany</json:string></affiliations></json:item><json:item><name>Ernst Binderup</name><affiliations><json:string>Department of Chemistry, LEO Pharmaceutical Products, DK‐2750 Ballerup, Denmark</json:string></affiliations></json:item><json:item><name>Fredrik Björkling</name><affiliations><json:string>Department of Chemistry, LEO Pharmaceutical Products, DK‐2750 Ballerup, Denmark</json:string></affiliations></json:item><json:item><name>Christina Mørk Hansen</name><affiliations><json:string>Department of Biochemistry, LEO Pharmaceutical Products, DK‐2750 Ballerup, Denmark</json:string></affiliations></json:item><json:item><name>Carsten Carlberg</name><affiliations><json:string>Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität, D‐40001 Düsseldorf, Germany</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>vitamin D analogues</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>vitamin D receptor</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ligand binding</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>limited protease digestion</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ligand‐dependent gel shift assay</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>gene regulation</value></json:item></subject><language><json:string>eng</json:string></language><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.</abstract><qualityIndicators><score>7.059</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>6</keywordCount><abstractCharCount>1514</abstractCharCount><pdfWordCount>4407</pdfWordCount><pdfCharCount>27699</pdfCharCount><pdfPageCount>11</pdfPageCount><abstractWordCount>221</abstractWordCount></qualityIndicators><title>Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity</title><genre><json:string>article</json:string></genre><host><volume>71</volume><pages><total>11</total><last>350</last><first>340</first></pages><issn><json:string>0730-2312</json:string></issn><issue>3</issue><subject><json:item><value>Research Article</value></json:item></subject><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1097-4644</json:string></eissn><title>Journal of Cellular Biochemistry</title><doi><json:string>10.1002/(ISSN)1097-4644</json:string></doi></host><publicationDate>1998</publicationDate><copyrightDate>1998</copyrightDate><doi><json:string>10.1002/(SICI)1097-4644(19981201)71:3>340::AID-JCB3>3.0.CO;2-C</json:string></doi><id>4A664E6AEFAC67319B0747E9A3F4D6B00A7FCC1E</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/4A664E6AEFAC67319B0747E9A3F4D6B00A7FCC1E/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/4A664E6AEFAC67319B0747E9A3F4D6B00A7FCC1E/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/4A664E6AEFAC67319B0747E9A3F4D6B00A7FCC1E/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>1998</date></publicationStmt><notesStmt><note>Medical Faculty of the Heinrich‐Heine University Düsseldorf</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity</title><author><persName><forename type="first">Marcus</forename><surname>Quack</surname></persName><affiliation>Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität, D‐40001 Düsseldorf, Germany</affiliation></author><author><persName><forename type="first">Andreas</forename><surname>Clarin</surname></persName><affiliation>Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität, D‐40001 Düsseldorf, Germany</affiliation></author><author><persName><forename type="first">Ernst</forename><surname>Binderup</surname></persName><affiliation>Department of Chemistry, LEO Pharmaceutical Products, DK‐2750 Ballerup, Denmark</affiliation></author><author><persName><forename type="first">Fredrik</forename><surname>Björkling</surname></persName><affiliation>Department of Chemistry, LEO Pharmaceutical Products, DK‐2750 Ballerup, Denmark</affiliation></author><author><persName><forename type="first">Christina Mørk</forename><surname>Hansen</surname></persName><affiliation>Department of Biochemistry, LEO Pharmaceutical Products, DK‐2750 Ballerup, Denmark</affiliation></author><author><persName><forename type="first">Carsten</forename><surname>Carlberg</surname></persName><note type="correspondence"><p>Correspondence: Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität Düsseldorf, Postfach 10 10 07, D‐40001 Düsseldorf, Germany</p></note><affiliation>Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität, D‐40001 Düsseldorf, Germany</affiliation></author></analytic><monogr><title level="j">Journal of Cellular Biochemistry</title><title level="j" type="abbrev">J. Cell. Biochem.</title><idno type="pISSN">0730-2312</idno><idno type="eISSN">1097-4644</idno><idno type="DOI">10.1002/(ISSN)1097-4644</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="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></monogr><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></fileDesc><profileDesc><creation><date>1998</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>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. 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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, <i>cis</i>‐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.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Characterization of EB1089 and Its Relatives</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity</title></titleInfo><name type="personal"><namePart type="given">Marcus</namePart><namePart type="family">Quack</namePart><affiliation>Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität, D‐40001 Düsseldorf, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andreas</namePart><namePart type="family">Clarin</namePart><affiliation>Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität, D‐40001 Düsseldorf, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ernst</namePart><namePart type="family">Binderup</namePart><affiliation>Department of Chemistry, LEO Pharmaceutical Products, DK‐2750 Ballerup, Denmark</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fredrik</namePart><namePart type="family">Björkling</namePart><affiliation>Department of Chemistry, LEO Pharmaceutical Products, DK‐2750 Ballerup, Denmark</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christina Mørk</namePart><namePart type="family">Hansen</namePart><affiliation>Department of Biochemistry, LEO Pharmaceutical Products, DK‐2750 Ballerup, Denmark</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carsten</namePart><namePart type="family">Carlberg</namePart><affiliation>Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität, D‐40001 Düsseldorf, Germany</affiliation><description>Correspondence: Institut für Physiologische Chemie I, Heinrich‐Heine‐Universität Düsseldorf, Postfach 10 10 07, D‐40001 Düsseldorf, Germany</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">1998-12-01</dateIssued><dateCaptured encoding="w3cdtf">1998-04-05</dateCaptured><dateValid encoding="w3cdtf">1998-06-08</dateValid><copyrightDate encoding="w3cdtf">1998</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">5</extent><extent unit="tables">1</extent><extent unit="references">32</extent><extent unit="words">5430</extent></physicalDescription><abstract 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.</abstract><note type="funding">Medical Faculty of the Heinrich‐Heine University Düsseldorf</note><subject lang="en"><genre>Keywords</genre><topic>vitamin D analogues</topic><topic>vitamin D receptor</topic><topic>ligand binding</topic><topic>limited protease digestion</topic><topic>ligand‐dependent gel shift assay</topic><topic>gene regulation</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Cellular Biochemistry</title></titleInfo><titleInfo type="abbreviated"><title>J. Cell. Biochem.</title></titleInfo><genre type="Journal">journal</genre><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0730-2312</identifier><identifier type="eISSN">1097-4644</identifier><identifier type="DOI">10.1002/(ISSN)1097-4644</identifier><identifier type="PublisherID">JCB</identifier><part><date>1998</date><detail type="volume"><caption>vol.</caption><number>71</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>340</start><end>350</end><total>11</total></extent></part></relatedItem><identifier type="istex">4A664E6AEFAC67319B0747E9A3F4D6B00A7FCC1E</identifier><identifier type="DOI">10.1002/(SICI)1097-4644(19981201)71:3<340::AID-JCB3>3.0.CO;2-C</identifier><identifier type="ArticleID">JCB3</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 1998 Wiley‐Liss, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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