Control of Apoptosis and Signaling by XIAP

XIAP 对细胞凋亡和信号传导的控制

基本信息

批准号：
7917092
负责人：
Colin S. Duckett
金额：
$ 6.76万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-18 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7917092
关键词：
Address Affect Apoptosis Apoptotic Binding Cancer Model Caspase Cell Death Cell Line Cell physiology Cessation of life Complement Cysteine Protease Data Development Dissection Engineering Factor X Family member Financial compensation Future Goals Hand Human Ink JUN gene Lead Malignant Neoplasms Mediating Minor Molecular Target Mus Mutagenesis NADH oxidase Nuclear Outcome Pathway interactions Physiological Play Process Property Proteins Role Screening procedure Signal Pathway Signal Transduction Signal Transduction Pathway Stimulus Structure System Transforming Growth Factors Transgenic Organisms Validation Work Xenograft Model Xenograft procedure Yeasts angiogenesis apoptosis inducing factor base cancer therapy carcinogenesis human BIRC4 protein in vivo inhibitor-of-apoptosis protein mutant novel overexpression response stress-activated protein kinase 1 therapy design tumor tumor progression tumorigenesis yeast two hybrid system

项目摘要

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.

描述（由申请人提供）：X连锁凋亡抑制剂（XIAP）的表达在许多类别的恶性类别中大大增强，抑制XIAP功能的策略在治疗癌症治疗方面表现出了很大的希望。尽管XIAP主要被认为是通过直接抑制caspase的凋亡细胞死亡途径的抑制剂，但我们的数据显示了XIAP的许多其他特性。这些活动暗示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，caspase xiap的caspase抑制活性可能是相对较小的功能。这些发现提出了几个重要的问题：XIAP的caspase抑制活性是否需要支持肿瘤发育？ XIAP是否通过独立于其caspase抑制功能的机制抑制细胞死亡？还是XIAP通过与凋亡无关的信号传导途径支持肿瘤发生？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型XIAP相关的蛋白质，该项目的目标是了解XIAP的作用以及这些新的相互作用蛋白在支持肿瘤中的作用。在AIM 1中，我们采用诱变方法来询问：XIAP中的哪些域与caspase无关的信号传导以及与我们新鉴定的相关蛋白质的相互作用？在AIM 2中，我们将解决以下问题：XIAP与经过验证的相关蛋白质之间相互作用的功能后果是什么？最后，我们将使用前两个目的中包含的信息来提出至关重要的问题：invivo xiap如何支持肿瘤发生？这项工作将对针对XIAP治疗肿瘤的策略的制定具有深远的影响，因为它将确定此类策略是否应解决该分子的caspase抑制性能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）是否代表了未来癌症治疗疗法的新靶标。