title: Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase.
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.
authors.affiliation: Department of Surgical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yu
authors.forename: T
authors.initials: T
authors.lastname: Jing
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.forename: M
authors.initials: M
authors.lastname: Tan
authors.forename: T J
authors.initials: TJ
authors.lastname: McDonnell
authors.forename: M C
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases; D002460:Cell Line; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D053938:DNA Fragmentation; D005347:Fibroblasts; D005434:Flow Cytometry; D006801:Humans; D007701:Kinetin; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D019926:Cyclin B; D056744:Cyclin B1; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases; D016213:Cyclins; D007701:Kinetin; D016376:Oligonucleotides, Antisense; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; C534700:Ccnb1 protein, mouse; C493957:Cdkn1a protein, mouse; C090046:olomoucine; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse