Control of Apoptosis and Signaling by XIAP

描述（申请人提供）：X-linked inhibitor of apoptosis （XIAP）的表达在许多类型的恶性肿瘤中显著增强，抑制XIAP功能的策略在癌症治疗中显示出巨大的前景。虽然XIAP主要被认为是通过直接抑制半胱天冬酶作为凋亡细胞死亡途径的抑制因子，但我们的数据揭示了XIAP的一些其他特性。这些活性暗示XIAP在独立于其caspase抑制特性的信号转导途径中发挥作用，实际上表明在体内，XIAP的caspase抑制活性可能是一个相对次要的功能。这些发现提出了几个重要的问题：XIAP的caspase抑制活性是支持肿瘤发展的必要和充分的吗？XIAP是否通过独立于caspase抑制功能的机制抑制细胞死亡？或者XIAP是否通过与细胞凋亡无关的信号通路支持肿瘤发生？为了进一步了解这些途径，我们已经确定并开始表征一组新的XIAP相关蛋白，该项目的目标是了解XIAP以及这些新的相互作用蛋白在支持肿瘤发生中的作用。在Aim 1中，我们采用诱变方法来询问：XIAP中的哪些结构域参与caspase非依赖性信号和与我们新发现的相关蛋白的相互作用？在目标2中，我们将解决这个问题：XIAP和验证的相关蛋白之间相互作用的功能后果是什么？最后，我们将利用前两个目标中包含的信息来提出一个关键问题：在体内，XIAP是如何支持肿瘤发生的？这项工作将对开发靶向XIAP治疗肿瘤的策略产生深远的影响，因为它将确定这些策略是否应该解决分子的caspase抑制特性或其生理功能的其他方面。最后，这些研究将使我们能够解决我们新描述的xiap相互作用蛋白，包括AIF，是否代表未来癌症治疗设计的新靶点。

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.