Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription
Identifieur interne : 000598 ( Main/Corpus ); précédent : 000597; suivant : 000599Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription
Auteurs : Thomas G. Hofmann ; Steffen P. Hehner ; Susanne Bacher ; Wulf Dröge ; M. Lienhard SchmitzSource :
- FEBS Letters [ 0014-5793 ] ; 1998.
Abstract
Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-κB. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound RU486 efficiently reduced NF-κB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IκB-α expression, but impaired the tumor necrosis factor (TNF)-α-induced degradation of IκB-α without affecting DNA binding of NF-κB. The structural requirements for the various functions of glucocorticoids are discussed.
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DOI: 10.1016/S0014-5793(98)01609-3
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription</title><author><name sortKey="Hofmann, Thomas G" sort="Hofmann, Thomas G" uniqKey="Hofmann T" first="Thomas G" last="Hofmann">Thomas G. Hofmann</name><affiliation><mods:affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Hehner, Steffen P" sort="Hehner, Steffen P" uniqKey="Hehner S" first="Steffen P" last="Hehner">Steffen P. Hehner</name><affiliation><mods:affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Bacher, Susanne" sort="Bacher, Susanne" uniqKey="Bacher S" first="Susanne" last="Bacher">Susanne Bacher</name><affiliation><mods:affiliation>Max Planck Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Droge, Wulf" sort="Droge, Wulf" uniqKey="Droge W" first="Wulf" last="Dröge">Wulf Dröge</name><affiliation><mods:affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Schmitz, M Lienhard" sort="Schmitz, M Lienhard" uniqKey="Schmitz M" first="M. Lienhard" last="Schmitz">M. Lienhard Schmitz</name><affiliation><mods:affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Corresponding author. Fax: (49) (6221) 423746. E-mail: l.schmitz@dkfz-heidelberg.de</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F</idno><date when="1998" year="1998">1998</date><idno type="doi">10.1016/S0014-5793(98)01609-3</idno><idno type="url">https://api.istex.fr/document/59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000598</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription</title><author><name sortKey="Hofmann, Thomas G" sort="Hofmann, Thomas G" uniqKey="Hofmann T" first="Thomas G" last="Hofmann">Thomas G. Hofmann</name><affiliation><mods:affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Hehner, Steffen P" sort="Hehner, Steffen P" uniqKey="Hehner S" first="Steffen P" last="Hehner">Steffen P. Hehner</name><affiliation><mods:affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Bacher, Susanne" sort="Bacher, Susanne" uniqKey="Bacher S" first="Susanne" last="Bacher">Susanne Bacher</name><affiliation><mods:affiliation>Max Planck Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Droge, Wulf" sort="Droge, Wulf" uniqKey="Droge W" first="Wulf" last="Dröge">Wulf Dröge</name><affiliation><mods:affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Schmitz, M Lienhard" sort="Schmitz, M Lienhard" uniqKey="Schmitz M" first="M. Lienhard" last="Schmitz">M. Lienhard Schmitz</name><affiliation><mods:affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Corresponding author. Fax: (49) (6221) 423746. E-mail: l.schmitz@dkfz-heidelberg.de</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">FEBS Letters</title><title level="j" type="abbrev">FEBS</title><idno type="ISSN">0014-5793</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998">1998</date><biblScope unit="volume">441</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="441">441</biblScope><biblScope unit="page" to="446">446</biblScope></imprint><idno type="ISSN">0014-5793</idno></series><idno type="istex">59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F</idno><idno type="DOI">10.1016/S0014-5793(98)01609-3</idno><idno type="PII">S0014-5793(98)01609-3</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0014-5793</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-κB. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound RU486 efficiently reduced NF-κB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IκB-α expression, but impaired the tumor necrosis factor (TNF)-α-induced degradation of IκB-α without affecting DNA binding of NF-κB. The structural requirements for the various functions of glucocorticoids are discussed.