Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations
Identifieur interne : 000E07 ( Istex/Corpus ); précédent : 000E06; suivant : 000E08Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations
Auteurs : Brnice A. Benayoun ; Frank Batista ; Jana Auer ; Aurlie Dipietromaria ; David L'Hte ; Elfride De Baere ; Reiner A. VeitiaSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-02-15.
Abstract
FOXL2 is a forkhead transcription factor, essential for ovarian function, whose mutations are responsible for the blepharophimosis syndrome, characterized by craniofacial defects, often associated with premature ovarian failure. Here, we show that cell stress upregulates FOXL2 expression in an ovarian granulosa cell model. Increased FOXL2 transcription might be mediated at least partly by self-activation. Moreover, using 2D-western blot, we show that the response of FOXL2 to stress correlates with a dramatic remodeling of its post-translational modification profile. Upon oxidative stress, we observe an increased recruitment of FOXL2 to several stress-response promoters, notably that of the mitochondrial manganese superoxide dismutase (MnSOD). Using several reporter systems, we show that FOXL2 transactivation is enhanced in this context. Models predict that gene upregulation in response to a signal should eventually be counterbalanced to restore the initial steady state. In line with this, we find that FOXL2 activity is repressed by the SIRT1 deacetylase. Interestingly, we demonstrate that SIRT1 transcription is, in turn, directly upregulated by FOXL2, which closes a negative-feedback loop. The regulatory relationship between FOXL2 and SIRT1 prompted us the test action of nicotinamide, an inhibitor of sirtuins, on FoxL2 expression/activity. According to our expectations, nicotinamide treatment increases FoxL2 transcription. Finally, we show that 11 disease-causing mutations in the ORF of FOXL2 induce aberrant regulation of FOXL2 and/or regulation of the FOXL2 stress-response target gene MnSOD. Taken together, our results establish that FOXL2 is an actor of the stress response and provide new insights into the pathogenic consequences of FOXL2 mutations.
Url:
DOI: 10.1093/hmg/ddn389
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ISTEX:8753D73676ADCA1F5BA91FBA5F642E9636EADA22Le document en format XML
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Benayoun</name><affiliation><mods:affiliation>INSERM U567, Team 21, Department of Genetics and Development</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Universit Denis Diderot, Paris VII, 75013 Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>cole Normale Suprieure, 75005 Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Batista, Frank" sort="Batista, Frank" uniqKey="Batista F" first="Frank" last="Batista">Frank Batista</name><affiliation><mods:affiliation>INSERM U567, Team 21, Department of Genetics and Development</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Universit Denis Diderot, Paris VII, 75013 Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Auer, Jana" sort="Auer, Jana" uniqKey="Auer J" first="Jana" last="Auer">Jana Auer</name><affiliation><mods:affiliation>INSERM U567, Team 21, Department of Genetics and Development</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</mods:affiliation></affiliation></author><author><name sortKey="Dipietromaria, Aurlie" sort="Dipietromaria, Aurlie" uniqKey="Dipietromaria A" first="Aurlie" last="Dipietromaria">Aurlie Dipietromaria</name><affiliation><mods:affiliation>INSERM U567, Team 21, Department of Genetics and Development</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Paris-Sud, Paris XI, 91400 Orsay, France</mods:affiliation></affiliation></author><author><name sortKey="L Hte, David" sort="L Hte, David" uniqKey="L Hte D" first="David" last="L'Hte">David L'Hte</name><affiliation><mods:affiliation>INSERM U567, Team 21, Department of Genetics and Development</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Unit de Gntique Molculaire Animale, INRA/Universit de Limoges, UMR 1061, Universit de Limoges, Limoges, France</mods:affiliation></affiliation></author><author><name sortKey="De Baere, Elfride" sort="De Baere, Elfride" uniqKey="De Baere E" first="Elfride" last="De Baere">Elfride De Baere</name><affiliation><mods:affiliation>Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Veitia, Reiner A" sort="Veitia, Reiner A" uniqKey="Veitia R" first="Reiner A." last="Veitia">Reiner A. Veitia</name><affiliation><mods:affiliation>INSERM U567, Team 21, Department of Genetics and Development</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Universit Denis Diderot, Paris VII, 75013 Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: reiner.veitia@inserm.fr</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-02-15">2009-02-15</date><biblScope unit="volume">18</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="632">632</biblScope><biblScope unit="page" to="644">644</biblScope></imprint><idno type="ISSN">0964-6906</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">FOXL2 is a forkhead transcription factor, essential for ovarian function, whose mutations are responsible for the blepharophimosis syndrome, characterized by craniofacial defects, often associated with premature ovarian failure. Here, we show that cell stress upregulates FOXL2 expression in an ovarian granulosa cell model. Increased FOXL2 transcription might be mediated at least partly by self-activation. Moreover, using 2D-western blot, we show that the response of FOXL2 to stress correlates with a dramatic remodeling of its post-translational modification profile. Upon oxidative stress, we observe an increased recruitment of FOXL2 to several stress-response promoters, notably that of the