Control of Apoptosis and Signaling by XIAP

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DESCRIPTION (provided by applicant): Expression of the X-linked inhibitor of apoptosis (XIAP) is greatly enhanced in many classes of malignancy, and strategies to suppress XIAP function are showing great promise in the treatment of cancer. Although XIAP is principally thought to function as a suppressor of the apoptotic cell death pathway through the direct inhibition of caspases, our data have revealed a number of additional properties of XIAP. These activities implicate XIAP as playing a role in signal transduction pathways that are independent of its caspase inhibitory properties, and actually suggest that in vivo the caspase suppressive activity of XIAP may be a relatively minor function. These findings raise several important questions: are the caspase inhibitory activities of XIAP necessary and sufficient to support tumor development? Does XIAP suppress cell death by a mechanism independent of its caspase inhibitory functions? Or does XIAP support oncogenesis through a signaling pathway that is unrelated to apoptosis? To further understand these pathways, we have identified and begun to characterize a set of novel XIAP associated proteins, and the goals of this project are to understand the role of XIAP, as well as these new interacting proteins, in supporting oncogenesis. In Aim 1 we take a mutagenesis approach to ask: which domains within XIAP are involved in caspase-independent signaling and interaction with our newly identified associated proteins? In Aim 2 we will address the question: what are the functional consequences of the interactions between XIAP and validated associated proteins? Finally, we will use the information contained in the first two Aims to ask the crucial question: in vivo how does XIAP support oncogenesis? This work will have profound implications for the development of strategies targeting XIAP for the treatment of tumors, because it will establish whether such strategies should address the caspase-inhibitory properties of the molecule or other aspects of its physiological functions. Finally, the studies will allow us to address whether our newly described XIAP-interacting proteins, including AIF, represent novel targets for the future design of therapies for the treatment of cancer.