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>Thomas G Hofmann</name><affiliations><json:string>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</json:string></affiliations></json:item><json:item><name>Steffen P Hehner</name><affiliations><json:string>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</json:string></affiliations></json:item><json:item><name>Susanne Bacher</name><affiliations><json:string>Max Planck Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany</json:string></affiliations></json:item><json:item><name>Wulf Dröge</name><affiliations><json:string>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</json:string></affiliations></json:item><json:item><name>M.Lienhard Schmitz</name><affiliations><json:string>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</json:string><json:string>Corresponding author. Fax: (49) (6221) 423746. E-mail: l.schmitz@dkfz-heidelberg.de</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Glucocorticoid</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Apoptosis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NF-κB</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Gene expression</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Cross-talk</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>EMSA, electrophoretic mobility shift assay</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>GCs, glucocorticoids</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>GR, glucocorticoid receptor</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>GREs, glucocorticoid-response elements</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>nGREs, negative GREs</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MMTV, mouse mammary tumor virus</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TNF, tumor necrosis factor</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-κB. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound RU486 efficiently reduced NF-κB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IκB-α expression, but impaired the tumor necrosis factor (TNF)-α-induced degradation of IκB-α without affecting DNA binding of NF-κB. The structural requirements for the various functions of glucocorticoids are discussed.</abstract><qualityIndicators><score>5.248</score><pdfVersion>1.2</pdfVersion><pdfPageSize>588 x 804 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>12</keywordCount><abstractCharCount>1162</abstractCharCount><pdfWordCount>3352</pdfWordCount><pdfCharCount>20806</pdfCharCount><pdfPageCount>6</pdfPageCount><abstractWordCount>158</abstractWordCount></qualityIndicators><title>Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription</title><pii><json:string>S0014-5793(98)01609-3</json:string></pii><genre><json:string>research-article</json:string></genre><host><volume>441</volume><pii><json:string>S0014-5793(00)X0200-1</json:string></pii><pages><last>446</last><first>441</first></pages><issn><json:string>0014-5793</json:string></issn><issue>3</issue><genre></genre><language><json:string>unknown</json:string></language><title>FEBS Letters</title><publicationDate>1998</publicationDate></host><categories><wos><json:string>BIOCHEMISTRY & MOLECULAR BIOLOGY</json:string><json:string>BIOPHYSICS</json:string><json:string>CELL BIOLOGY</json:string></wos></categories><publicationDate>1998</publicationDate><copyrightDate>1998</copyrightDate><doi><json:string>10.1016/S0014-5793(98)01609-3</json:string></doi><id>59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>ELSEVIER</publisher><availability><p>ELSEVIER</p></availability><date>1998</date></publicationStmt><notesStmt><note type="content">Fig. 1: List of the different steroids tested. The positions of the different C-atoms are indicated for hydrocortisone.</note><note type="content">Fig. 2: Effects of various GCs on transactivation. L929 cells were transiently transfected with the MMTV-luciferase reporter construct. One day after transfection, cells were stimulated for 12 h with the various GCs at concentrations of 10−6 M (grey bars) and 10−7 M (black bars). Luciferase activity contained in equal amounts of cell extracts was determined. The mean of four separate experiments is shown, standard deviations are indicated by bars.</note><note type="content">Fig. 3: Analysis of GC-induced apoptosis. A: CEM C7 cells were treated for 48 h with 1 μM dexamethasone or for 24 h with 1 μM vinblastine, which was used as a positive control. The fragmentation of DNA into oligonucleosomes was determined by horizontal agarose gel electrophoresis followed by staining with ethidium bromide. B: Comparative analysis of GC-induced apoptosis. CEM C7 T-cells were incubated for 48 h with 10−6 M (grey bars) or 10−7 M (black bars) of the indicated GC. RU486 was added at the indicated concentration to 1 μM of the respective GC. Apoptosis was measured by FACS analysis and the percentage of hypoploid cells is given. Mean values from 4 independent experiments are shown, bars show standard deviations.