mitochondrial manganese superoxide dismutase (MnSOD). Using several reporter systems, we show that FOXL2 transactivation is enhanced in this context. Models predict that gene upregulation in response to a signal should eventually be counterbalanced to restore the initial steady state. In line with this, we find that FOXL2 activity is repressed by the SIRT1 deacetylase. Interestingly, we demonstrate that SIRT1 transcription is, in turn, directly upregulated by FOXL2, which closes a negative-feedback loop. The regulatory relationship between FOXL2 and SIRT1 prompted us the test action of nicotinamide, an inhibitor of sirtuins, on FoxL2 expression/activity. According to our expectations, nicotinamide treatment increases FoxL2 transcription. Finally, we show that 11 disease-causing mutations in the ORF of FOXL2 induce aberrant regulation of FOXL2 and/or regulation of the FOXL2 stress-response target gene MnSOD. Taken together, our results establish that FOXL2 is an actor of the stress response and provide new insights into the pathogenic consequences of FOXL2 mutations.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Brnice A. 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Veitia</name><affiliations><json:string>INSERM U567, Team 21, Department of Genetics and Development</json:string><json:string>CNRS UMR8104, Institut Cochin, 75014 Paris, France</json:string><json:string>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</json:string><json:string>Universit Denis Diderot, Paris VII, 75013 Paris, France</json:string><json:string>E-mail: reiner.veitia@inserm.fr</json:string></affiliations></json:item></author><articleId><json:string>ddn389</json:string></articleId><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>FOXL2 is a forkhead transcription factor, essential for ovarian function, whose mutations are responsible for the blepharophimosis syndrome, characterized by craniofacial defects, often associated with premature ovarian failure. Here, we show that cell stress upregulates FOXL2 expression in an ovarian granulosa cell model. Increased FOXL2 transcription might be mediated at least partly by self-activation. Moreover, using 2D-western blot, we show that the response of FOXL2 to stress correlates with a dramatic remodeling of its post-translational modification profile. Upon oxidative stress, we observe an increased recruitment of FOXL2 to several stress-response promoters, notably that of the mitochondrial manganese superoxide dismutase (MnSOD). Using several reporter systems, we show that FOXL2 transactivation is enhanced in this context. Models predict that gene upregulation in response to a signal should eventually be counterbalanced to restore the initial steady state. In line with this, we find that FOXL2 activity is repressed by the SIRT1 deacetylase. Interestingly, we demonstrate that SIRT1 transcription is, in turn, directly upregulated by FOXL2, which closes a negative-feedback loop. The regulatory relationship between FOXL2 and SIRT1 prompted us the test action of nicotinamide, an inhibitor of sirtuins, on FoxL2 expression/activity. According to our expectations, nicotinamide treatment increases FoxL2 transcription. Finally, we show that 11 disease-causing mutations in the ORF of FOXL2 induce aberrant regulation of FOXL2 and/or regulation of the FOXL2 stress-response target gene MnSOD. 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Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissionsoxfordjournals.org</p></availability><date>2008-11-14</date></publicationStmt><notesStmt><note>The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations</title><author xml:id="author-0000"><persName><forename type="first">Brnice A.</forename><surname>Benayoun</surname></persName><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Universit Denis Diderot, Paris VII, 75013 Paris, France</affiliation><affiliation>cole Normale Suprieure, 75005 Paris, France</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Frank</forename><surname>Batista</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</note><affiliation>The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</affiliation><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Universit Denis Diderot, Paris VII, 75013 Paris, France</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Jana</forename><surname>Auer</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</note><affiliation>The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</affiliation><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Aurlie</forename><surname>Dipietromaria</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</note><affiliation>The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</affiliation><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Paris-Sud, Paris XI, 91400 Orsay, France</affiliation></author><author xml:id="author-0004"><persName><forename type="first">David</forename><surname>L'Hte</surname></persName><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Unit de Gntique Molculaire Animale, INRA/Universit de Limoges, UMR 1061, Universit de Limoges, Limoges, France</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Elfride</forename><surname>De Baere</surname></persName><affiliation>Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Reiner A.