title: 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.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Russell K
authors.initials: RK
authors.lastname: Dorer
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhong
authors.forename: John A
authors.initials: JA
authors.lastname: Tallarico
authors.forename: Wing Hung
authors.initials: WH
authors.lastname: Wong
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchison
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Murray
mesh_terms: D001969:Bromobenzenes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D020090:Chromosome Segregation / Q000187:drug effects* / Q000502:physiology; D017931:DNA Primers; D004121:Dimethyl Sulfoxide; D004305:Dose-Response Relationship, Drug; D018386:Kinetochores / Q000378:metabolism; D046228:Microarray Analysis; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors*; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D001969:Bromobenzenes; D017931:DNA Primers; D029701:Saccharomyces cerevisiae Proteins; C504073:cincreasin; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C093416:MPS1 protein, S cerevisiae; D004121:Dimethyl Sulfoxide