</note><note type="content">Fig. 4: Comparative analysis of NF-κB transrepression by GCs. L929 cells stably transfected with an NF-κB-controlled luciferase reporter gene were preincubated with 10−6 M (grey bars) or 10−7 M (black bars) of the indicated GCs for 1 h. Subsequently transcription was induced by the addition of TNF-α (2000 U/ml) for 10 h and luciferase activity was determined. Mean values from 3 independent experiments are displayed, bars represent standard deviations.</note><note type="content">Fig. 5: Impact of various GCs on DNA binding of NF-κB and IκB-α degradation. A: TNF-α (2000 U/ml) was added for 15 min to L929 cells that were preincubated as shown for 1 h with 1 μM of the indicated GCs. Total cell extracts were prepared and DNA binding of activated NF-κB was measured by EMSA (upper). The filled arrowhead indicates the location of the DNA-NF-κB complex, the circle indicates the position of a constitutively DNA-binding protein and the open arrowhead points to the unbound oligonucleotide. The same extracts were tested for the IκB-α protein in a Western blot (lower). The arrow points to the IκB-α protein. B: L929 cells were grown for 8 h in the presence of 1 μM of the various GCs, the indicated cells were subsequently treated for 15 min with TNF-α (2000 U/ml). Equal amounts of total cellular proteins were analyzed by immunoblotting for the occurrence of IκB-α which was detected with a polyclonal α-IκB-α antibody.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription</title><author><persName><forename type="first">Thomas G</forename><surname>Hofmann</surname></persName><affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</affiliation></author><author><persName><forename type="first">Steffen P</forename><surname>Hehner</surname></persName><affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</affiliation></author><author><persName><forename type="first">Susanne</forename><surname>Bacher</surname></persName><affiliation>Max Planck Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany</affiliation></author><author><persName><forename type="first">Wulf</forename><surname>Dröge</surname></persName><affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</affiliation></author><author><persName><forename type="first">M.Lienhard</forename><surname>Schmitz</surname></persName><email>l.schmitz@dkfz-heidelberg.de</email><affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</affiliation></author></analytic><monogr><title level="j">FEBS Letters</title><title level="j" type="abbrev">FEBS</title><idno type="pISSN">0014-5793</idno><idno type="PII">S0014-5793(00)X0200-1</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998"></date><biblScope unit="volume">441</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="441">441</biblScope><biblScope unit="page" to="446">446</biblScope></imprint></monogr><idno type="istex">59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F</idno><idno type="DOI">10.1016/S0014-5793(98)01609-3</idno><idno type="PII">S0014-5793(98)01609-3</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1998</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-κB. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound RU486 efficiently reduced NF-κB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IκB-α expression, but impaired the tumor necrosis factor (TNF)-α-induced degradation of IκB-α without affecting DNA binding of NF-κB. The structural requirements for the various functions of glucocorticoids are discussed.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Glucocorticoid</term></item><item><term>Apoptosis</term></item><item><term>NF-κB</term></item><item><term>Gene expression</term></item><item><term>Cross-talk</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Abbreviations</head><item><term>EMSA, electrophoretic mobility shift assay</term></item><item><term>GCs, glucocorticoids</term></item><item><term>GR, glucocorticoid receptor</term></item><item><term>GREs, glucocorticoid-response elements</term></item><item><term>nGREs, negative GREs</term></item><item><term>MMTV, mouse mammary tumor virus</term></item><item><term>TNF, tumor necrosis factor</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1998-10-29">Received</change><change when="1998-11-25">Modified</change><change when="1998">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity><istex:entity