Tumor necrosis factor (TNF-alpha) represents a family of cytokines which induce a wide number of biological effects that directly influence cell growth, cell differentiation, and programmed cell death. The prototype molecule TNF-alpha, is known to be involved in different pathological conditions including septic shock, rheumatoid arthritis, autoimmunity, HIV gene expression, cachexia, and cytotoxicity. Although the actions of TNF- alpha are mediated by two different cell surface receptors of M/r 55,000 and 75,000 daltons, little is known about how these receptors carry out signal transduction. Other growth factor and cytosine families convey their signals across the cell membrane by stimulating specific phosphorylation events after ligand binding. The two TNF receptors form a structurally related family that includes the Fas antigen, CD27, CD30, CD40 and OX40. The grant will test the hypothesis that TNF-alpha action requires additional signaling molecules, which are likely to interact either directly or indirectly with the TNF receptors. These activities may include tyrosine phosphorylation and hydrolysis of sphingomyelin to ceramide. Recent evidence indicates ceramide may act as a second messenger to promote programmed cell death by the TNT-alpha family of cytokines. This proposal will clone the mammalian sphingomyelinase enzyme that is believed to be responsible for TNF signal transduction and identify how ligand binding to this family of receptors leads to the activation of the sphingomyelinase activity. These studies will ultimately elucidate the molecular mechanisms that are responsible for TNF-alpha action during normal and disease states.
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