Cytokine Signal Transduction in P19 Embryonal Carcinoma Cells: Regulation of Stat3-Mediated Transactivation Occurs Independently of p21ras-Erk Signaling
Identifieur interne : 000680 ( Main/Corpus ); précédent : 000679; suivant : 000681Cytokine Signal Transduction in P19 Embryonal Carcinoma Cells: Regulation of Stat3-Mediated Transactivation Occurs Independently of p21ras-Erk Signaling
Auteurs : André A. F. L. Van Puijenbroek ; Paul T. Van Der Saag ; Paul J. CofferSource :
- Experimental Cell Research [ 0014-4827 ] ; 1999.
English descriptors
Abstract
Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are members of a subfamily of related cytokines that share gp130 as common signal-transducing receptor component. CNTF has recently been demonstrated to induce increased survival and neuronal differentiation of P19 embryonal carcinoma (EC) cells; however, the molecular mechanisms underlying these effects are still elusive. Here we report that CNTF and LIF, but not interleukin-6, activated signal transducers and activators of transcription (STAT)–reporter constructs in P19 EC cells. Supershift analysis revealed that the STAT-element binding complex contained the transcription factor Stat3. Binding of Stat3 was inhibited by protein tyrosine kinase inhibitors, but not by the broad serine/threonine protein kinase inhibitor, H7. However, H7 inhibited CNTF-induced Stat3 transactivation. Using a dominant-negative p21ras construct and a specific inhibitor of mitogen-activated protein kinase kinase (MEK; PD098059) we demonstrated that CNTF-induced Stat3 transactivation was independent of the p21ras-mitogen-activated protein kinase (MAPK) pathway, while CNTF-induced MAPK activation was p21ras- and MEK-dependent. Taken together, our results demonstrate the activation of the p21ras-MAPK and STAT signal transduction pathways in response to CNTF and LIF in P19 EC cells and reveal that there is no modulating crosstalk between these pathways. Furthermore, our data suggest that CNTF- and LIF-induced Stat3 activation in P19 EC cells involves an H7-sensitive p21ras/MAPK- and Ca2+-independent kinase.
Url:
DOI: 10.1006/excr.1999.4576
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Coffer</name><affiliation><mods:affiliation>Department of Pulmonary Diseases, G03.550, University Medical Centre, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Experimental Cell Research</title><title level="j" type="abbrev">YEXCR</title><idno type="ISSN">0014-4827</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999">1999</date><biblScope unit="volume">251</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="465">465</biblScope><biblScope unit="page" to="476">476</biblScope></imprint><idno type="ISSN">0014-4827</idno></series><idno type="istex">39BD9C563E3056308154826E5714E8580798A6E9</idno><idno type="DOI">10.1006/excr.1999.4576</idno><idno type="PII">S0014-4827(99)94576-7</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0014-4827</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>CNTF</term><term>ERK</term><term>LIF</term><term>P19</term><term>RAS</term><term>STAT</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are members of a subfamily of related cytokines that share gp130 as common signal-transducing receptor component. CNTF has recently been demonstrated to induce increased survival and neuronal differentiation of P19 embryonal carcinoma (EC) cells; however, the molecular mechanisms underlying these effects are still elusive. Here we report that CNTF and LIF, but not interleukin-6, activated signal transducers and activators of transcription (STAT)–reporter constructs in P19 EC cells. Supershift analysis revealed that the STAT-element binding complex contained the transcription factor Stat3. Binding of Stat3 was inhibited by protein tyrosine kinase inhibitors, but not by the broad serine/threonine protein kinase inhibitor, H7. However, H7 inhibited CNTF-induced Stat3 transactivation. Using a dominant-negative p21ras construct and a specific inhibitor of mitogen-activated protein kinase kinase (MEK; PD098059) we demonstrated that CNTF-induced Stat3 transactivation was independent of the p21ras-mitogen-activated protein kinase (MAPK) pathway, while CNTF-induced MAPK activation was p21ras- and MEK-dependent. Taken together, our results demonstrate the activation of the p21ras-MAPK and STAT signal transduction pathways in response to CNTF and LIF in P19 EC cells and reveal that there is no modulating crosstalk between these pathways. Furthermore, our data suggest that CNTF- and LIF-induced Stat3 activation in P19 EC cells involves an H7-sensitive p21ras/MAPK- and Ca2+-independent kinase.