Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase
Overexpression of the receptor tyrosine kinase p185ErbB2 confers Taxol resistance in breast cancers. Here, we investigated the underlying mechanisms and found that overexpression of p185ErbB2 inhibits Taxol-induced apoptosis. Taxol activates p34Cdc2 kinase in MDA-MB-435 breast cancer cells, leading...
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| Veröffentlicht in: | Molecular cell 1998-11, Vol.2 (5), p.581-591 |
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| creator | Yu, D Jing, T Liu, B Yao, J Tan, M McDonnell, T J Hung, M C |
| description | Overexpression of the receptor tyrosine kinase p185ErbB2 confers Taxol resistance in breast cancers. Here, we investigated the underlying mechanisms and found that overexpression of p185ErbB2 inhibits Taxol-induced apoptosis. Taxol activates p34Cdc2 kinase in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of p34Cdc2 and a dominant-negative mutant of p34Cdc2 blocked Taxol-induced apoptosis in these cells. Overexpression of p185ErbB2 in MDA-MB-435 cells by transfection transcriptionally upregulates p21Cip1, which associates with p34Cdc2, inhibits Taxol-mediated p34Cdc2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21Cip1 antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, p185ErbB2 was unable to inhibit Taxol-induced apoptosis. Therefore, p21Cip1 participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185ErbB2-overexpressing breast cancer cells. |
| doi_str_mv | 10.1016/s1097-2765(00)80157-4 |
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Here, we investigated the underlying mechanisms and found that overexpression of p185ErbB2 inhibits Taxol-induced apoptosis. Taxol activates p34Cdc2 kinase in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of p34Cdc2 and a dominant-negative mutant of p34Cdc2 blocked Taxol-induced apoptosis in these cells. Overexpression of p185ErbB2 in MDA-MB-435 cells by transfection transcriptionally upregulates p21Cip1, which associates with p34Cdc2, inhibits Taxol-mediated p34Cdc2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21Cip1 antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, p185ErbB2 was unable to inhibit Taxol-induced apoptosis. Therefore, p21Cip1 participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185ErbB2-overexpressing breast cancer cells.</description><identifier>ISSN: 1097-2765</identifier><identifier>DOI: 10.1016/s1097-2765(00)80157-4</identifier><identifier>PMID: 9844631</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Apoptosis - drug effects ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; CDC2 Protein Kinase - antagonists & inhibitors ; CDC2 Protein Kinase - genetics ; CDC2 Protein Kinase - metabolism ; CDC2-CDC28 Kinases ; Cell Line ; Cyclin B - metabolism ; Cyclin B1 ; Cyclin-Dependent Kinase 2 ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclin-Dependent Kinases - genetics ; Cyclin-Dependent Kinases - metabolism ; Cyclins - genetics ; Cyclins - metabolism ; DNA Fragmentation ; Fibroblasts ; Flow Cytometry ; Humans ; Kinetin ; Mice ; Oligonucleotides, Antisense - genetics ; Paclitaxel - pharmacology ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Purines - pharmacology ; Receptor, ErbB-2 - genetics ; Receptor, ErbB-2 - metabolism ; Transfection ; Tumor Cells, Cultured ; Up-Regulation - genetics</subject><ispartof>Molecular cell, 1998-11, Vol.2 (5), p.581-591</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3164-228d4a7866b59b21e4404cd4c0e99b28d4d234021bc7219932b955d96acc2e7a3</citedby><cites>FETCH-LOGICAL-c3164-228d4a7866b59b21e4404cd4c0e99b28d4d234021bc7219932b955d96acc2e7a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9844631$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, D</creatorcontrib><creatorcontrib>Jing, T</creatorcontrib><creatorcontrib>Liu, B</creatorcontrib><creatorcontrib>Yao, J</creatorcontrib><creatorcontrib>Tan, M</creatorcontrib><creatorcontrib>McDonnell, T J</creatorcontrib><creatorcontrib>Hung, M C</creatorcontrib><title>Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>Overexpression of the receptor tyrosine kinase p185ErbB2 confers Taxol resistance in breast cancers. Here, we investigated the underlying mechanisms and found that overexpression of p185ErbB2 inhibits Taxol-induced apoptosis. Taxol activates p34Cdc2 kinase in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of p34Cdc2 and a dominant-negative mutant of p34Cdc2 blocked Taxol-induced apoptosis in these cells. Overexpression of p185ErbB2 in MDA-MB-435 cells by transfection transcriptionally upregulates p21Cip1, which associates with p34Cdc2, inhibits Taxol-mediated p34Cdc2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21Cip1 antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, p185ErbB2 was unable to inhibit Taxol-induced apoptosis. Therefore, p21Cip1 participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185ErbB2-overexpressing breast cancer cells.