Abstract
ErbB2 overexpression confers resistance to taxol-induced apoptosis by inhibiting p34(Cdc2) activation. One mechanism is via ErbB2-mediated upregulation of p21(Cip1), which inhibits Cdc2. Here, we report that the inhibitory phosphorylation on Cdc2 tyrosine (Y)15 (Cdc2-Y15-p) is elevated in ErbB2-overexpressing breast cancer cells and primary tumors. ErbB2 binds to and colocalizes with cyclin B-Cdc2 complexes and phosphorylates Cdc2-Y15. The ErbB2 kinase domain is sufficient to directly phosphorylate Cdc2-Y15. Increased Cdc2-Y15-p in ErbB2-overexpressing cells corresponds with delayed M phase entry. Expressing a nonphosphorylatable mutant of Cdc2 renders cells more sensitive to taxol-induced apoptosis. Thus, ErbB2 membrane RTK can confer resistance to taxol-induced apoptosis by directly phosphorylating Cdc2.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis*
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Breast / metabolism
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Breast / pathology
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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CDC2 Protein Kinase / metabolism*
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Cell Cycle Proteins / metabolism
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Cells, Cultured
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Cyclin B / metabolism
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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DNA Fragmentation
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Drug Resistance, Neoplasm
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Female
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Humans
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In Situ Nick-End Labeling
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Mitosis
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Paclitaxel / pharmacology*
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Phosphorylation
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Receptor, ErbB-2 / metabolism*
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Tumor Cells, Cultured
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Tyrosine / metabolism*
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cdc25 Phosphatases / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin B
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Tyrosine
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Receptor, ErbB-2
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CDC2 Protein Kinase
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CDC25C protein, human
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cdc25 Phosphatases
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Paclitaxel