Selenium is an essential trace element currently under consideration as a chemopreventive agent. Although there is over 25 years of animal studies, and human clinical data as well, indicating the efficacy of selenium in cancer prevention, the mechanism of action remains unknown. The long term goals of his proposal are to determine the mechanism by which selenium prevents cancer and gain a better understanding of how selenium regulates the synthesis of selenium- containing proteins. In the first Specific Aim, the hypothesis that selenium reduces the levels of DNA damage following radiation exposure will be investigated by providing selenium, and the glutathione peroxidase mimetic drug ebselen, following irradiation and quantifying oxidative lesions in DNA and DNA strand breaks. Changes in the expression of stress response genes due to low level selenium supplementation of tissue culture media will also be investigated. In the second Specific Aim, the mechanism by which selenium regulates selenoprotein biosynthesis will be determined by focusing on selenium- induced methylation of the dedicated tRNA molecule that recognizes in- frame UGA codons within selenoprotein mRNAs as the amino acid selenocysteine. The role of SECIS (Selenocysteine insertion sequence) elements present in the 3' untranslated region of selenoprotein mRNAs in the translational regulation of selenoprotein biosynthesis will also be assessed. This will be accomplished using a specialized reporter construct that permits the rapid quantification of UGA readthrough under a variety of experimental conditions. In the third Specific Aim, a transgenic mouse model in which selenoprotein levels are reduced due to the presence of a mutated selenocysteine tRNA, will be used to establish the role of selenoproteins in the protection offered by selenium supplementation. Collectively, these studies will provide new insight on how selenium protects cells from radiation-induced mutagenesis and may lead to novel approaches to increase the beneficial properties of this nutrient.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA081153-07
Application #
6747294
Study Section
Radiation Study Section (RAD)
Program Officer
Malone, Winfred F
Project Start
1998-08-15
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
7
Fiscal Year
2004
Total Cost
$258,744
Indirect Cost
Name
University of Illinois at Chicago
Department
Nutrition
Type
Schools of Allied Health Profes
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Hu, Yajun; Benya, Richard V; Carroll, Robert E et al. (2005) Allelic loss of the gene for the GPX1 selenium-containing protein is a common event in cancer. J Nutr 135:3021S-3024S
Nasr, Mohamed A; Fedele, Mark J; Esser, Karyn et al. (2004) GPx-1 modulates Akt and P70S6K phosphorylation and Gadd45 levels in MCF-7 cells. Free Radic Biol Med 37:187-95
Hu, Ya Jun; Dolan, M Eileen; Bae, Richard et al. (2004) Allelic loss at the GPx-1 locus in cancer of the head and neck. Biol Trace Elem Res 101:97-106
Jameson, Ruth R; Diamond, Alan M (2004) A regulatory role for Sec tRNA[Ser]Sec in selenoprotein synthesis. RNA 10:1142-52
Hornberger, Troy A; McLoughlin, Thomas J; Leszczynski, Jori K et al. (2003) Selenoprotein-deficient transgenic mice exhibit enhanced exercise-induced muscle growth. J Nutr 133:3091-7
Hu, Ya Jun; Diamond, Alan M (2003) Role of glutathione peroxidase 1 in breast cancer: loss of heterozygosity and allelic differences in the response to selenium. Cancer Res 63:3347-51
Jameson, Ruth R; Carlson, Bradley A; Butz, Michael et al. (2002) Selenium influences the turnover of selenocysteine tRNA([Ser]Sec) in Chinese hamster ovary cells. J Nutr 132:1830-5
Mansur, D B; Kataoka, Y; Grdina, D J et al. (2001) Radiosensitivity of mammalian cell lines engineered to overexpress cytosolic glutathione peroxidase. Radiat Res 155:536-42
Diamond, A M; Hu, Y J; Mansur, D B (2001) Glutathione peroxidase and viral replication: implications for viral evolution and chemoprevention. Biofactors 14:205-10
Moustafa, M E; Carlson, B A; El-Saadani, M A et al. (2001) Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA. Mol Cell Biol 21:3840-52

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