Tumor necrosis factor is a cytokine with potential for the treatment of cancer which also promotes immunity, antiviral responses, metabolic changes that accompany diseases, the insulin resistance of non-insulin dependent diabetes and inflammatory processes, including those that lead to arthritis. To promote the pontential of TNF as a therapeutic agent and to abrogate its pathological activities requires insight into how TNF works. The first step in TNF action is binding to either of two distinct receptors. Each receptor promotes cellular responses but neither contains intrinsic tyrosine kinase activity or any motif which suggests how a signal is transmitted into the cell. Receptors without tyrosine kinase activity bind to accessory proteins which mediate interaction with signaling cascades thereby promoting biological effects. Signal transduction pathways which are
initiated by members of the TNF superfamily utilize receptors which are devoid of intransic catalytic activity. Isolation and characterization of death domain (TRADD, FADD, RIP) and TRAF domain-containing proteins (TRAF-1, TRAF-2, TRAF-3) have partially bridged a large molecular gap within one of several signaling pathways which originate at the plasma membrane and terminate in the nucleus. The ability of these two protein families to selectively dimerize and bind to related receptors allows them to govern diverse cellular responses which culminate in cellular proliferation, differentiation, effector functions, and apoptosis.
|