c‐Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin‐based therapy
Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c‐Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin....
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Veröffentlicht in: | International journal of cancer 2008-01, Vol.122 (2), p.289-297 |
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creator | Galan‐Moya, Eva M. Hernandez‐Losa, Javier Aceves Luquero, Clara I. de la Cruz‐Morcillo, Miguel A. Ramírez‐Castillejo, Carmen Callejas‐Valera, Juan L. Arriaga, Angel Aranburo, Antonio Fernandez Cajal, Santiago Ramón y Silvio Gutkind, J. Sánchez‐Prieto, Ricardo |
description | Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c‐Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c‐Abl. Indeed, c‐Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c‐Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia‐derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c‐Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c‐Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act. © 2007 Wiley‐Liss, Inc. |
doi_str_mv | 10.1002/ijc.23063 |
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In this sense, a growing body of evidences supports the role of c‐Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c‐Abl. Indeed, c‐Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c‐Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia‐derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c‐Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c‐Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act. © 2007 Wiley‐Liss, Inc.</description><identifier>ISSN: 0020-7136</identifier><identifier>EISSN: 1097-0215</identifier><identifier>DOI: 10.1002/ijc.23063</identifier><identifier>PMID: 17893873</identifier><identifier>CODEN: IJCNAW</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Benzamides ; Biological and medical sciences ; Cell Line, Tumor ; cisplatin ; Cisplatin - pharmacology ; Cycloheximide - pharmacology ; c‐Abl ; Gene Expression Regulation, Leukemic ; Gene Expression Regulation, Neoplastic ; General aspects ; Humans ; Imatinib Mesylate ; MAP Kinase Kinase 6 - metabolism ; MAP Kinase Signaling System ; Medical sciences ; MKK6 ; Models, Biological ; p38 MAPK ; p38 Mitogen-Activated Protein Kinases - metabolism ; Pharmacology. 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In this sense, a growing body of evidences supports the role of c‐Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c‐Abl. Indeed, c‐Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c‐Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia‐derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c‐Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c‐Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act. © 2007 Wiley‐Liss, Inc.</description><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Benzamides</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>cisplatin</subject><subject>Cisplatin - pharmacology</subject><subject>Cycloheximide - pharmacology</subject><subject>c‐Abl</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>General aspects</subject><subject>Humans</subject><subject>Imatinib Mesylate</subject><subject>MAP Kinase Kinase 6 - metabolism</subject><subject>MAP Kinase Signaling System</subject><subject>Medical sciences</subject><subject>MKK6</subject><subject>Models, Biological</subject><subject>p38 MAPK</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - pharmacology</subject><subject>Protein Synthesis Inhibitors - pharmacology</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-abl - metabolism</subject><subject>Pyrimidines - pharmacology</subject><subject>Tumors</subject><issn>0020-7136</issn><issn>1097-0215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFO3DAQhq2qqCy0h74A8qWVegiM7SS2ua1WLSxQtYf2HDneiTD1JmnsBeXGI_CMPAleshInxGWskb-Zf_T_hHxmcMwA-Im7scdcQCnekRkDLTPgrHhPZukPMslEuU8OQrgBYKyA_APZZ1JpoaSYkWAf7x_mtafGRndrIgbaC0V_zn9fUteusMdU2uhH2jXUxUDjOHTBtUj_udYEnOZcHE_pct17Z010XRvSLLUu9D61bVKoE7qi8RoH048fyV5jfMBPu_eQ_P3x_c_iPLv6dbZczK8ymzMtstwKySU0WpaoNBZlU-tSrXgjpSl1zutCaOC6QcaVxVyVmHPQRtUg6pyXXBySr9Pefuj-bzDEau2CRe9Ni90mVBJAMZXDmyCHggODIoHfJtAmE8KATdUPbm2GsWJQbaOoUhTVcxSJPdot3dRrXL2QO-8T8GUHmGCNbwbTJsteOK23mtvrTibuznkcX1eslheLSfoJhEqgyQ</recordid><startdate>20080115</startdate><enddate>20080115</enddate><creator>Galan‐Moya, Eva M.</creator><creator>Hernandez‐Losa, Javier</creator><creator>Aceves Luquero, Clara I.</creator><creator>de la Cruz‐Morcillo, Miguel A.