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>CDC2 Protein Kinase - antagonists & inhibitors</subject><subject>CDC2 Protein Kinase - genetics</subject><subject>CDC2 Protein Kinase - metabolism</subject><subject>CDC2-CDC28 Kinases</subject><subject>Cell Line</subject><subject>Cyclin B - metabolism</subject><subject>Cyclin B1</subject><subject>Cyclin-Dependent Kinase 2</subject><subject>Cyclin-Dependent Kinase Inhibitor p21</subject><subject>Cyclin-Dependent Kinases - genetics</subject><subject>Cyclin-Dependent Kinases - metabolism</subject><subject>Cyclins - genetics</subject><subject>Cyclins - metabolism</subject><subject>DNA Fragmentation</subject><subject>Fibroblasts</subject><subject>Flow Cytometry</subject><subject>Humans</subject><subject>Kinetin</subject><subject>Mice</subject><subject>Oligonucleotides, Antisense - genetics</subject><subject>Paclitaxel - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Purines - pharmacology</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>Transfection</subject><subject>Tumor Cells, Cultured</subject><subject>Up-Regulation - genetics</subject><issn>1097-2765</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtOwzAQRb0AlVL4hEpeIZAI2I7z8BKi8pAqdUFZW36VmqaxsRNo_54Uoq5GM3PPjHQAmGJ0hxHO7yNGrEhIkWfXCN2UCGdFQk_A-Dg-A-cxfiKEaVayERixktI8xWPgF98mmJ0PJkbrGuhWcBbkI4GydmoT4VLsXJ3YRnfKaCi8862LNkK5h10PfXS1aAfOE1xZj2_hz9qqNbTN2krbRuhTWmlF4MY2IpoLcLoSdTSXQ52A96fZsnpJ5ovn1-phnqgU5zQhpNRUFGWey4xJgg2liCpNFTKs7_ulJilFBEtVEMxYSiTLMs1yoRQxhUgn4Or_rg_uqzOx5Vsblalr0RjXRV4gjCguyz6Y_QdVcDEGs-I-2K0Ie44RP9jlbweN_KCRI8T_7HLac9PhQSe3Rh-pQW36C9nVdw8</recordid><startdate>199811</startdate><enddate>199811</enddate><creator>Yu, D</creator><creator>Jing, T</creator><creator>Liu, B</creator><creator>Yao, J</creator><creator>Tan, M</creator><creator>McDonnell, T J</creator><creator>Hung, M C</creator><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>7X8</scope></search><sort><creationdate>199811</creationdate><title>Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase</title><author>Yu, D ; Jing, T ; Liu, B ; Yao, J ; Tan, M ; McDonnell, T J ; Hung, M C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3164-228d4a7866b59b21e4404cd4c0e99b28d4d234021bc7219932b955d96acc2e7a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>CDC2 Protein Kinase - antagonists & inhibitors</topic><topic>CDC2 Protein Kinase - genetics</topic><topic>CDC2 Protein Kinase - metabolism</topic><topic>CDC2-CDC28 Kinases</topic><topic>Cell Line</topic><topic>Cyclin B - metabolism</topic><topic>Cyclin B1</topic><topic>Cyclin-Dependent Kinase 2</topic><topic>Cyclin-Dependent Kinase Inhibitor p21</topic><topic>Cyclin-Dependent Kinases - genetics</topic><topic>Cyclin-Dependent Kinases - metabolism</topic><topic>Cyclins - genetics</topic><topic>Cyclins - metabolism</topic><topic>DNA Fragmentation</topic><topic>Fibroblasts</topic><topic>Flow Cytometry</topic><topic>Humans</topic><topic>Kinetin</topic><topic>Mice</topic><topic>Oligonucleotides, Antisense - genetics</topic><topic>Paclitaxel - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Purines - pharmacology</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>Receptor, ErbB-2 - metabolism</topic><topic>Transfection</topic><topic>Tumor Cells, Cultured</topic><topic>Up-Regulation - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, D</creatorcontrib><creatorcontrib>Jing, T</creatorcontrib><creatorcontrib>Liu, B</creatorcontrib><creatorcontrib>Yao, J</creatorcontrib><creatorcontrib>Tan, M</creatorcontrib><creatorcontrib>McDonnell, T J</creatorcontrib><creatorcontrib>Hung, M C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, D</au><au>Jing, T</au><au>Liu, B</au><au>Yao, J</au><au>Tan, M</au><au>McDonnell, T J</au><au>Hung, M C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>1998-11</date><risdate>1998</risdate><volume>2</volume><issue>5</issue><spage>581</spage><epage>591</epage><pages>581-591</pages><issn>1097-2765</issn><abstract>Overexpression of the receptor tyrosine kinase p185ErbB2 confers Taxol resistance in breast cancers. Here, we investigated the underlying mechanisms and found that overexpression of p185ErbB2 inhibits Taxol-induced apoptosis. Taxol activates p34Cdc2 kinase in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of p34Cdc2 and a dominant-negative mutant of p34Cdc2 blocked Taxol-induced apoptosis in these cells. Overexpression of p185ErbB2 in MDA-MB-435 cells by transfection transcriptionally upregulates p21Cip1, which associates with p34Cdc2, inhibits Taxol-mediated p34Cdc2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21Cip1 antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, p185ErbB2 was unable to inhibit Taxol-induced apoptosis. Therefore, p21Cip1 participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185ErbB2-overexpressing breast cancer cells.</abstract><cop>United States</cop><pmid>9844631</pmid><doi>10.1016/s1097-2765(00)80157-4</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis - drug effects Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology CDC2 Protein Kinase - antagonists & inhibitors CDC2 Protein Kinase - genetics CDC2 Protein Kinase - metabolism CDC2-CDC28 Kinases Cell Line Cyclin B - metabolism Cyclin B1 Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinases - genetics Cyclin-Dependent Kinases - metabolism Cyclins - genetics Cyclins - metabolism DNA Fragmentation Fibroblasts Flow Cytometry Humans Kinetin Mice Oligonucleotides, Antisense - genetics Paclitaxel - pharmacology Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Purines - pharmacology Receptor, ErbB-2 - genetics Receptor, ErbB-2 - metabolism Transfection Tumor Cells, Cultured Up-Regulation - genetics |
| title | Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase |
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