</forename><surname>Veitia</surname></persName><email>reiner.veitia@inserm.fr</email><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Universit Denis Diderot, Paris VII, 75013 Paris, France</affiliation></author><idno type="istex">8753D73676ADCA1F5BA91FBA5F642E9636EADA22</idno><idno type="DOI">10.1093/hmg/ddn389</idno><idno type="ArticleID">ddn389</idno></analytic><monogr><title level="j">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><idno type="PublisherID">hmg</idno><idno type="PublisherID-hwp">hmg</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-02-15"></date><biblScope unit="volume">18</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="632">632</biblScope><biblScope unit="page" to="644">644</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008-11-14</date></creation><abstract><p>FOXL2 is a forkhead transcription factor, essential for ovarian function, whose mutations are responsible for the blepharophimosis syndrome, characterized by craniofacial defects, often associated with premature ovarian failure. Here, we show that cell stress upregulates FOXL2 expression in an ovarian granulosa cell model. Increased FOXL2 transcription might be mediated at least partly by self-activation. Moreover, using 2D-western blot, we show that the response of FOXL2 to stress correlates with a dramatic remodeling of its post-translational modification profile. Upon oxidative stress, we observe an increased recruitment of FOXL2 to several stress-response promoters, notably that of the mitochondrial manganese superoxide dismutase (MnSOD). Using several reporter systems, we show that FOXL2 transactivation is enhanced in this context. Models predict that gene upregulation in response to a signal should eventually be counterbalanced to restore the initial steady state. In line with this, we find that FOXL2 activity is repressed by the SIRT1 deacetylase. Interestingly, we demonstrate that SIRT1 transcription is, in turn, directly upregulated by FOXL2, which closes a negative-feedback loop. The regulatory relationship between FOXL2 and SIRT1 prompted us the test action of nicotinamide, an inhibitor of sirtuins, on FoxL2 expression/activity. According to our expectations, nicotinamide treatment increases FoxL2 transcription. Finally, we show that 11 disease-causing mutations in the ORF of FOXL2 induce aberrant regulation of FOXL2 and/or regulation of the FOXL2 stress-response target gene MnSOD. Taken together, our results establish that FOXL2 is an actor of the stress response and provide new insights into the pathogenic consequences of FOXL2 mutations.</p></abstract></profileDesc><revisionDesc><change when="2008-11-14">Created</change><change when="2009-02-15">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/8753D73676ADCA1F5BA91FBA5F642E9636EADA22/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddn389</article-id><article-id pub-id-type="publisher-id">ddn389</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Benayoun</surname><given-names>Bérénice A.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Batista</surname><given-names>Frank</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Auer</surname><given-names>Jana</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Dipietromaria</surname><given-names>Aurélie</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af6">6</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>L'Hôte</surname><given-names>David</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>De Baere</surname><given-names>Elfride</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Veitia</surname><given-names>Reiner A.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>INSERM U567, Team 21, Department of Genetics and Development</addr-line></aff><aff id="af2"><label>2</label><addr-line>CNRS UMR8104</addr-line>, <institution>Institut Cochin</institution>, <addr-line>75014 Paris</addr-line>, <country>France</country></aff><aff id="af3"><label>3</label><institution>Faculté de Médecine Cochin-Port-Royal, Université Paris Descartes</institution>, <addr-line>Paris 75014</addr-line>, <country>France</country></aff><aff id="af4"><label>4</label><institution>Université Denis Diderot, Paris VII</institution>, <addr-line>75013 Paris</addr-line>, <country>France</country></aff><aff id="af5"><label>5</label><institution>École Normale Supérieure</institution>, <addr-line>75005 Paris</addr-line>, <country>France</country></aff><aff id="af6"><label>6</label><institution>Paris-Sud, Paris XI</institution>, <addr-line>91400 Orsay</addr-line>, <country>France</country></aff><aff id="af7"><label>7</label><institution>Unité de Génétique Moléculaire Animale, INRA/Université de Limoges, UMR 1061, Université de Limoges</institution>, <addr-line>Limoges</addr-line>, <country>France</country></aff><aff id="af8"><label>8</label><institution>Center for Medical Genetics, Ghent University Hospital</institution>, <addr-line>9000 Ghent</addr-line>, <country>Belgium</country></aff><author-notes><fn id="FN1"><label>†</label><p>The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</p></fn><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>INSERM E21-GDPM</addr-line>, <institution>Institut Cochin</institution>, <addr-line>24, Rue du Faubourg Saint-Jacques, 75014 Paris</addr-line>, <country>France</country>. Tel: <phone>+33 144412301</phone>; Fax: <fax>+33 144412302</fax>; Email: <email>reiner.veitia@inserm.fr</email></corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>2</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>14</day><month>11</month><year>2008</year></pub-date><volume>18</volume><issue>4</issue><fpage>632</fpage><lpage>644</lpage><copyright-statement>© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2009</copyright-year><abstract><p>FOXL2 is a forkhead transcription factor, essential for ovarian function, whose mutations are responsible for the blepharophimosis syndrome, characterized by craniofacial defects, often associated with premature ovarian failure. Here, we show that cell stress upregulates FOXL2 expression in an ovarian granulosa cell model. Increased FOXL2 transcription might be mediated at least partly by self-activation. Moreover, using 2D-western blot, we show that the response of FOXL2 to stress correlates