Signal Transduction Pathways in CD30-positive Lymphomas

描述（由申请人提供）：CD30是一种细胞表面受体，通常存在于一小部分淋巴样细胞中，但其表达和活性在霍奇金病、间变性大细胞淋巴瘤和某些白血病的恶性细胞中不受调节。CD30与其同源配体结合后，触发了一系列复杂的细胞内信号级联反应，并且已经确定了许多参与这些途径的信号转导中间体，包括TRAFs， c-IAPs以及最近发现的芳烃核转运体（ARNT）。CD30信号的强度和持续时间被认为在很大程度上是通过调节这些信号中间体的细胞内定位和稳定性来调节的。特别是，TRAFs和c-IAPs已被证明可以作为E3泛素连接酶，它们可以靶向自身以及几种已知底物，进行泛素化，在某些情况下，这导致26S蛋白酶体的降解。泛素化在这些通路中的作用尚不清楚，CD30在正常淋巴细胞中使用的信号通路尚未与在淋巴母细胞样细胞中的信号通路进行比较。为了进一步了解CD30发挥其作用的机制，我们在目标1中提出，扩展一些具有争议的未发表数据，以回答关键问题：CD30:TRAF:c-IAP信号复合物的靶标是什么？在Aim 2中，我们将采用生化和成像方法来询问：TRAFs， c-IAPs和相关蛋白如何参与cd30诱导的信号传导？在Aim 3中，我们将扩展这些观察结果来问：如何利用CD30信号级联来靶向CD30阳性免疫增生性疾病？这些研究将使我们能够探索这种蛋白的正常生理作用，以及它在CD30+恶性肿瘤中功能失调的方式。

DESCRIPTION (provided by applicant): CD30 is a cell surface receptor normally found in a small subset of lymphoid cells, but whose expression and activity are deregulated in malignant cells found in Hodgkin's Disease, anaplastic large cell lymphoma and certain leukemias. A complex array of intracellular signaling cascades are triggered following the engagement of CD30 with its cognate ligand, and a number of signal transduction intermediates have been identified that participate in these pathways, including TRAFs, c-IAPs and, more recently, the aryl hydrocarbon nuclear translocator (ARNT). The strength and duration of CD30 signaling is thought to be modulated, in large part, by regulating the intracellular localization and stability of these signaling intermediates. In particular, the TRAFs and c-IAPs have been shown to function as E3 ubiquitin ligases that can target themselves, as well as several known substrates, for ubiquitinylation, and in some cases this leads to degradation by the 26S proteasome. The roles of ubiquitinylation in these pathways are not well understood, and the signaling pathways employed by CD30 in normal lymphocytes have not been compared to those in lymphoblastoid cells. To further understand the mechanisms by which CD30 exerts its effects we propose, in Aim 1, to expand on some provocative unpublished data to answer the crucial question: what are the targets of the CD30:TRAF:c-IAP signaling complex? In Aim 2 we will take biochemical and imaging approaches to ask: how do the TRAFs, c-IAPs and associated proteins participate in CD30-induced signaling? In Aim 3 we will extend these observations to ask: how can the CD30 signaling cascade be exploited to target CD30-positive immunoproliferative disease? These studies will allow us to explore both the normal physiological role of this protein as well as the ways in which its functions are deregulated in CD30+ malignancies. PUBLIC HEALTH RELEVANCE: This study will enhance our understanding of the pathogenesis of CD30-positive leukemias and lymphomas, and may lead to novel modalities for treatment. We will focus on characterizing the roles of CD30, as well as recently described signaling intermediates, in contributing to the development of these neoplastic diseases.