A small-molecule inhibitor of Mps1 blocks the spindle-checkpoint response to a lack of tension on mitotic chromosomes

Curr Biol. 2005 Jun 7;15(11):1070-6. doi: 10.1016/j.cub.2005.05.020.

Abstract

The spindle checkpoint prevents chromosome loss by preventing chromosome segregation in cells with improperly attached chromosomes [1, 2 and 3]. The checkpoint senses defects in the attachment of chromosomes to the mitotic spindle [4] and the tension exerted on chromosomes by spindle forces in mitosis [5, 6 and 7]. Because many cancers have defects in chromosome segregation, this checkpoint may be required for survival of tumor cells and may be a target for chemotherapy. We performed a phenotype-based chemical-genetic screen in budding yeast and identified an inhibitor of the spindle checkpoint, called cincreasin. We used a genome-wide collection of yeast gene-deletion strains and traditional genetic and biochemical analysis to show that the target of cincreasin is Mps1, a protein kinase required for checkpoint function [8]. Despite the requirement for Mps1 for sensing both the lack of microtubule attachment and tension at kinetochores, we find concentrations of cincreasin that selectively inhibit the tension-sensitive branch of the spindle checkpoint. At these concentrations, cincreasin causes lethal chromosome missegregation in mutants that display chromosomal instability. Our results demonstrate that Mps1 can be exploited as a target and that inhibiting the tension-sensitive branch of the spindle checkpoint may be a way of selectively killing cancer cells that display chromosomal instability.

Publication types

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

MeSH terms

  • Bromobenzenes / chemical synthesis
  • Bromobenzenes / metabolism
  • Bromobenzenes / pharmacology*
  • Chromosome Segregation / drug effects*
  • Chromosome Segregation / physiology
  • DNA Primers
  • Dimethyl Sulfoxide
  • Dose-Response Relationship, Drug
  • Kinetochores / metabolism
  • Microarray Analysis
  • Microtubules / metabolism
  • Mitosis / physiology*
  • Phenotype
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Saccharomyces cerevisiae / physiology*
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors*
  • Spindle Apparatus / drug effects*
  • Spindle Apparatus / metabolism
  • Spindle Apparatus / physiology

Substances

  • Bromobenzenes
  • DNA Primers
  • Saccharomyces cerevisiae Proteins
  • cincreasin
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • MPS1 protein, S cerevisiae
  • Dimethyl Sulfoxide