SY23-4

Our group has been studying the consequence of mitotic checkpoint defects on the acquisition of aneuploidy and tumor initiation in mammals. The mitotic checkpoint apparatus monitors faithful attachment of the mitotic spindle to kinetochores and blocks the metaphase-to-anaphase transition if failures occur. Reduced expression of one component of the mitotic checkpoint apparatus, Mad2, leads to an increase in chromosome instability which can be traced to the premature liberation of separase, a protease which cleaves the cohesin protein which bind sister chromatids together. In mice, such chromosome instability has been shown to lead to lung adenocarcinomas with long latencies. Human tumors with reduced Mad2 expression have been reported, consistent with Mad2 being a bona fide tumor suppressor gene. Complete loss of Mad2 expression in human carcinoma cells and primary cells in culture leads to rapid cell death due to premature degradation of cyclin B and failures in mitotic spindle assembly. Thus complete Mad2 loss of function both acutely challenges the mitotic checkpoint (by prevent kinetochore attachment) and incapacitates it thereby leading to mitotic catastrophe. Mad2 is the first example therefore of a tumor suppressor gene which is essential for somatic cell viability. Recent experiments also indicate that overexpression of Mad2 in tumor cells, as a consequence of Rb loss and E2F activation, can also lead to the acquisition of aneuploidy by delaying the separation of sister chromatids as cells attempt to escape the mitotic block imposed by Mad2 overexpression. Preliminary analysis of animals overexpressing a Mad2 transgene will also be discussed.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]