The pleotropic symptoms of Vitamin A deficiency include a marked immune deficiency. During the past decade our group has defined a tissue culture model, has shown that cell survival/death decisions are regulated by retinol, has identified several novel retinol metabolites important for lymphocyte survival, and has solved their structure. 14-hydroxy retro- retinol (HRR) is the prototype of agonistically acting retinoids, supporting lymphocyte survival, whereas anhydroretinol (AR) most often induces apoptosis. Both retro-retinoids can be traced fa br back in evolution to invertebrates, implying a very basic biological role. By contrast, retinoic acid is an invention of vertebrates. During the last grant period we have identified serine/threonine kinases, cRaf and PKC, as the principal receptors of retro-retinoids. Binding occurs at high affinity at the cysteine-rich domain that these kinases share in common, and bound retinol and HRR enhance the activation of phosphotransferase activity by oxidizing agents. We have formulated the working hypothesis that the cys domain functions as a retinoid-regulated redox switch. Retinoids act as catalysts to target special cysteines for selective oxidation. The proposed work will seek to identify the crucial step in the cRaf activation cycle where redox activation occurs (AIM number 1), to define the chemical changes in the oxidized cys domain, and the possible changes in redox potential created by bound retinoids (AIM number 2), and to identify the precise cysteine residues undergoing oxidation. If substantiated the new paradigm will lead to an understanding of how redox activation can be targeted effectively to signaling molecules. Redox regulation is increasingly accepted as controlling factor of immune cells in innate and adaptive immune reactions. The significance of retinoids lies in their capacity to fine-tune this redox signaling network. The marked differences in redox regulation among different retinoids, especially the capacity in AR to block redox signaling that we have demonstrated, may also allow translation into cancer therapy.
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