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>André A.F.L. van Puijenbroek</name><affiliations><json:string>Hubrecht Laboratory, The Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands</json:string></affiliations></json:item><json:item><name>Paul T. van der Saag</name><affiliations><json:string>Hubrecht Laboratory, The Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands</json:string></affiliations></json:item><json:item><name>Paul J. Coffer</name><affiliations><json:string>Department of Pulmonary Diseases, G03.550, University Medical Centre, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>P19</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>LIF</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CNTF</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>STAT</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ERK</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>RAS</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are members of a subfamily of related cytokines that share gp130 as common signal-transducing receptor component. CNTF has recently been demonstrated to induce increased survival and neuronal differentiation of P19 embryonal carcinoma (EC) cells; however, the molecular mechanisms underlying these effects are still elusive. Here we report that CNTF and LIF, but not interleukin-6, activated signal transducers and activators of transcription (STAT)–reporter constructs in P19 EC cells. Supershift analysis revealed that the STAT-element binding complex contained the transcription factor Stat3. Binding of Stat3 was inhibited by protein tyrosine kinase inhibitors, but not by the broad serine/threonine protein kinase inhibitor, H7. However, H7 inhibited CNTF-induced Stat3 transactivation. Using a dominant-negative p21ras construct and a specific inhibitor of mitogen-activated protein kinase kinase (MEK; PD098059) we demonstrated that CNTF-induced Stat3 transactivation was independent of the p21ras-mitogen-activated protein kinase (MAPK) pathway, while CNTF-induced MAPK activation was p21ras- and MEK-dependent. Taken together, our results demonstrate the activation of the p21ras-MAPK and STAT signal transduction pathways in response to CNTF and LIF in P19 EC cells and reveal that there is no modulating crosstalk between these pathways. 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CNTF has recently been demonstrated to induce increased survival and neuronal differentiation of P19 embryonal carcinoma (EC) cells; however, the molecular mechanisms underlying these effects are still elusive. Here we report that CNTF and LIF, but not interleukin-6, activated signal transducers and activators of transcription (STAT)–reporter constructs in P19 EC cells. Supershift analysis revealed that the STAT-element binding complex contained the transcription factor Stat3. Binding of Stat3 was inhibited by protein tyrosine kinase inhibitors, but not by the broad serine/threonine protein kinase inhibitor, H7. However, H7 inhibited CNTF-induced Stat3 transactivation. Using a dominant-negative p21ras construct and a specific inhibitor of mitogen-activated protein kinase kinase (MEK; PD098059) we demonstrated that CNTF-induced Stat3 transactivation was independent of the p21ras-mitogen-activated protein kinase (MAPK) pathway, while CNTF-induced MAPK activation was p21ras- and MEK-dependent. Taken together, our results demonstrate the activation of the p21ras-MAPK and STAT signal transduction pathways in response to CNTF and LIF in P19 EC cells and reveal that there is no modulating crosstalk between these pathways. Furthermore, our data suggest that CNTF- and LIF-induced Stat3 activation in P19 EC cells involves an H7-sensitive p21ras/MAPK- and Ca2+-independent kinase.