Taxol-induced p34(cdc2) kinase activation and apoptosis inhibited by 12- O-Tetradecanoylphorbol-13-acetate in human breast MCF-7 carcinoma cells

Shing Chuan Shen, Tze Sing Huang, Shiou Hwa Jee, Min Lang Kuo

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96 引文 斯高帕斯(Scopus)

摘要

The p34(cdc2) kinase is a highly regulated serine-threonine kinase that, when complexed with cyclins A and B, controls cell entry into mitosis. Recently, premature activation of p34(cdc2) was shown to be required for apoptosis induced by a wide variety of agents. Here, we show that Taxol induced p34(cdc2) kinase activity with a peak at 6 h in human breast carcinoma MCF-7 cells. We subsequently observed that the activation of CPP32/Yama protease as well as the cleavage of its substrate poly(ADP- ribose) polymerase occurred 9 h after Taxol treatment. Olomoucine, a potent p34(cdc2) inhibitor, effectively prevented Taxol-induced p34(cdc2) kinase activation and subsequent apoptosis. Furthermore, the treatment of cells with cyclin B1-specific antisense oligonucleotide also blocked Taxol-induced apoptosis, suggesting that cyclin B1-associated p34c(cdc2) kinase plays an important role in the induction of apoptosis by Taxol. 12-O- Tetradecanoylphorbol-13-acetate (TPA), a protein kinase C activator, was found to exert strong protection against Taxol-induced cell death in MCF-7 cells. TPA inhibited Taxol-mediated activation of p34(cdc2) kinase by preventing the dephosphorylation of the Tyr-15 residue on p34(cdc2) without altering the levels of Cdc2 and cyclin B1. In contrast, the ability of Taxol to enhance tubulin polymerization was not Inhibited by TPA. These findings suggest that modulation of protein kinase C signaling can protect against Taxol-induced cell death by inhibiting p34(cdc2) kinase activation.

原文英語
頁(從 - 到)23-29
頁數7
期刊Cell Growth and Differentiation
9
發行號1
出版狀態已發佈 - 1998

ASJC Scopus subject areas

  • 分子生物學
  • 細胞生物學

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