Our lab focuses on two areas: analysis of a lineage specifying transcription factor, Microphthalmia; and mechanisms of p53-dependent apoptosis. Microphthalmia is a helix-loop-helix transcription factor which is essential to normal melanocyte, osteoclast, and mast cell development and function. We have identified its role as a major signaling intermediate in pathways activated by Steel/c-Kit, M-CSF/c-fms, and melanocyte stimulating hormone. Its expression and function may also be of importance in melanoma growth and has now been shown to be of considerable diagnostic utility. Our studies on p53 and apoptosis revolve around the importance of the p53 tumor suppressor in mediating a decision between growth arrest and apoptotic death following cellular stress. Because of its unique ability to trigger arrest in untransformed fibroblasts vs. apoptosis in oncogene transformed fibroblasts, its function offers a built in therapeutic window for tumor selective killing. To understand the mechanistic basis for its apoptotic activity we have devised a cell free system in which p53 protein appears to trigger a cascade resulting in caspase activation. Cellular extracts are being fractionated and the apoptotic intermediates are being isolated. This strategy has also uncovered potential inhibitory activities in extracts from certain tumors. The identification and characterization of these factors may add to our understanding of the regulation of cancer cell death and provide potential therapeutic targets.