Weakening the Spindle Assembly Checkpoint by reduced expression of its components induces chromosome instability and aneuploidy that are hallmarks of cancer cells. The tumor suppressor p14 ARF is overexpressed in response to oncogenic stimuli to stabilize p53 halting cell progression. Previously, we found that lack or reduced expression of p14 ARF is involved in the maintenance of aneuploid cells in primary human cells, suggesting that it could be part of a pathway controlling their proliferation. (Michel et al., 2001), as well as mice that are heterozygous for Centromere Protein E (CENPE) exhibit whole chromosome aneuploidy associated with the increase of spontaneous tumors (Weaver and Cleveland, 2007).Although aneuploidy could potentially increase the risk of neoplastic transformation, this seems to occur when it is associated with mutations in tumor suppressor genes.Consistent with this hypothesis, aneuploidy caused by MAD2 haploinsufficiency has been shown to increase both the frequency and number of tumors in a p53 AE background (Holland and Cleveland, 2009). Additionally, it was shown that aneuploidy in near diploid HCT116 cells is associated with activation of the p38-p53-p21 waf1 axis (Thompson and Compton, 2010). A p53-controlled pathway could also play an important role in contrast to aneuploidy, resulting from various cellular insults like an altered spindle checkpoint, thus preserving chromosomal stability.Previously, we showed that aneuploidy caused by MAD2 haploinsufficiency activated a p53-dependent senescence pathway in IMR90 human fibroblasts to counteract aneuploidy deleterious effects . On the contrary, aneuploidy promoted by MAD2 post-transcriptional silencing appeared to be well tolerated in MCF10A epithelial cells where the ARF gene coding for p14 ARF is deleted . In addition, we showed that primary human fibroblasts (IMR90) perceived DNMT1 absence, that would result in DNA

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Most human tumors are characterized by aneuploidy that is believed to be the consequence of chromosomal instability (CIN). The mechanism(s) leading to aneuploidy and the pathways that allow its tolerance are not completely understood. The Spindle Assembly Checkpoint (SAC) is a cellular surveillance mechanism working during mitosis, and alterations of genes that encode components of the SAC weakening the mitotic checkpoint, induce aneuploidy by chromosome mis-segregation. We induced aneuploidy in near-diploid tumor cells by simultaneous depletion of the SAC proteins MAD2 and BUBR1 by RNA interference in the attempt to gain further insight on the cellular responses to aneuploidy. Individual reduction of MAD2 and BUBR1 protein levels caused defective mitosis and aneuploidy, while co-depletion of MAD2 and BUBR1 caused cell cycle arrest and cell death in addition to aneuploidy. The simultaneous reduction of the two SAC proteins induced high percentage of hyperdiploid cells and p53 stabilization suggesting that hyperdiploidy could activate a p53 controlled pathway. The results indicate that p53 is required to induce cell cycle arrest and cell death when the mitotic checkpoint is strongly perturbed, thereby preventing aneuploid cell propagation.