Apoptosis Induction by Nuclear-localized TRADD

描述(申请人提供)：肿瘤坏死因子(TNF)信号转导途径 受体TNFRI和TNFR2参与细胞死亡和保护 在中风或其他脑损伤后。我们必须了解这些不同 如果我们要开发出将组织损伤降到最低的方法，信号通路就会起作用 中风或其他创伤后。一种众所周知的TNFRI导致细胞死亡 激活caspase级联并被caspase抑制的细胞凋亡途径 抑制剂，如zVAD.fink。然而，肿瘤坏死因子也可以通过一种机制杀死细胞。 这是zVAD.fink无法阻止的，这也可能有助于 肿瘤坏死因子诱导的组织损伤。这一途径致死的分子机制 细胞是未知的。我们最近有一个令人惊讶的发现，Tradd，一个 接头蛋白，通过与TNFR1结合介导下游信号传导。 细胞膜，不仅仅是一种细胞质蛋白。相反，Tradd穿梭于 并通过活跃的核进出口走出核。此外，一个 与Tradd分离的结构域仅定位在其所在的细胞核中 通过一种不被zVAD.fmk抑制的机制诱导细胞凋亡。我们 因此，假设：来自Tradd的核信号有助于 由肿瘤坏死因子引起的抵抗细胞死亡。 在这里，我们建议用以下具体目标来检验这一假设。1) 确定TRANDD核进出口在诱导细胞中的作用 死亡。2)确定Tradd是如何从细胞核诱导细胞死亡的。我们的 研究涉及NS-00-01 I的R21机制在 遵循以下方式。我们的实验将提供关于 这一意外的核活动的意义和作用机制 贸易和。建立了受体的核穿梭的概念 相互作用蛋白激活一条新的使徒途径。在这里提出的工作 也应该为未来的项目奠定坚实的基础，以确定这些 活动会导致中风或其他疾病引起的组织损伤 脑部创伤。这一信息可能会导致改善治疗策略 受损脑组织中肿瘤坏死因子信号通路的操作。

DESCRIPTION (Provided By Applicant): Tumor necrosis factor (TNF) signaling via the receptors TNFRI and TNFR2 contributes to both cell death and protection after stroke or other brain trauma. We must understand how these different signaling pathways work if we are to develop ways to minimize tissue damage after stroke or other trauma. TNFRI causes cell death by a well-understood apoptosis pathway that activates a caspase cascade and is inhibited by caspase inhibitors such as zVAD.fink. However, TNF can also kill cells by a mechanism that cannot be inhibited by zVAD.fink, and which may also contribute to TNF-induced tissue damage. The molecular mechanism by which this pathway kills cells is unknown. We recently made the surprising discovery that TRADD, an adaptor protein that mediates downstream signaling through TNFR1 binding at the cell membrane, is not solely a cytoplasmic protein. Rather, TRADD shuttles into and out of the nucleus via active nuclear import and export. Furthermore, an isolated domain from TRADD is localized exclusively in the nucleus where it induces apoptosis via a mechanism that is not inhibited by zVAD.fmk. We therefore hypothesize: nuclear signaling from TRADD contributes to the resistant cell death that is caused by TNF. Here, we propose to test this hypothesis with the following specific aims. 1) To determine the role of TRADD nuclear import and export in inducing cell death. 2) To determine how TRADD induces cell death from the nucleus. Our studies relate to the purpose of the R21 mechanism for NS-00-01 I in the following ways. Our experiments will provide the first information regarding the significance and mechanism of action of this unexpected nuclear activity of TRADD and. establish the concept that nuclear shuttling of a receptor interacting protein activates a novel apostolic pathway. The work proposed here should also form a strong basis for future projects to determine how these activities contribute to the tissue damage that is caused by stroke or other brain trauma. This information may lead to improved strategies for therapeutic manipulation of TNF signaling pathways in damaged brain tissues.