Talk Title: "How Do Cells Maintain Stable Levels od Retinoic Acid: The Utility of Paradoxical Components in Biological Circuits."
Natalia Kedishvili (University of Alabama-Birmingham School of Medicine)
The work in my lab is focused on the enzymes and the mechanisms that control the biosynthesis of the bioactive derivative of vitamin A, retinoic acid . Retinoic acid is a powerful small lipid molecule that exerts genomic actions through binding and activating nuclear transcription factors, retinoic acid receptors (RARs) , and non-genomic actions through binding to mRNAs in the cytoplasm , and activation of kinases via cellular retinoic acid binding protein type 1 . Either too much or too little of retinoic acid is equally harmful; hence, the levels of retinoic acid in the cells are tightly controlled. The mechanisms that control the biosynthesis and degradation of retinoic acid are not yet fully understood. The research conducted in our laboratory uncovered the existence of a multisubunit protein complex that controls the baseline levels of retinoic acid in many cells. This complex is composed of at least two subunits of retinol dehydrogenase 10 (RDH10) and 2 or more subunits of dehydrogenase reductase 3 (DHRS3). Together, these two proteins form an oligomeric retinoid oxidoreductase complex (ROC) that regulates the rate of retinoic acid biosynthesis . As we are progressing towards a better understanding of the fundamental mechanisms that control retinoic acid levels, new important and intriguing questions arise about the structure and regulation of the ROC; about the existence of other retinol dehydrogenases that may function in a cell-specific manner; about the mechanisms that disrupt the retinoic acid homeostasis, leading to disease; and about potential therapeutic interventions aimed to restore the homeostasis. This work has been continuously supported by the National Institute on Alcohol and Alcoholism for over 20 years. In addition to our basic science research, we are interested in identifying novel chemopreventive agents, rexinoids, which bind to retinoid X receptors (RXR) in the nucleus and inhibit carcinogenesis in UV-exposed skin. Our preliminary data suggest that a rexinoid developed at UAB, UAB30, acts by increasing the endogenous levels of anticarcinogenic retinoic acid in human and mouse skin . This work is conducted in collaboration with Drs. Muccio, Athar, Elmets and Atigadda, and has been supported by a pilot project from the Comprehensive Cancer Center at UAB.