""""""""The TNF/NGF receptor superfamily is comprised of a number of related cell surface molecules which play crucial roles in regulating the balance between cell proliferation and cell death. Defects in these receptors or their ligands have been implicated in a range of disorders including Hodgkin's disease, anaplastic large cell lymphoma, systemic lupus erythematosus, and X-linked immunoproliferative disease."""""""" """"""""Recent studies have begun to define the signaling pathways utilized by the TNF/NGF receptors. Two distinct sets of proteins have been identified which bind to these receptors. The death-domain-containing proteins such as TRADD and FADD can be recruited directly to death domains found in the cytoplasmic tails of the type 1 TNF receptor and Fas. These molecules have been shown to mediate signals from the receptors and to activate a variety of downstream factors, such as the caspase family of cysteine proteases, which induce programmed cell death (apoptosis). In contrast, the TNF receptor-associated factors (TRAFs) bind to elements in the cytoplasmic tails of CD30, CD40, and the type 2 TNF receptor, and have been shown to activate the pleiotropic transcription factor NF kappa B, as well as the JNK (c-Jun NH2-terminal kinase) family of serine-threonine kinases. Both NF kappa B and JNK have been implicated in the regulation of cell survival."""""""" """"""""We and others have recently identified a third set of proteins which play a role in signaling by the TNF receptor superfamily: the IAP (inhibitor of apoptosis) proteins. The iapgenes were first discovered in insect viral genomes, where they are required for maximal infectivity, but homologs of iaphave subsequently been found in Drosophila, mouse, and human genomes. Three bona fide human homologs have been identified: two of these interact with the TRAF proteins, but the third, hILP (human IAP-like protein), does not. Interestingly, hILP is a potent inhibitor of caspase-mediated apoptosis, and the hilpgene locus maps to a region which is associated with Duncan's syndrome, an X-linked immunoproliferative disorder."""""""" """"""""Our primary research objective is to characterize the signaling pathways employed by the TNF/NGF receptor superfamily. By molecular genetic techniques, we are examining the roles of the TRAFs and IAPs in the activation of NF kappa B and JNK, and are defining the protein-protein interactions between these factors and the different components of the TNF receptor superfamily signaling complexes in order to better understand their role in autoimmune disease progression and lymphomagenesis.""""""""
