APOPTOSIS--THE ROLES OF P35 AND IAP

细胞经历凋亡(程序性细胞死亡)的能力是 对正常发育、分化和动态平衡至关重要 并提供了一种主要的防御机制 抵御病毒入侵。细胞凋亡途径的阻断(S)导致 成人的肿瘤发生和胚胎的异常发育。理解 细胞识别和传递信号的分子基础 因此，导致细胞死亡是确定细胞死亡的分子基础的核心 肿瘤发生、生长和分化以及病毒复制。这个 改变细胞对凋亡信号的反应的能力将增强 预防或可能治愈一些疾病的能力，包括 癌症和病毒感染以及对正常情况的洞察 发育和组织维护。 本课题的重点是了解两种类型的作用机制。 杆状病毒衍生的p35和IAP基因，它们阻止细胞凋亡 无脊椎动物和脊椎动物都表明它们在 细胞凋亡途径中的一个点。根据它们的序列 多肽产物，这两种类型的基因似乎有明显的作用 路径上的不同点。IAP含有锌结合结构域 DNA结合蛋白的特征，与P53相关 蛋白质，MDM2；因此，IAP可能在信号识别点附近起作用 并对DNA受损或病毒入侵的存在做出专门的反应。 我们将确定IAPS是否通过调节其他基因的表达来发挥作用 或者直接通过核相互作用来采取行动。相比之下，p35似乎 直接在控制生命的时间点阻止细胞凋亡 死亡决定。我们将确定p35如何与或废除 控制这一步骤的其他基因(如Ced-3(ICE)和Ced-9)的功能 (Bcl2))。P35和IAP相互作用的特征将提供 洞察病毒如何中和细胞凋亡防御系统 并可提供可用于控制细胞凋亡途径的工具。

The ability of cells to undergo apoptosis (programmed cell death) is crucial to the normal development, differentiation and homeostasis of multicellular organisms and also provides a primary defense mechanism against viral invasion. Disruption of apoptotic pathway(s) results in oncogenesis in adults and abnormal development in embryos. Understanding the molecular basis by which cells identify and transduce the signals leading to cell death is thus central to defining the molecular basis of oncogenesis, growth and differentiation, and viral replication. The ability to modify cellular responses to apoptotic signals will enhance the ability to prevent, or possibly cure, a number of diseases including cancer and viral infections as well as provide insight into normal development and tissue maintenance. This project focuses on understanding the mechanism of action of two types of genes, baculovirus-derived p35 and iap genes, which block apoptosis in both invertebrates and vertebrates indicating that they act a crucial point in the apoptotic pathway. Based on the sequence of their polypeptide products, these two types of genes appear to act at distinctly differently points in the pathway. Iaps contain zinc binding domains characteristic of DNA binding proteins and are related to a p53-associated protein, MDM2; thus iaps probably act near the signal recognition point and respond specifically to the presence of damaged DNA or viral invasion. We will determine if iaps act by regulating the expression of other genes or act directly through nuclear interactions. In contrast, p35 appears to act directly in blocking apoptosis at the point governing the life vs. death decision. We will determine how p35 interacts with or abrogates the function of other genes governing this step (e.g., ced-3 (ICE) and ced-9 (bcl-2)). Characterization of p35 and iap interactions will provide insight into how viruses can counteract cellular apoptotic defense systems and may provide tools which can be used to control apoptotic pathways.