Selenium is an essential trace element, which has provoked considerable interest due to the recent identification of prokaryotic and eukaryotic proteins that contain the amino acid, selenocysteine. Incorporation of selenocysteine into these proteins requires a novel translation step in which UGA specifies selenocysteine insertion instead of termination. This is conferred by a complex interaction between specific components of the translation machinery and secondary structures in selenoprotein mRNAs, termed SECIS elements.
The specific aims of this proposal are 1) to investigate differential SECIS element function for different regions of the mRNA for selenoprotein P (see below), and to investigate the factors contributing to the differential activities of these elements and to the """"""""hierarchy of selenoprotein synthesis"""""""", 2) to investigate the effects of coding region sequences on selenocysteine incorporation efficiency, 3) to investigate the effects of translation initiation rates on selenoprotein synthesis, and 4) to determine the optimal levels and ratios of the factors involved in this process, with the goal of developing a system for more efficient selenoprotein synthesis. The identification of selenocysteine in numerous mammalian and lower eukaryotic proteins during the past decade has provided new insights into the functions of this trace nutrient. Studies of selenocysteine incorporation in type 1 iodothyronine deiodinase opened the door for investigation of the requirements for eukaryotic selenoprotein synthesis, and the features that distinguish this pathway from the mechanism in prokaryotes. More recently, studies of the biosynthesis of selenoprotein P, which contains 10 - 17 selenocysteine residues, have provided an ideal system in which to investigate the efficiency of selenocysteine incorporation. While significant progress has been made in recent years, investigation of the complex interplay between the mRNA secondary structures, a novel SECIS binding protein, the selenocysteine-specific elongation factor, and other components of the translational machinery remains foremost among the tasks ahead. Examination of physiological circumstances contributing to tissue-specific differences in selenocysteine incorporation will help to explain how the animal has adapted to maximize utilization of this trace element, with crucial implications for advancing our understanding of the roles of selenium in health and disease. Finally, studies of eukaryotic selenoprotein synthesis have provided unexpected insights into the mechanisms of translation and termination of protein synthesis. Continuing studies of this process will surely unveil new and exciting information about the complex workings of the translation machinery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052963-08
Application #
6655108
Study Section
Nutrition Study Section (NTN)
Program Officer
May, Michael K
Project Start
1997-09-01
Project End
2006-07-31
Budget Start
2003-09-01
Budget End
2004-07-31
Support Year
8
Fiscal Year
2003
Total Cost
$204,450
Indirect Cost
Name
University of Hawaii
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
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Stoytcheva, Zoia R; Berry, Marla J (2009) Transcriptional regulation of mammalian selenoprotein expression. Biochim Biophys Acta 1790:1429-40
Castellano, Sergi; Gladyshev, Vadim N; Guigo, Roderic et al. (2008) SelenoDB 1.0 : a database of selenoprotein genes, proteins and SECIS elements. Nucleic Acids Res 36:D332-8
Squires, Jeffrey E; Stoytchev, Ilko; Forry, Erin P et al. (2007) SBP2 binding affinity is a major determinant in differential selenoprotein mRNA translation and sensitivity to nonsense-mediated decay. Mol Cell Biol 27:7848-55
Xu, Xue-Ming; Carlson, Bradley A; Zhang, Yan et al. (2007) New developments in selenium biochemistry: selenocysteine biosynthesis in eukaryotes and archaea. Biol Trace Elem Res 119:234-41
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Hoffmann, Peter R; Hoge, Simone C; Li, Ping-An et al. (2007) The selenoproteome exhibits widely varying, tissue-specific dependence on selenoprotein P for selenium supply. Nucleic Acids Res 35:3963-73
Xu, Xue-Ming; Carlson, Bradley A; