ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia
Identifieur interne : 001D55 ( Istex/Corpus ); précédent : 001D54; suivant : 001D56ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia
Auteurs : Luke R. G. Pike ; Kanchan Phadwal ; Anna Katharina Simon ; Adrian L. HarrisSource :
- Molecular Biology Reports [ 0301-4851 ] ; 2012-12-01.
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Abstract
Abstract: Intratumoral hypoxia is associated with poor prognosis, regardless of the mode of therapy. Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia.
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DOI: 10.1007/s11033-012-1975-3
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Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. 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Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. 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Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>ATF4</term></item><item><term>Unfolded protein response</term></item><item><term>BH3-only protein</term></item><item><term>Harakiri</term></item><item><term>HRK</term></item><item><term>Hypoxia</term></item><item><term>Integrated stress response</term></item></list></keywords></textClass><textClass><keywords scheme="Journal-Subject-Collection"><list><label>Biomedical and Life Sciences</label><item><term>SC3</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>Life Sciences</head><item><term>Animal Biochemistry</term></item><item><term>Animal Anatomy / Morphology / Histology</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2012-07-24">Created</change><change 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hypoxia</ArticleTitle><ArticleFirstPage>10811</ArticleFirstPage><ArticleLastPage>10822</ArticleLastPage><ArticleHistory><RegistrationDate><Year>2012</Year><Month>10</Month><Day>1</Day></RegistrationDate><Received><Year>2012</Year><Month>7</Month><Day>24</Day></Received><Accepted><Year>2012</Year><Month>10</Month><Day>1</Day></Accepted><OnlineDate><Year>2012</Year><Month>10</Month><Day>23</Day></OnlineDate></ArticleHistory><ArticleCopyright><CopyrightHolderName>Springer Science+Business Media Dordrecht</CopyrightHolderName><CopyrightYear>2012</CopyrightYear></ArticleCopyright><ArticleGrants Type="Regular"><MetadataGrant Grant="OpenAccess"></MetadataGrant><AbstractGrant Grant="OpenAccess"></AbstractGrant><BodyPDFGrant Grant="Restricted"></BodyPDFGrant><BodyHTMLGrant Grant="Restricted"></BodyHTMLGrant><BibliographyGrant Grant="Restricted"></BibliographyGrant><ESMGrant Grant="Restricted"></ESMGrant></ArticleGrants></ArticleInfo><ArticleHeader><AuthorGroup><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Luke</GivenName><GivenName>R.</GivenName><GivenName>G.</GivenName><FamilyName>Pike</FamilyName></AuthorName><Contact><Email>lrgpike@gmail.com</Email></Contact></Author><Author AffiliationIDS="Aff2 Aff3"><AuthorName DisplayOrder="Western"><GivenName>Kanchan</GivenName><FamilyName>Phadwal</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff2 Aff3"><AuthorName DisplayOrder="Western"><GivenName>Anna</GivenName><GivenName>Katharina</GivenName><FamilyName>Simon</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1" CorrespondingAffiliationID="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Adrian</GivenName><GivenName>L.</GivenName><FamilyName>Harris</FamilyName></AuthorName><Contact><Phone>+44-1865-222457</Phone><Fax>+44-1865-222431</Fax><Email>aharris.lab@imm.ox.ac.uk</Email></Contact></Author><Affiliation ID="Aff1"><OrgDivision>Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories</OrgDivision><OrgName>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford</OrgName><OrgAddress><Street>Headington</Street><City>Oxford</City><Postcode>OX3 9DS</Postcode><Country Code="GB">UK</Country></OrgAddress></Affiliation><Affiliation ID="Aff2"><OrgDivision>Nuffield Department of Medicine</OrgDivision><OrgName>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital</OrgName><OrgAddress><City>Oxford</City><Country Code="GB">UK</Country></OrgAddress></Affiliation><Affiliation ID="Aff3"><OrgName>BRC Translational Immunology BRC lab, NIHR</OrgName><OrgAddress><City>Oxford</City><Country Code="GB">UK</Country></OrgAddress></Affiliation></AuthorGroup><Abstract ID="Abs1" Language="En" OutputMedium="All"><Heading>Abstract</Heading><Para>Intratumoral hypoxia is associated with poor prognosis, regardless of the mode of therapy. Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia.</Para></Abstract><KeywordGroup Language="En" OutputMedium="All"><Heading>Keywords</Heading><Keyword>ATF4</Keyword><Keyword>Unfolded protein response</Keyword><Keyword>BH3-only protein</Keyword><Keyword>Harakiri</Keyword><Keyword>HRK</Keyword><Keyword>Hypoxia</Keyword><Keyword>Integrated stress response</Keyword></KeywordGroup><ArticleNote Type="ESMHint"><Heading>Electronic supplementary material</Heading><SimplePara>The online version of this article (doi:<ExternalRef><RefSource>10.1007/s11033-012-1975-3</RefSource><RefTarget Address="10.1007/s11033-012-1975-3" TargetType="DOI"></RefTarget></ExternalRef>) contains supplementary material, which is available to authorized users.</SimplePara></ArticleNote></ArticleHeader><NoBody></NoBody></Article></Issue></Volume></Journal></Publisher></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia</title></titleInfo><name type="personal"><namePart type="given">Luke</namePart><namePart type="given">R.</namePart><namePart type="given">G.</namePart><namePart type="family">Pike</namePart><affiliation>Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, OX3 9DS, Oxford, UK</affiliation><affiliation>E-mail: lrgpike@gmail.com</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kanchan</namePart><namePart type="family">Phadwal</namePart><affiliation>Nuffield Department of Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK</affiliation><affiliation>BRC Translational Immunology BRC lab, NIHR, Oxford, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anna</namePart><namePart type="given">Katharina</namePart><namePart type="family">Simon</namePart><affiliation>Nuffield Department of Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK</affiliation><affiliation>BRC Translational Immunology BRC lab, NIHR, Oxford, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Adrian</namePart><namePart type="given">L.</namePart><namePart type="family">Harris</namePart><affiliation>Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, OX3 9DS, Oxford, UK</affiliation><affiliation>E-mail: aharris.lab@imm.ox.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="OriginalPaper" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>Springer Netherlands</publisher><place><placeTerm type="text">Dordrecht</placeTerm></place><dateCreated encoding="w3cdtf">2012-07-24</dateCreated><dateIssued encoding="w3cdtf">2012-12-01</dateIssued><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract lang="en">Abstract: Intratumoral hypoxia is associated with poor prognosis, regardless of the mode of therapy. Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia.</abstract><subject lang="en"><genre>Keywords</genre><topic>ATF4</topic><topic>Unfolded protein response</topic><topic>BH3-only protein</topic><topic>Harakiri</topic><topic>HRK</topic><topic>Hypoxia</topic><topic>Integrated stress response</topic></subject><relatedItem type="host"><titleInfo><title>Molecular Biology Reports</title><subTitle>An International Journal on Molecular and Cellular Biology</subTitle></titleInfo><titleInfo type="abbreviated"><title>Mol Biol Rep</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>Springer</publisher><dateIssued encoding="w3cdtf">2012-11-02</dateIssued><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><subject><genre>Journal-Subject-Collection</genre><topic authority="SpringerSubjectCodes" authorityURI="Biomedical and Life Sciences">SC3</topic></subject><subject><genre>Life Sciences</genre><topic>Animal Biochemistry</topic><topic>Animal Anatomy / Morphology / Histology</topic></subject><identifier type="ISSN">0301-4851</identifier><identifier type="eISSN">1573-4978</identifier><identifier type="JournalID">11033</identifier><identifier type="IssueArticleCount">148</identifier><identifier type="VolumeIssueCount">12</identifier><part><date>2012</date><detail type="volume"><number>39</number><caption>vol.</caption></detail><detail type="issue"><number>12</number><caption>no.</caption></detail><extent unit="pages"><start>10811</start><end>10822</end></extent></part><recordInfo><recordOrigin>Springer Science+Business Media Dordrecht, 2012</recordOrigin></recordInfo></relatedItem><identifier type="istex">947E42CAE9D5469915A897E6D11BD2B0014EC44D</identifier><identifier type="ark">ark:/67375/VQC-SJ2V1HW0-L</identifier><identifier type="DOI">10.1007/s11033-012-1975-3</identifier><identifier type="ArticleID">1975</identifier><identifier type="ArticleID">s11033-012-1975-3</identifier><accessCondition type="use and reproduction" contentType="copyright">Springer Science+Business Media Dordrecht, 2012</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-3XSW68JL-F">springer</recordContentSource><recordOrigin>Springer Science+Business Media Dordrecht, 2012</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/VQC-SJ2V1HW0-L/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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