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>P19</term></item><item><term>LIF</term></item><item><term>CNTF</term></item><item><term>STAT</term></item><item><term>ERK</term></item><item><term>RAS</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1999-04-21">Received</change><change when="1999-06-03">Modified</change><change when="1999">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/39BD9C563E3056308154826E5714E8580798A6E9/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: 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:docType><istex:document><converted-article version="4.5.2" docsubtype="fla" xml:lang="en"><item-info><jid>YEXCR</jid><aid>94576</aid><ce:pii>S0014-4827(99)94576-7</ce:pii><ce:doi>10.1006/excr.1999.4576</ce:doi><ce:copyright type="full-transfer" year="1999">Academic Press</ce:copyright></item-info><head><ce:dochead><ce:textfn>Regular Article</ce:textfn></ce:dochead><ce:title>Cytokine Signal Transduction in P19 Embryonal Carcinoma Cells: Regulation of Stat3-Mediated Transactivation Occurs Independently of p21ras-Erk Signaling</ce:title><ce:author-group><ce:author><ce:given-name>André A.F.L.</ce:given-name><ce:surname>van Puijenbroek</ce:surname><ce:cross-ref refid="A1"><ce:sup>a</ce:sup></ce:cross-ref><ce:cross-ref refid="FN1"><ce:sup>1</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Paul T.</ce:given-name><ce:surname>van der Saag</ce:surname><ce:cross-ref refid="A1"><ce:sup>a</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Paul J.</ce:given-name><ce:surname>Coffer</ce:surname><ce:cross-ref refid="A2"><ce:sup>b</ce:sup></ce:cross-ref><ce:cross-ref refid="FN2"><ce:sup>2</ce:sup></ce:cross-ref></ce:author><ce:affiliation id="A1"><ce:label>a</ce:label><ce:textfn>Hubrecht Laboratory, The Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands</ce:textfn></ce:affiliation><ce:affiliation id="A2"><ce:label>b</ce:label><ce:textfn>Department of Pulmonary Diseases, G03.550, University Medical Centre, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands</ce:textfn></ce:affiliation><ce:footnote id="FN1"><ce:label>1</ce:label><ce:note-para>Current address: Department of Adult Oncology, Dana-Faber Cancer Institute and Harvard Medical School, 244 Binney Street (SM852), Boston MA 02115.</ce:note-para></ce:footnote><ce:footnote id="FN2"><ce:label>2</ce:label><ce:note-para>To whom correspondence and reprint requests should be addressed. G03.550, Department of Pulmonary Diseases, University Medical Centre, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Fax: 31-30-2542155. E-mail: P.Coffer@hli.azu.nl.</ce:note-para></ce:footnote></ce:author-group><ce:date-received day="21" month="4" year="1999"></ce:date-received><ce:date-revised day="3" month="6" year="1999"></ce:date-revised><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are members of a subfamily of related cytokines that share gp130 as common signal-transducing receptor component. CNTF has recently been demonstrated to induce increased survival and neuronal differentiation of P19 embryonal carcinoma (EC) cells; however, the molecular mechanisms underlying these effects are still elusive. Here we report that CNTF and LIF, but not interleukin-6, activated signal transducers and activators of transcription (STAT)–reporter constructs in P19 EC cells. Supershift analysis revealed that the STAT-element binding complex contained the transcription factor Stat3. Binding of Stat3 was inhibited by protein tyrosine kinase inhibitors, but not by the broad serine/threonine protein kinase inhibitor, H7. However, H7 inhibited CNTF-induced Stat3 transactivation. Using a dominant-negative p21ras construct and a specific inhibitor of mitogen-activated protein kinase kinase (MEK; PD098059) we demonstrated that CNTF-induced Stat3 transactivation was independent of the p21ras-mitogen-activated protein kinase (MAPK) pathway, while CNTF-induced MAPK activation was p21ras- and MEK-dependent. Taken together, our results demonstrate the activation of the p21ras-MAPK and STAT signal transduction pathways in response to CNTF and LIF in P19 EC cells and reveal that there is no modulating crosstalk between these pathways. Furthermore, our data suggest that CNTF- and LIF-induced Stat3 activation in P19 EC cells involves an H7-sensitive p21ras/MAPK- and Ca<ce:sup>2+</ce:sup>-independent kinase.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>P19</ce:text></ce:keyword><ce:keyword><ce:text>LIF</ce:text></ce:keyword><ce:keyword><ce:text>CNTF</ce:text></ce:keyword><ce:keyword><ce:text>STAT</ce:text></ce:keyword><ce:keyword><ce:text>ERK</ce:text></ce:keyword><ce:keyword><ce:text>RAS</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Cytokine Signal Transduction in P19 Embryonal Carcinoma Cells: Regulation of Stat3-Mediated Transactivation Occurs Independently of p21ras-Erk Signaling</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Cytokine Signal Transduction in P19 Embryonal Carcinoma Cells: Regulation of Stat3-Mediated Transactivation Occurs Independently of p21ras-Erk Signaling</title></titleInfo><name type="personal"><namePart type="given">André A.F.L.