) Collectively, malignancies of B-lymphocytes rank fifth among causes of cancer in North America, with >60,000 new cases diagnosed yearly in the USA alone. CD40 is a TNF Receptor (TNFR) family member expressed on mature B-cells. CD40 has a profound influence on apoptosis. Though CD40 upregulates levels of Fas, an apoptosis-inducing TNFR member, it also delivers signals that are cytoprotective, inducing expression of several bcl-2 family genes (bcl-XL, mcl-1, bfl-1), a Fas-antagonist (Flip), and caspase-inhibitors (cIAP-1; cIAP-2). In most B-cell neoplasms, CD40 protects from apoptosis and promotes resistance to chemotherapy. A need exists therefore to understand more about mechanisms of CD40, so that strategies for interfering with its function can be devised. The cytosolic domain of CD40 binds directly or indirectly to several TRAF family proteins, including TRAF-1, 2, 5, and 6. Several TRAFs, including TRAF-2, 5, and 6, interact with protein kinases that induce NF-kB and other transcription factors, but other TRAFs (TRAF-1, 3, 4) do not. The precise roles played by individual TRAF-family members within the context of apoptosis suppression by CD40 remain largely unknown. Further complicating matters, we have discovered 3 additional TRAF domain-containing proteins which can bind certain previously described TRAFs. Understanding which TRAFs play essential non-redundant roles in apoptosis suppression and the biochemical mechanisms involved, therefore, represent important goals if appropriate strategies are to be devised for attacking CD40-signaling in malignant or autoreactive B-cells. The submitted proposal proposes to address 5 questions of relevance to mechanisms of TRAFs in CD40-signaling: (1) Is apoptosis suppression by CD40 exclusively TRAF-dependent?; (2) What are the roles of each of the previously identified TRAF family members in apoptosis suppression by CD40?; (3) Is there a role for the any of the novel TRAF domain-containing proteins in CD40 signaling in B-cells?; (4) What are the signal transduction events which TRAFs employ for affecting expression of apoptosis-regulatory genes?; and (5) Do TRAFs participate in lymphomagenesis in vivo, using transgenic mice? The results will contribute to strategies for eradicating malignant and autoreactive B-cells.
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