Modeling disease in the mouse: lessons from DNA damage response and cell cycle control genes

The advent of gene targeting has allowed the dissection of many essential cellular pathways, including those involved in cell cycle regulation, signal transduction, and development. However, it is becoming increasingly clear that the simple gene deletion strategy may not be sufficient for the modeling of many cancer syndromes. In this Prospect article, we will discuss the strengths and weaknesses of mouse models, how they have advanced from gene deletions to truncations, point mutations, and conditional mouse models in which expression or loss of the gene of interest is controlled either temporally or spatially. We will also consider future directions for the use of mouse models in cancer. The vastness of the field necessitates focusing on a few specific examples with the unfortunate exclusion of many excellent studies from our discussion. As such, we focus on a few specific models of human cancer syndromes, however many of the themes discussed here are applicable to other systems of genetic manipulation and may be applied across fields.