CD40 is a member of the Tumor Necrosis Factor Receptor (TNF-R) family that is expressed on mature B-lymphocytes and several types of epithelial cancers. When bound by its ligand or crosslinked with antibodies, CD40 generates signals that rescue germinal center B-cells from apoptosis and promote mitogenesis. Conversely, in epithelial cancer cells, CD40 ligation has been reported to promote apoptosis and induce cell cycle arrest. CD40 is absolutely essential in vivo for survival of germinal center B-cells and for generation of T-dependent antibody responses, suggesting that this receptor plays a critical role in the immune system. The mechanisms by which CD40 regulates apoptosis are unknown. The cytosolic domain of CD40 contains no motifs that suggest a means for signal transduction. Using interaction cloning techniques, we identified cDNAs encoding a novel protein CD40-binding protein: CD40-Associated Protein-1 (CAP-1). CAP-1 contains a RING-finger, zinc fingers, and a TRAF-domain, a novel dimerization domain found in putative signal transducing proteins that interact with other members of the TNF-R family. The functions of CAP-1 however remain largely unknown. Experimental investigations are therefore proposed to elucidate the mechanisms by which CD40 regulates cell life and death, with particular emphasis on testing the hypothesis that CAP-1 plays an important role in the signal transduction mechanisms by which CD40 controls apoptosis. Gene transfer and antisense approaches, studies of mutants of CAP-1, biochemical evaluations of protein interactions, and production of CAP-1 transgenic and knock-out mice, among other techniques, will be employed to address the fundamental questions of: (1) What is the role of CAP-1 in the CD40- signaling mechanisms that suppress cell death and induce mitogenesis in B- cells?; (2) How does CD40 promote apoptosis in epithelial cancers and what are the effects of CAP-1 on this process?; and (3) What is the in vivo role of CAP-1 in CD40 function? The information may provide insights that eventually contribute to improved therapies for cancer, as well as autoimmune and immunodeficiency disorders.
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