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

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.

• Authors: Russell K Dorer, Sheng Zhong, John A Tallarico, Wing Hung Wong, Timothy J Mitchison, Andrew W Murray
• Journal: Current biology : CB (Curr Biol) Vol. 15 Issue 11 Pg. 1070-6 (Jun 07 2005) ISSN: 0960-9822 [Print] England
• PMID: 15936280 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

• Bromobenzenes (chemical synthesis, metabolism, pharmacology)
• Chromosome Segregation (drug effects, 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, metabolism, physiology)