Mutations in a small number of genes are found in a large fraction of human melanomas. For instance, so-called “driver” mutations in the “famous” melanoma genes BRAF, NRAS, and CDKN2A, are each found in ~20-50% of melanomas. Less frequent driver mutations have also been reported. We’ve been studying a multi-protein complex called the Anaphase Promoting Complex (APC), which contains fifteen distinct proteins. Although none of the APC subunits is mutated at a high frequency in melanomas, collectively, about 30% of melanomas contain a mutation in at least one APC subunit, making the APC as frequent a target for mutation as the well-known drivers. The APC is an enzyme responsible for the elimination of certain regulatory proteins. These are not defective proteins, but rather proteins that have completed their functions and need to be removed before subsequent functions can occur. Our hypothesis is that a mutation-caused reduction in APC activity favors melanoma development. There are two key predictions of this hypothesis that need to be tested. First is that melanoma cells have reduced APC function, which we will test in patient-derived cell lines that are maintained at Yale. The second prediction is that the APC mutations seen in patients are responsible for reduced APC activity, rather than just being random mutations of no consequence. (Melanomas have a high frequency of such background mutations.) We will test this prediction by putting the same mutations into normal cells and testing whether they result in reduced APC activity. These studies will add to our basic understanding of the development of melanoma, lead to the development of new prognostic markers, and possibly reveal a novel therapeutic target.