Aurora-A and ch-TOG act in a common pathway in control of spindle pole integrity

Oncogene. 2008 Nov 20;27(51):6539-49. doi: 10.1038/onc.2008.252. Epub 2008 Jul 28.

Abstract

Mitotic spindle assembly is a highly regulated process, crucial to ensure the correct segregation of duplicated chromosomes in daughter cells and to avoid aneuploidy, a common feature of tumors. Among the most important spindle regulators is Aurora-A, a mitotic centrosomal kinase frequently overexpressed in tumors. Here, we investigated the role of Aurora-A in spindle pole organization in human cells. We show that RNA interference-mediated Aurora-A inactivation causes pericentriolar material fragmentation in prometaphase, yielding the formation of spindles with supernumerary poles. This fragmentation does not necessarily involve centrioles and requires microtubules (MTs). Aurora-A-depleted prometaphases mislocalize the MT-stabilizing protein colonic hepatic tumor-overexpressed gene (ch-TOG), which abnormally accumulates at spindle poles, as well as the mitotic centromere-associated kinesin (MCAK), the major functional antagonist of ch-TOG, which delocalizes from poles. ch-TOG is required for extrapole formation in prometaphases lacking Aurora-A, because co-depletion of Aurora-A and ch-TOG mitigates the fragmented pole phenotype. These results indicate a novel function of Aurora-A, the regulation of ch-TOG and MCAK localization, and highlight a common pathway involving the three factors in control of spindle pole integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinases
  • Humans
  • Kinesin / metabolism
  • Metaphase / drug effects
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / physiology*
  • Mitosis / drug effects
  • Models, Biological
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA, Small Interfering / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / metabolism*
  • Spindle Apparatus / physiology
  • Tissue Distribution
  • Tumor Cells, Cultured

Substances

  • CKAP5 protein, human
  • KIF2C protein, human
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Kinesin