Dysregulated expression of inhibitors of apoptosis (programmed cell death) contributes to cancer by aberrantly extending cell viability, favoring mutations and resistance to therapy. The recent identification of the survivin pathway has suggested that excessive inhibition of apoptosis may constitute a common feature of all human cancers, influencing onset, progression and outcome of malignancy. Survivin was identified as an inhibitor of apoptosis of the LkP gene family, uniquely expressed in mitosis in a cell cycle-regulated manner and localized to the mitotic apparatus. Undetectable in normal adult tissues, survivin becomes the fourth most expressed transcript in cancer, where it correlates with a more aggressive disease and abbreviated life expectancy. Recently, our understanding of the survivin pathway has increased considerably. The crystal structure of survivin has been solved, the critical caspase targeted by survivin has been identified, and the regulation of this pathway by survivin phosphorylation at mitosis has been defined. Importantly, expression of a dominant negative survivin mutant prevented tumor formation and inhibited growth of established tumors, in vivo. The hypothesis underlying the present application is that survivin maintains a critical apoptosis checkpoint at initosis, and that interference with this process is sufficient to cause spontaneous apoptosis of cancer cells. In the first specific aim, we will characterize the structure-function requirements of survivin phosphorylation, its kinetics and regulation, and identify post-phosphorylation events influencing survivin stability. In the second specific aim, we will elucidate the survivin-caspase interaction and its role on caspase activity, processing, mitochondrial homeostasis, and we will reconstitute the survivin pathway in knockout animals deficient in selected apoptosome genes. In the third specific aim, we will use a transgenic approach and adenoviral delivery of a dominant negative survivin mutant to elucidate the contribution of the survivin pathway in tumor formation with respect to oncogene expression, exposure to mutagen or loss of a p53 allele. The overall goal of these studies is to credential the survivin pathway as a potential new therapeutic target in cancer.
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