</creator><creator>Ramírez‐Castillejo, Carmen</creator><creator>Callejas‐Valera, Juan L.</creator><creator>Arriaga, Angel</creator><creator>Aranburo, Antonio Fernandez</creator><creator>Cajal, Santiago Ramón y</creator><creator>Silvio Gutkind, J.</creator><creator>Sánchez‐Prieto, Ricardo</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley-Liss</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20080115</creationdate><title>c‐Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin‐based therapy</title><author>Galan‐Moya, Eva M. ; Hernandez‐Losa, Javier ; Aceves Luquero, Clara I. ; de la Cruz‐Morcillo, Miguel A. ; Ramírez‐Castillejo, Carmen ; Callejas‐Valera, Juan L. ; Arriaga, Angel ; Aranburo, Antonio Fernandez ; Cajal, Santiago Ramón y ; Silvio Gutkind, J. ; Sánchez‐Prieto, Ricardo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4193-4c37270f976e89e56fb968d2f77a6942b539029fe128ce486e4209a8b03b42623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Benzamides</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>cisplatin</topic><topic>Cisplatin - pharmacology</topic><topic>Cycloheximide - pharmacology</topic><topic>c‐Abl</topic><topic>Gene Expression Regulation, Leukemic</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>General aspects</topic><topic>Humans</topic><topic>Imatinib Mesylate</topic><topic>MAP Kinase Kinase 6 - metabolism</topic><topic>MAP Kinase Signaling System</topic><topic>Medical sciences</topic><topic>MKK6</topic><topic>Models, Biological</topic><topic>p38 MAPK</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - pharmacology</topic><topic>Protein Synthesis Inhibitors - pharmacology</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-abl - metabolism</topic><topic>Pyrimidines - pharmacology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Galan‐Moya, Eva M.</creatorcontrib><creatorcontrib>Hernandez‐Losa, Javier</creatorcontrib><creatorcontrib>Aceves Luquero, Clara I.</creatorcontrib><creatorcontrib>de la Cruz‐Morcillo, Miguel A.</creatorcontrib><creatorcontrib>Ramírez‐Castillejo, Carmen</creatorcontrib><creatorcontrib>Callejas‐Valera, Juan L.</creatorcontrib><creatorcontrib>Arriaga, Angel</creatorcontrib><creatorcontrib>Aranburo, Antonio Fernandez</creatorcontrib><creatorcontrib>Cajal, Santiago Ramón y</creatorcontrib><creatorcontrib>Silvio Gutkind, J.</creatorcontrib><creatorcontrib>Sánchez‐Prieto, Ricardo</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Galan‐Moya, Eva M.</au><au>Hernandez‐Losa, Javier</au><au>Aceves Luquero, Clara I.</au><au>de la Cruz‐Morcillo, Miguel A.</au><au>Ramírez‐Castillejo, Carmen</au><au>Callejas‐Valera, Juan L.</au><au>Arriaga, Angel</au><au>Aranburo, Antonio Fernandez</au><au>Cajal, Santiago Ramón y</au><au>Silvio Gutkind, J.</au><au>Sánchez‐Prieto, Ricardo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>c‐Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin‐based therapy</atitle><jtitle>International journal of cancer</jtitle><addtitle>Int J Cancer</addtitle><date>2008-01-15</date><risdate>2008</risdate><volume>122</volume><issue>2</issue><spage>289</spage><epage>297</epage><pages>289-297</pages><issn>0020-7136</issn><eissn>1097-0215</eissn><coden>IJCNAW</coden><abstract>Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c‐Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c‐Abl. Indeed, c‐Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c‐Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia‐derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c‐Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c‐Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act. © 2007 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>17893873</pmid><doi>10.1002/ijc.23063</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Antineoplastic agents Antineoplastic Agents - pharmacology Benzamides Biological and medical sciences Cell Line, Tumor cisplatin Cisplatin - pharmacology Cycloheximide - pharmacology c‐Abl Gene Expression Regulation, Leukemic Gene Expression Regulation, Neoplastic General aspects Humans Imatinib Mesylate MAP Kinase Kinase 6 - metabolism MAP Kinase Signaling System Medical sciences MKK6 Models, Biological p38 MAPK p38 Mitogen-Activated Protein Kinases - metabolism Pharmacology. Drug treatments Piperazines - pharmacology Protein Synthesis Inhibitors - pharmacology Protein-Tyrosine Kinases - metabolism Proto-Oncogene Proteins c-abl - metabolism Pyrimidines - pharmacology Tumors |
title | c‐Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin‐based therapy |
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