Role of Mitotic Checkpoint Defects in Mouse Tumor Models

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DESCRIPTION (provided by applicant): 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.