Aneuploidy is a hallmark of cancer cells in which chromosomes are inappropriately partitioned between daughter cells due to aberrant mitosis. Faithful segregation of chromosomes during each cell division is normally ensured by the mitotic spindle checkpoint, which delays the onset of anaphase until every chromosome has successfully attached to the spindles. Defects in the mitotic checkpoint decrease genome stability and promote aneuploidy. The mitotic spindle checkpoint is highly robust as a single improperly attached kinetochore is sufficient to block cell cycle progression and generate sustainable mitotic arrest at metaphase. Once proper kinetochore attachment is achieved, checkpoint signaling is extinguished allowing the cells exit metaphase and transition into anaphase. The precise mechanisms underlying the toggle-like switching behavior of the spindle checkpoint system are not very well understood. The goal of this proposal is to test whether there is bistability in the mitotic spindle checkpoint signaling pathway using a systems biology approach combining quantitative experimental studies with computational modeling analysis. A systems understanding of the logic of spindle checkpoint is critical to determine why drugs work or not and reveal new avenues for developing more effective anti-cancer drugs. This proposal is aimed to obtain a quantitative understanding of this process using a combination of experiments and modeling.

PUBLIC HEALTH RELEVANCE: This proposal is aimed to obtain a quantitative understanding of mitotic spindle checkpoint signaling pathway using a combination of experimental and modeling approach.

F33GM093670

2010-05-21

2010-11-20