Role of the Spindle Checkpoint in Preventing Breast Cancers

摘要

In most of the cancer cells, chromosomal number is unstable. it has been long speculated that genome instability may be a direct cause of human cancer including breast cancer. In order to test this hypothesis, we like to abrogate the spindle checkpoint, a major surveillance mechanism responsible for maintenance of the normal chromosome number. Human/Mouse p55CDC Is a target of the checkpoint. A negative dominant mutant of p55CDC that Is unable to bind to Mad2 would abrogate the checkpoint. We have generated several such p55CDC mutants that have lost the ability to interact with Mad2, but otherwise normal. Expression of these mutants in Hela cells abrogated the spindle checkpoint expectedly. In BJ cell line, they are however toxic and we failed to establish an experimental system to test if a loss of the checkpoint causes chromosome instability and neoplasmic transformation. Alternatively, we propose overexpression of Cmt2, a novel Mad2- binding protein we have identified recently. Our characterization indicates that Cmt2 may directly interact with the p55CDC-Mad2 complex and promote dissociation of the complex.