Selenoprotein as a target for cancer prevention

University Of Nebraska Lincoln, Lincoln NE

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Abstract

DESCRIPTION (provided by applicant): Recent human clinical trials have demonstrated a cancer-chemopreventive effect of dietary selenium, and additional trials are underway. Evidence has also accumulated for the role of selenium in reducing cancer incidence in animal model systems. However, the molecular basis for chemoprevention by this essential trace element remains unknown. This project will employ biochemical and genetic techniques and mouse model systems to functionally characterize a recently identified 15 kDa selenoprotein and to determine its role in cancer prevention. Preliminary studies suggest that the effect of selenium in cancer may be mediated by this selenoprotein. Data are presented that indicate that the 15 kDa protein gene locus is deleted and expression of the selenoprotein is altered in certain cancers. The human selenoprotein gene has two polymorphic sites within 3'-UTR that exhibit ethnic distribution and influence incorporation of selenocysteine into protein. The two human alleles respond differentially to selenium supplementation. Preliminary data also show an association between the 15 kDa selenoprotein and UDP-glucose glycoprotein glucosyltransferase in the endoplasmic reticulum of mammalian cells implicating the selenoprotein in the quality control of protein folding. Proposed studies include 1) characterization of the 15 kDa protein function using a combination of genetic and biochemical approaches, with emphasis on elucidating the role of the selenoprotein in regulation of protein folding; 2) characterization of the consequences of 15 kDa protein deficiency in knockout mice; and 3) testing the hypothesis that increased expression of the 15 kDa protein may protect against developing cancer in mice.