Signal Transduction Pathways in CD30-positive Lymphomas

描述（由申请人提供）：CD 30是一种细胞表面受体，通常存在于淋巴样细胞的一个小亚群中，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中发现的恶性细胞中失调。在CD 30与其同源配体接合后，触发了一系列复杂的细胞内信号传导级联，并且已经鉴定了许多参与这些途径的信号转导中间体，包括TRAF、c-IAP和最近的芳烃核转运蛋白（ARNT）。CD 30信号传导的强度和持续时间被认为在很大程度上通过调节这些信号传导中间体的细胞内定位和稳定性来调节。特别地，TRAF和c-IAP已经显示出作为E3泛素连接酶的功能，其可以靶向自身以及几种已知的底物，用于泛素化，并且在某些情况下，这导致26 S蛋白酶体的降解。泛素化在这些途径中的作用还没有很好的理解，CD 30在正常淋巴细胞中使用的信号传导途径还没有与淋巴母细胞中的信号传导途径进行比较。为了进一步了解CD 30发挥其作用的机制，我们在目标1中提出，扩展一些挑衅性的未发表的数据来回答关键问题：CD 30：TRAF：c-IAP信号复合物的靶点是什么？在目标2中，我们将采取生物化学和成像方法来问：TRAFs，c-IAP和相关蛋白如何参与CD 30诱导的信号传导？在目标3中，我们将扩展这些观察，以问：如何利用CD 30信号级联靶向CD 30阳性免疫增殖性疾病？这些研究将使我们能够探索这种蛋白质的正常生理作用以及其功能在CD 30+恶性肿瘤中失调的方式。

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further understand the mechanisms by which CD30 exerts its effects we propose, in Aim 1, to expand on some provocative unpublished data to answer the crucial question: what are the targets of the CD30:TRAF:c-IAP signaling complex?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.