with a dramatic remodeling of its post-translational modification profile. Upon oxidative stress, we observe an increased recruitment of FOXL2 to several stress-response promoters, notably that of the mitochondrial manganese superoxide dismutase (<italic>MnSOD</italic>). Using several reporter systems, we show that FOXL2 transactivation is enhanced in this context. Models predict that gene upregulation in response to a signal should eventually be counterbalanced to restore the initial steady state. In line with this, we find that FOXL2 activity is repressed by the SIRT1 deacetylase. Interestingly, we demonstrate that SIRT1 transcription is, in turn, directly upregulated by FOXL2, which closes a negative-feedback loop. The regulatory relationship between FOXL2 and SIRT1 prompted us the test action of nicotinamide, an inhibitor of sirtuins, on FoxL2 expression/activity. According to our expectations, nicotinamide treatment increases FoxL2 transcription. Finally, we show that 11 disease-causing mutations in the ORF of <italic>FOXL2</italic> induce aberrant regulation of FOXL2 and/or regulation of the FOXL2 stress-response target gene <italic>MnSOD</italic>. Taken together, our results establish that FOXL2 is an actor of the stress response and provide new insights into the pathogenic consequences of <italic>FOXL2</italic> mutations.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations</title></titleInfo><name type="personal"><namePart type="given">Brnice A.</namePart><namePart type="family">Benayoun</namePart><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Universit Denis Diderot, Paris VII, 75013 Paris, France</affiliation><affiliation>cole Normale Suprieure, 75005 Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Frank</namePart><namePart type="family">Batista</namePart><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Universit Denis Diderot, Paris VII, 75013 Paris, France</affiliation><description>The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jana</namePart><namePart type="family">Auer</namePart><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><description>The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Aurlie</namePart><namePart type="family">Dipietromaria</namePart><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Paris-Sud, Paris XI, 91400 Orsay, France</affiliation><description>The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David</namePart><namePart type="family">L'Hte</namePart><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Unit de Gntique Molculaire Animale, INRA/Universit de Limoges, UMR 1061, Universit de Limoges, Limoges, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elfride</namePart><namePart type="family">De Baere</namePart><affiliation>Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Reiner A.</namePart><namePart type="family">Veitia</namePart><affiliation>INSERM U567, Team 21, Department of Genetics and Development</affiliation><affiliation>CNRS UMR8104, Institut Cochin, 75014 Paris, France</affiliation><affiliation>Facult de Mdecine Cochin-Port-Royal, Universit Paris Descartes, Paris 75014, France</affiliation><affiliation>Universit Denis Diderot, Paris VII, 75013 Paris, France</affiliation><affiliation>E-mail: reiner.veitia@inserm.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2009-02-15</dateIssued><dateCreated encoding="w3cdtf">2008-11-14</dateCreated><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>FOXL2 is a forkhead transcription factor, essential for ovarian function, whose mutations are responsible for the blepharophimosis syndrome, characterized by craniofacial defects, often associated with premature ovarian failure. Here, we show that cell stress upregulates FOXL2 expression in an ovarian granulosa cell model. Increased FOXL2 transcription might be mediated at least partly by self-activation. Moreover, using 2D-western blot, we show that the response of FOXL2 to stress correlates with a dramatic remodeling of its post-translational modification profile. Upon oxidative stress, we observe an increased recruitment of FOXL2 to several stress-response promoters, notably that of the mitochondrial manganese superoxide dismutase (MnSOD). Using several reporter systems, we show that FOXL2 transactivation is enhanced in this context. Models predict that gene upregulation in response to a signal should eventually be counterbalanced to restore the initial steady state. In line with this, we find that FOXL2 activity is repressed by the SIRT1 deacetylase. Interestingly, we demonstrate that SIRT1 transcription is, in turn, directly upregulated by FOXL2, which closes a negative-feedback loop. The regulatory relationship between FOXL2 and SIRT1 prompted us the test action of nicotinamide, an inhibitor of sirtuins, on FoxL2 expression/activity. According to our expectations, nicotinamide treatment increases FoxL2 transcription. Finally, we show that 11 disease-causing mutations in the ORF of FOXL2 induce aberrant regulation of FOXL2 and/or regulation of the FOXL2 stress-response target gene MnSOD. Taken together, our results establish that FOXL2 is an actor of the stress response and provide new insights into the pathogenic consequences of FOXL2 mutations.</abstract><note type="footnotes">The authors wish it to be known that, in their opinion, the second, third and fourth authors contributed equally to this work.</note><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>632</start><end>644</end></extent></part></relatedItem><identifier type="istex">8753D73676ADCA1F5BA91FBA5F642E9636EADA22</identifier><identifier type="DOI">10.1093/hmg/ddn389</identifier><identifier type="ArticleID">ddn389</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2008. 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