SYSTEM="gr4" NDATA="IMAGE" name="gr4"></istex:entity><istex:entity SYSTEM="gr5" NDATA="IMAGE" name="gr5"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla"><item-info><jid>FEBS</jid><aid>21354</aid><ce:pii>S0014-5793(98)01609-3</ce:pii><ce:doi>10.1016/S0014-5793(98)01609-3</ce:doi><ce:copyright year="1998" type="society">Federation of European Biochemical Societies</ce:copyright></item-info><head><ce:title>Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription</ce:title><ce:author-group><ce:author><ce:given-name>Thomas G</ce:given-name><ce:surname>Hofmann</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref></ce:author><ce:author><ce:given-name>Steffen P</ce:given-name><ce:surname>Hehner</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref></ce:author><ce:author><ce:given-name>Susanne</ce:given-name><ce:surname>Bacher</ce:surname><ce:cross-ref refid="AFF2">b</ce:cross-ref></ce:author><ce:author><ce:given-name>Wulf</ce:given-name><ce:surname>Dröge</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref></ce:author><ce:author><ce:given-name>M.Lienhard</ce:given-name><ce:surname>Schmitz</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>b</ce:label><ce:textfn>Max Planck Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Corresponding author. Fax: (49) (6221) 423746. E-mail: l.schmitz@dkfz-heidelberg.de</ce:text></ce:correspondence></ce:author-group><ce:date-received day="29" month="10" year="1998"></ce:date-received><ce:date-revised day="25" month="11" year="1998"></ce:date-revised><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-κB. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound RU486 efficiently reduced NF-κB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IκB-α expression, but impaired the tumor necrosis factor (TNF)-α-induced degradation of IκB-α without affecting DNA binding of NF-κB. The structural requirements for the various functions of glucocorticoids are discussed.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>Glucocorticoid</ce:text></ce:keyword><ce:keyword><ce:text>Apoptosis</ce:text></ce:keyword><ce:keyword><ce:text>NF-κB</ce:text></ce:keyword><ce:keyword><ce:text>Gene expression</ce:text></ce:keyword><ce:keyword><ce:text>Cross-talk</ce:text></ce:keyword></ce:keywords><ce:keywords class="abr"><ce:section-title>Abbreviations</ce:section-title><ce:keyword><ce:text>EMSA, electrophoretic mobility shift assay</ce:text></ce:keyword><ce:keyword><ce:text>GCs, glucocorticoids</ce:text></ce:keyword><ce:keyword><ce:text>GR, glucocorticoid receptor</ce:text></ce:keyword><ce:keyword><ce:text>GREs, glucocorticoid-response elements</ce:text></ce:keyword><ce:keyword><ce:text>nGREs, negative GREs</ce:text></ce:keyword><ce:keyword><ce:text>MMTV, mouse mammary tumor virus</ce:text></ce:keyword><ce:keyword><ce:text>TNF, tumor necrosis factor</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-κB-dependent transcription</title></titleInfo><name type="personal"><namePart type="given">Thomas G</namePart><namePart type="family">Hofmann</namePart><affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Steffen P</namePart><namePart type="family">Hehner</namePart><affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Susanne</namePart><namePart type="family">Bacher</namePart><affiliation>Max Planck Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wulf</namePart><namePart type="family">Dröge</namePart><affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M.Lienhard</namePart><namePart type="family">Schmitz</namePart><affiliation>German Cancer Research Center (DKFZ), Department of Immunochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany</affiliation><affiliation>Corresponding author. Fax: (49) (6221) 423746. E-mail: l.schmitz@dkfz-heidelberg.de</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1998</dateIssued><dateCaptured encoding="w3cdtf">1998-10-29</dateCaptured><dateModified encoding="w3cdtf">1998-11-25</dateModified><copyrightDate encoding="w3cdtf">1998</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-κB. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound RU486 efficiently reduced NF-κB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IκB-α expression, but impaired the tumor necrosis factor (TNF)-α-induced degradation of IκB-α without affecting DNA binding of NF-κB. The structural requirements for the various functions of glucocorticoids are discussed.</abstract><note type="content">Fig. 1: List of the different steroids tested. The positions of the different C-atoms are indicated for hydrocortisone.