</namePart><namePart type="family">van Puijenbroek</namePart><affiliation>Hubrecht Laboratory, The Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands</affiliation><description>Current address: Department of Adult Oncology, Dana-Faber Cancer Institute and Harvard Medical School, 244 Binney Street (SM852), Boston MA 02115.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul T.</namePart><namePart type="family">van der Saag</namePart><affiliation>Hubrecht Laboratory, The Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul J.</namePart><namePart type="family">Coffer</namePart><affiliation>Department of Pulmonary Diseases, G03.550, University Medical Centre, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands</affiliation><description>To whom correspondence and reprint requests should be addressed. G03.550, Department of Pulmonary Diseases, University Medical Centre, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Fax: 31-30-2542155. E-mail: P.Coffer@hli.azu.nl.</description><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">1999</dateIssued><dateCaptured encoding="w3cdtf">1999-04-21</dateCaptured><dateModified encoding="w3cdtf">1999-06-03</dateModified><copyrightDate encoding="w3cdtf">1999</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">Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are members of a subfamily of related cytokines that share gp130 as common signal-transducing receptor component. CNTF has recently been demonstrated to induce increased survival and neuronal differentiation of P19 embryonal carcinoma (EC) cells; however, the molecular mechanisms underlying these effects are still elusive. Here we report that CNTF and LIF, but not interleukin-6, activated signal transducers and activators of transcription (STAT)–reporter constructs in P19 EC cells. Supershift analysis revealed that the STAT-element binding complex contained the transcription factor Stat3. Binding of Stat3 was inhibited by protein tyrosine kinase inhibitors, but not by the broad serine/threonine protein kinase inhibitor, H7. However, H7 inhibited CNTF-induced Stat3 transactivation. Using a dominant-negative p21ras construct and a specific inhibitor of mitogen-activated protein kinase kinase (MEK; PD098059) we demonstrated that CNTF-induced Stat3 transactivation was independent of the p21ras-mitogen-activated protein kinase (MAPK) pathway, while CNTF-induced MAPK activation was p21ras- and MEK-dependent. Taken together, our results demonstrate the activation of the p21ras-MAPK and STAT signal transduction pathways in response to CNTF and LIF in P19 EC cells and reveal that there is no modulating crosstalk between these pathways. Furthermore, our data suggest that CNTF- and LIF-induced Stat3 activation in P19 EC cells involves an H7-sensitive p21ras/MAPK- and Ca2+-independent kinase.</abstract><note type="content">Section title: Regular Article</note><subject lang="en"><genre>Keywords</genre><topic>P19</topic><topic>LIF</topic><topic>CNTF</topic><topic>STAT</topic><topic>ERK</topic><topic>RAS</topic></subject><relatedItem type="host"><titleInfo><title>Experimental Cell Research</title></titleInfo><titleInfo type="abbreviated"><title>YEXCR</title></titleInfo><genre type="Journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">19990915</dateIssued></originInfo><identifier type="ISSN">0014-4827</identifier><identifier type="PII">S0014-4827(00)X0042-0</identifier><part><date>19990915</date><detail type="volume"><number>251</number><caption>vol.</caption></detail><detail type="issue"><number>2</number><caption>no.</caption></detail><extent unit="issue pages"><start>257</start><end>501</end></extent><extent unit="pages"><start>465</start><end>476</end></extent></part></relatedItem><identifier type="istex">39BD9C563E3056308154826E5714E8580798A6E9</identifier><identifier type="DOI">10.1006/excr.1999.4576</identifier><identifier type="PII">S0014-4827(99)94576-7</identifier><accessCondition type="use and reproduction" contentType="">© 1999Academic Press</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>Academic Press, ©1999</recordOrigin></recordInfo></mods></metadata><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/39BD9C563E3056308154826E5714E8580798A6E9/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">ONCOLOGY</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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