The mitotic checkpoint gene Mad2 has been shown in metazoans to be an important part of the mitotic checkpoint apparatus through biochemical and genetic experiments. Mad2 is a component of the machinery which arrests a cell prior to the metaphase to anaphase transition if all the chromosomes are not attached to the mitotic spindle apparatus. Partial loss of function mutations predisposes mammalian cells to chromosome missegregation events and lung tumor initiation in vivo after long latency. Unlike lower eukaryotes, in mammalian cells Mad2 is an essential gene both during development and in somatic cells making complete loss of function an unlikely event in tumor progression. Recent experiments indicate that overexpression of Mad2 as a result of the loss of the tumor suppressor Rb and consequent E2F activation can also lead to chromosome instability. In the current proposal, we will try to model these gain of function effects in the mouse. Preliminary results indicate that Mad2 overexpression by itself can initiate tumorigenesis in the mouse and accelerate lung tumorigenesis in tumor prone animals overexpressing the K-ras oncogene. How chromosome instability contributes to the initiation and progression of disease will be explored. These experiments should allow us to shed further light on the role of mitotic checkpoint abnormalities in human disease.
|Marks, Daniel Henry; Thomas, Rozario; Chin, Yvette et al. (2017) Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit. Cell Rep 19:1832-1845|
|Schvartzman, Juan-Manuel; Duijf, Pascal H G; Sotillo, Rocio et al. (2011) Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. Cancer Cell 19:701-14|
|Sotillo, Rocio; Schvartzman, Juan-Manuel; Socci, Nicholas D et al. (2010) Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 464:436-40|
|Schvartzman, Juan-Manuel; Sotillo, Rocio; Benezra, Robert (2010) Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer 10:102-15|
|Sotillo, Rocio; Schvartzman, Juan-Manuel; Benezra, Robert (2009) Very CIN-ful: whole chromosome instability promotes tumor suppressor loss of heterozygosity. Cancer Cell 16:451-2|
|Sotillo, Rocio; Hernando, Eva; Diaz-Rodriguez, Elena et al. (2007) Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11:9-23|