Nuclear Signaling by TRADD

描述（由申请方提供）：衔接蛋白TRADD调节来自肿瘤坏死因子α（TNF）受体TNFR 1的促凋亡和抗凋亡信号传导。TNFR 1对细胞存活和凋亡的调节涉及多种疾病，包括缺血性损伤、神经变性、感染、炎性疾病和癌症。导致TNFR 1诱导的细胞凋亡的一个重要途径需要TRADD与另一种称为FADD的衔接子结合，然后FADD招募并激活半胱天冬酶8，导致下游半胱天冬酶激活和细胞死亡。当TRADD与TNFR 1的细胞内死亡结构域结合时，这发生在细胞质中。然而，多方面的证据表明，这并不是TNFR 1（以及TNFR 1复合物的成分，例如TRADD）诱导细胞凋亡的唯一机制。如果我们能够了解这些分子诱导细胞凋亡的其他方式，我们可能能够开发合理的策略来操纵这些反应，以改善TNF信号传导重要的疾病的治疗。 在NINDS R21（NS 42662）的支持下，我们最近取得了令人惊讶的发现，TRADD不仅是一种细胞质蛋白，而且可以在细胞质和细胞核之间穿梭，在那里它与早幼粒细胞白血病蛋白（PML）核小体相关。核TRADD刺激细胞凋亡途径，其在机制上不同于成熟的细胞质途径。核途径需要p53和PML，并被Bcl-xL抑制。我们推测，这一途径通过PML核小体和p53依赖性信号诱导细胞凋亡，导致线粒体功能障碍。我们进一步假设，这一途径解释了一些TNF诱导的细胞死亡，不能占既定的细胞质途径。为了验证我们的假设，我们有以下具体目标。1)通过核TRADD鉴定细胞凋亡所需的调节因子。2)通过核TRADD确定p53在细胞凋亡中的作用。3)确定PML核体在核TRADD诱导的细胞凋亡中的作用。4)确定核TRADD在介导TNF依赖性信号中的作用。这些研究应该提供一个新的细胞凋亡途径，可能在各种人类疾病中发挥作用的详细调查。

DESCRIPTION (provided by applicant): The adapter protein TRADD regulates pro- and anti-apoptotic signaling from the Tumor Necrosis Factor alpha (TNF) receptor TNFR1. TNFR1 regulation of cell survival and apoptosis is implicated in diverse diseases including ischemic injury, neurodegeneration, infections, inflammatory disease and cancer. An important pathway leading to TNFR1-induced apoptosis requires binding of TRADD to another adapter called FADD, which then recruits and activates caspase 8 leading to activation of downstream caspases and cell death. This occurs in the cytoplasm when TRADD binds to the intracellular death domain of TNFR1. However, multiple lines of evidence indicate that this is not the only mechanism by which TNFR1 (and thus components of the TNFR1 complex such as TRADD) induce apoptosis. If we can understand the other ways that these molecules induce apoptosis we may be able to develop rational strategies to manipulate these responses to improve treatments for diseases where TNF signaling is important. With the support of an NINDS R21 (NS42662), we recently made the surprising discovery that TRADD is not just a cytoplasmic protein but instead can shuttle between the cytoplasm and the nucleus where it is associated with promyelocytic leukemia protein (PML) nuclear bodies. Nuclear TRADD stimulates an apoptosis pathway that is mechanistically distinct from the well-established cytoplasmic pathway. The nuclear pathway requires p53 and PML and is inhibited by Bcl-xL. We hypothesize that this pathway induces apoptosis through PML nuclear body- and p53-dependent signals that cause mitochondria dysfunction. We further hypothesize that this pathway explains some of the TNF-induced cell death that cannot be accounted for by the established cytoplasmic pathway. To test our hypothesis, we have the following specific aims. 1) Identify the regulators that are required for apoptosis by nuclear TRADD. 2) Determine the role of p53 in apoptosis by nuclear TRADD. 3) Determine the role of PML nuclear bodies in apoptosis induced by nuclear TRADD. 4) Determine the role of nuclear TRADD in mediating TNF-dependent signals. These studies should provide a detailed investigation of a novel apoptosis pathway that may have a role in various human diseases.