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

Abstract

Summary Multiple 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. Significance Chromosome instability (CIN) is thought to be the major evolutionary driving force for tumor progression. Here we show that overexpression of the mitotic checkpoint gene Mad2 is required for the CIN observed upon inhibition of the Rb and p53 pathways, two pathways frequently inactivated in human cancer. Our results demonstrate that acquisition of CIN is hard-wired into loss of the major tumor suppressor pathways via hyperactivation of the mitotic checkpoint pathway. The inhibition of these tumor suppressor pathways in the early stages of cancer progression may account for the widespread presence of CIN in tumors in the absence of other genetic events and underscores the therapeutic value of targeting aneuploid cells.

Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors

“…The increase in the spindle checkpoint protein Mad2 leads to aberrant checkpoint function, as well as aneuploidy and tumorigenesis (4,6,8,27). For faithful segregation of chromosomes at each division, cells must ensure that each pair of sister chromatids is correctly attached to spindle microtubules from opposite poles before the onset of anaphase.…”

“…High levels of Mad2 also resulted in the formation of aggressive tumors in multiple organs (5). Recent studies show that overexpression of Mad2 is caused by loss of the tumor suppressor Rb or p53 (6,7). Mad2 is overexpressed in many cancers (Table S1), such as malignant lymphoma, liver cancer, lung cancer, soft tissue sarcoma, hepatocellular carcinoma, gastric cancer, colorectal carcinoma, and human osteosarcoma (8).…”

RB1: a prototype tumor suppressor and an enigma

“…Thus, the mitotic defects resulting from pRB inactivation may be relevant in many cancers. Significantly, the mitotic defects associated with pRB loss can be suppressed by knockdown of the checkpoint protein Mad2 (Hernando et al 2004;Sotillo et al 2010;Schvartzman et al 2011), depletion of Wapl (to increase cohesin loading) (Manning et al 2014b), addition of nucleosides (which improves replication dynamics and chromosome cohesion) (Bester et al 2011;Burrell et al 2013;Manning et al 2014a), or manipulations that change chromatin marks at centromeric and pericentromeric heterochromatin (Manning et al 2014b;Tanno et al 2015). These raise the intriguing idea that it may be possible to reduce genome instability caused by RB1 mutation.…”

Killing cells by targeting mitosis

“…Recent data suggest that inactivation of major tumor suppressor pathways, such as pRb or p53, leads to a mitotic stress due to the overexpression of the SAC regulator Mad2, suggesting that CIN may be an early, common event in tumor cells. 91,92 On the other hand, the induction of strong and acute CIN (e.g., by SAC abrogation) may be detrimental for cell viability, and this is now considered as a possible therapeutic strategy (see figure and main text). The relevance of stable aneuploidies for cancer development of therapy is more complex.…”