Regulation of mitosis and taxane response by Daxx and Rassf1

Oncogene. 2012 Jan 5;31(1):13-26. doi: 10.1038/onc.2011.211. Epub 2011 Jun 6.

Abstract

Current theories suggest that mitotic checkpoint proteins are essential for proper cellular response to taxanes, a widely used family of chemotherapeutic compounds. We recently showed that absence or depletion of protein Daxx increases cellular taxol (paclitaxel) resistance-a common trait of patients diagnosed with several malignancies, including breast cancer. Further investigation of Daxx-mediated taxol response revealed that Daxx is important for the proper timing of mitosis progression and cyclin B stability. Daxx interacts with mitotic checkpoint protein RAS-association domain family protein 1 (Rassf1) and partially colocalizes with this protein during mitosis. Rassf1/Daxx depletion or expression of Daxx-binding domain of Rassf1 elevates cyclin B stability and increases taxol resistance in cells and mouse xenograft models. In breast cancer patients, we observed the inverse correlation between Daxx and clinical response to taxane-based chemotherapy. These data suggest that Daxx and Rassf1 define a mitotic stress checkpoint that enables cells to exit mitosis as micronucleated cells (and eventually die) when encountered with specific mitotic stress stimuli, including taxol. Surprisingly, depletion of Daxx or Rassf1 does not change the activity of E3 ubiquitin ligase anaphase promotion complex/C in in vitro settings, suggesting the necessity of mitotic cellular environment for proper activation of this checkpoint. Daxx and Rassf1 may become useful predictive markers for the proper selection of patients for taxane chemotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Anaphase
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Breast Neoplasms / drug therapy
  • Cell Cycle
  • Cell Line, Tumor
  • Co-Repressor Proteins
  • Cyclin B1 / analysis
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Mice
  • Mitosis / drug effects*
  • Molecular Chaperones
  • Nuclear Proteins / physiology*
  • Paclitaxel / pharmacology*
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Phytogenic
  • Co-Repressor Proteins
  • Cyclin B1
  • DAXX protein, human
  • Molecular Chaperones
  • Nuclear Proteins
  • RASSF1 protein, human
  • Tumor Suppressor Proteins
  • Paclitaxel