Signal Transduction Pathways in CD30-positive Lymphomas

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further understand the mechanisms by which CD30 exerts its effects we propose, in Aim 1, to expand on some provocative unpublished data to answer the crucial question: what are the targets of the CD30:TRAF:c-IAP signaling complex?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