</note><note type="content">Fig. 2: Effects of various GCs on transactivation. L929 cells were transiently transfected with the MMTV-luciferase reporter construct. One day after transfection, cells were stimulated for 12 h with the various GCs at concentrations of 10−6 M (grey bars) and 10−7 M (black bars). Luciferase activity contained in equal amounts of cell extracts was determined. The mean of four separate experiments is shown, standard deviations are indicated by bars.</note><note type="content">Fig. 3: Analysis of GC-induced apoptosis. A: CEM C7 cells were treated for 48 h with 1 μM dexamethasone or for 24 h with 1 μM vinblastine, which was used as a positive control. The fragmentation of DNA into oligonucleosomes was determined by horizontal agarose gel electrophoresis followed by staining with ethidium bromide. B: Comparative analysis of GC-induced apoptosis. CEM C7 T-cells were incubated for 48 h with 10−6 M (grey bars) or 10−7 M (black bars) of the indicated GC. RU486 was added at the indicated concentration to 1 μM of the respective GC. Apoptosis was measured by FACS analysis and the percentage of hypoploid cells is given. Mean values from 4 independent experiments are shown, bars show standard deviations.</note><note type="content">Fig. 4: Comparative analysis of NF-κB transrepression by GCs. L929 cells stably transfected with an NF-κB-controlled luciferase reporter gene were preincubated with 10−6 M (grey bars) or 10−7 M (black bars) of the indicated GCs for 1 h. Subsequently transcription was induced by the addition of TNF-α (2000 U/ml) for 10 h and luciferase activity was determined. Mean values from 3 independent experiments are displayed, bars represent standard deviations.</note><note type="content">Fig. 5: Impact of various GCs on DNA binding of NF-κB and IκB-α degradation. A: TNF-α (2000 U/ml) was added for 15 min to L929 cells that were preincubated as shown for 1 h with 1 μM of the indicated GCs. Total cell extracts were prepared and DNA binding of activated NF-κB was measured by EMSA (upper). The filled arrowhead indicates the location of the DNA-NF-κB complex, the circle indicates the position of a constitutively DNA-binding protein and the open arrowhead points to the unbound oligonucleotide. The same extracts were tested for the IκB-α protein in a Western blot (lower). The arrow points to the IκB-α protein. B: L929 cells were grown for 8 h in the presence of 1 μM of the various GCs, the indicated cells were subsequently treated for 15 min with TNF-α (2000 U/ml). Equal amounts of total cellular proteins were analyzed by immunoblotting for the occurrence of IκB-α which was detected with a polyclonal α-IκB-α antibody.</note><subject><genre>Keywords</genre><topic>Glucocorticoid</topic><topic>Apoptosis</topic><topic>NF-κB</topic><topic>Gene expression</topic><topic>Cross-talk</topic></subject><subject><genre>Abbreviations</genre><topic>EMSA, electrophoretic mobility shift assay</topic><topic>GCs, glucocorticoids</topic><topic>GR, glucocorticoid receptor</topic><topic>GREs, glucocorticoid-response elements</topic><topic>nGREs, negative GREs</topic><topic>MMTV, mouse mammary tumor virus</topic><topic>TNF, tumor necrosis factor</topic></subject><relatedItem type="host"><titleInfo><title>FEBS Letters</title></titleInfo><titleInfo type="abbreviated"><title>FEBS</title></titleInfo><genre type="Journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">19981228</dateIssued></originInfo><identifier type="ISSN">0014-5793</identifier><identifier type="PII">S0014-5793(00)X0200-1</identifier><part><date>19981228</date><detail type="volume"><number>441</number><caption>vol.</caption></detail><detail type="issue"><number>3</number><caption>no.</caption></detail><extent unit="issue pages"><start>343</start><end>486</end></extent><extent unit="pages"><start>441</start><end>446</end></extent></part></relatedItem><identifier type="istex">59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F</identifier><identifier type="DOI">10.1016/S0014-5793(98)01609-3</identifier><identifier type="PII">S0014-5793(98)01609-3</identifier><accessCondition type="use and reproduction" contentType="">© 1998Federation of European Biochemical Societies</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>Federation of European Biochemical Societies, ©1998</recordOrigin></recordInfo></mods></metadata><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/59FDEE053A7356E33ACE0FB23D5F43E42F8D2A0F/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">BIOCHEMISTRY & MOLECULAR BIOLOGY</classCode><classCode scheme="WOS">BIOPHYSICS</classCode><classCode scheme="WOS">CELL BIOLOGY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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