Paul R.Copeland Associate Professor UMDNJ Dept. of Molecular Genetics, Microbiology & Immunology Room 819W Piscataway. NJ 08854 (732) 235-4670 FAX - 5223 paul.copeland@umdnj.edu

Regulation of gene expression at the translational level. incorporation and utilization of selenocysteine

Our primary research question targets the protein synthetic machinery as one of the primary sites for the regulation of gene expression and an important sensor of the status of cellular metabolite concentrations including trace elements. The utilization of selenium exemplifies this relationship. and is required for the synthesis and function of an essential group of proteins that contain the amino acid selenocysteine (Sec). In fact. many selenoproteins are known to provide protection from cellular damage and transformation. thus making the synthesis and regulation of these proteins an essential area of research. Sec is incorporated into these proteins by a translational recoding event at specific Stop (UGA) codons that are found upstream of stable stem-loop structures known as Sec insertion sequence (SECIS) elements. While the UGA codon and the SECIS element are the only known cis-acting elements required for Sec incorporation. at least two trans-acting factors are also required: 1) the Sec-specific elongation factor (eEFSec) and 2) a SECIS binding protein (SBP2). One of the ultimate goals for selenocysteine research is to be able to specifically regulate the expression of potentially beneficial selenoproteins in vivo. In order to achieve this goal. we must understand all of the factors that contribute not only to the basic Sec incorporation reaction but also to the regulation of this process. In addition to characterizing the structure and function of the known factors. much of our work is designed to test hypotheses regarding the identity and function of novel factors involved in the synthesis of selenoproteins utilizing both mammalian systems as well as yeast. a eukaryotic system that is devoid of the Sec incorporation machinery. The results derived from these experiments will not only significantly add to our current knowledge of Sec incorporation. but they will also provide insight into the basic mechanisms of protein synthesis during the elongation and termination phases.

Within the realm of selenium biology. it has been established that increases in dietary selenium significantly reduce the incidence of prostate cancer. but the molecular basis for this effect is unknown. There are two major pathways for selenium bio-activity: 1) through the formation of selenium-containing small molecules that may promote chemopreventive apoptosis and/or 2) through the synthesis of anti-oxidative selenium-containing proteins (selenoproteins). Much of the current work on this problem focuses on the former of these possibilities. while very little effort has been directed toward understanding the role of regulated selenoprotein synthesis. Our study of the basic mechanisms required for Sec incorporation leaves us in an ideal position to carefully assess the contribution of the Sec incorporation pathway to chemoprevention using prostate cancer as a model. Toward this end. we are currently monitoring selenoprotein synthesis in normal and cancerous prostate cells as well as developing a cell-culture model for selenium chemoprevention.

Selected Publications

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