Overexpression of ErbB2 blocks taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase
Overexpression of ErbB2 blocks taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase
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DOI：
10.1016/s1097-2765(00)80157-4
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发表时间：
1998-11-01
期刊：
影响因子：
16
通讯作者：
Hung, MC
中科院分区：
文献类型：
--
作者：
Yu, DH;Tian, J;Hung, MC
受体酪氨酸激酶p185（ErbB 2）的过表达赋予乳腺癌紫杉醇耐药。在这里，我们研究了潜在的机制，发现过表达p185（ErbB 2）抑制紫杉醇诱导的细胞凋亡。紫杉醇激活MDA-MB-435乳腺癌细胞中的p34（Cdc 2）激酶，导致细胞周期停滞在G2/M期，随后发生凋亡。p34的化学抑制剂（Cdc 2）和p34的显性负突变体（Cdc 2）阻断了紫杉醇诱导的这些细胞的凋亡。通过转染在MDA-MB-435细胞中过表达p185（ErbB 2）可转录上调与p34（Cdc 2）相关的p21（Cip 1），抑制紫杉醇介导的p34（Cdc 2）活化，延迟细胞进入G2/M期，从而抑制紫杉醇诱导的凋亡。在p21（Cip 1）反义转染的MDA-MB-435细胞或p21（-/-）MEF细胞中，p185（ErbB 2）不能抑制Taxol诱导的凋亡。因此，p21（Cip 1）参与G2/M检查点的调节，该检查点有助于对p185（ErbB 2）过表达乳腺癌细胞中紫杉醇诱导的凋亡的抵抗。
Overexpression of the receptor tyrosine kinase p185(ErbB2) confers Taxol resistance in breast cancers. Here, we investigated the underlying mechanisms and found that overexpression of p185(ErbB2) inhibits Taxol-induced apoptosis. Taxol activates p34(Cdc2) 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 p34(Cdc2) and a dominant-negative mutant of p34(Cdc2) blocked Taxol-induced apoptosis in these cells. Overexpression of p185(ErbB2) in MDA-MB-435 cells by transfection transcriptionally upregulates p21(Cip1), which associates with p34(Cdc2), inhibits Taxol-mediated p34(Cdc2) activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21(Cip1) antisense-transfected MDA-MB-435 cells or in p21(-/-) MEF cells, p185(ErbB2) was unable to inhibit Taxol-induced apoptosis. Therefore, p21(Cip1) participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185(ErbB2)-overexpressing breast cancer cells.