TY - JOUR
T1 - Overexpression of ErbB2 blocks taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase
AU - Dihua, Yu
AU - Jing, Tong
AU - Liu, Bolin
AU - Yao, Jun
AU - Tan, Ming
AU - McDonnell, Timothy J.
AU - Hung, Mien Chie
N1 - Funding Information:
The authors thank Dr. Wafik S. El-Deiry for the GST-p21 Cip1 construct; Dr. Guillermina Lozano for p21 −/− MEF and wt MEF; Dr. Jeffrey W. Harper for pCMVcdk2-dn and pCMVcdk4-dn; Dr. William Klein, Dr. Daniel Carson, and Ms. Rebecca Grijalva for critical reading of the manuscript; Mr. Dantong Sun for technical assistance; and Ms. Karen Ramirez for flow cytometry analysis. This research was supported by Grants CA60488 from the National Institutes of Health (to D. Y.), DAMD17-98-1-8338 from the United States Army Medical Research and Materiel Command (USAMRMC) (to D. Y.), M. D. Anderson Breast Cancer Research Program Fund (to D. Y.), and predoctoral fellowships from USAMRMC (T. J. and M. T.) and from R. B. Hite foundation (J. Y.)
PY - 1998/11
Y1 - 1998/11
N2 - 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 p21Clp1, which associates with p34Cdc2, inhibits Taxol-mediated p34Cdc2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21Clp1 antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, p185ErbB2 was unable to inhibit Taxol-induced apoptosis. Therefore, p21Clp1 participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185ErbB2-overexpressing breast cancer cells.
AB - 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 p21Clp1, which associates with p34Cdc2, inhibits Taxol-mediated p34Cdc2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21Clp1 antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, p185ErbB2 was unable to inhibit Taxol-induced apoptosis. Therefore, p21Clp1 participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185ErbB2-overexpressing breast cancer cells.
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U2 - 10.1016/s1097-2765(00)80157-4
DO - 10.1016/s1097-2765(00)80157-4
M3 - Article
C2 - 9844631
AN - SCOPUS:0032214980
SN - 1097-2765
VL - 2
SP - 581
EP - 591
JO - Molecular cell
JF - Molecular cell
IS - 5
ER -