Transcriptional upregulation and activation of p55Cdc via p34(cdc2) in Taxol-induced apoptosis

Oncogene. 2001 May 3;20(20):2537-43. doi: 10.1038/sj.onc.1204366.

Abstract

Paclitaxel (Taxol) is a potent and highly effective antineoplastic agent for the treatment of advanced, drug-refractory, metastatic breast cancers. Taxol not only induces tubulin polymerization, stabilizes microtubules, blocks cell cycle progression, and induces apoptosis, but it also alters gene expression. Here, we have identified that Taxol can upregulate expression of the gene encoding the cell cycle protein p55Cdc by using cDNA array technique. Taxol induced p55Cdc mRNA expression through activation of the p55Cdc promoter, which led to increase p55Cdc protein expression. Taxol also activated p55Cdc-associated kinase. In addition, overexpression of the p55Cdc gene resulted in cell death in both HeLa cells and NIH3T3 cells in a dose-dependent manner. A dominant-negative mutant of p34(cdc2) blocked Taxol-induced p55Cdc activation and inhibited p55Cdc-induced and Taxol-induced cell death. Our data suggest that transcriptional upregulation of p55Cdc and activation of p55Cdc by Taxol-mediated p34(cdc2) activation play a critical role in Taxol-induced cell death.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • CDC2 Protein Kinase / antagonists & inhibitors
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • CDC2 Protein Kinase / physiology*
  • Cdc20 Proteins
  • Cell Cycle Proteins*
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • HeLa Cells
  • Humans
  • Mice
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Paclitaxel / pharmacology*
  • Protein Biosynthesis
  • Proteins / genetics
  • Proteins / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects
  • Up-Regulation / physiology

Substances

  • Antineoplastic Agents, Phytogenic
  • Cdc20 Proteins
  • Cdc20 protein, mouse
  • Cell Cycle Proteins
  • Proteins
  • RNA, Messenger
  • CDC20 protein, human
  • CDC2 Protein Kinase
  • Paclitaxel