Mad2 Is a Critical Mediator of the Chromosome Instability Observed upon Rb and p53 Pathway Inhibition

SummaryMultiple mechanisms have been proposed to explain how Rb and p53 tumor suppressor loss lead to chromosome instability (CIN). It was recently shown that Rb pathway inhibition causes overexpression of the mitotic checkpoint gene Mad2, but whether Mad2 overexpression is required to generate CIN in this context is unknown. Here, we show that CIN in cultured cells lacking Rb family proteins requires Mad2 upregulation and that this upregulation is also necessary for CIN and tumor progression in vivo. Mad2 is also repressed by p53 and its upregulation is required for CIN in a p53 mutant tumor model. These results demonstrate that Mad2 overexpression is a critical mediator of the CIN observed upon inactivation of two major tumor suppressor pathways.

► p53 represses Mad2 expression via induction of p21 and crosstalk to the Rb pathway ► Mad2 upregulation mediates the genomic instability seen upon Rb pathway inhibition ► Elevated Mad2 enhances transformation and mediates aggressive mammary tumor formation ► Normalization of elevated Mad2 rescues genomic instability in a p53 tumor model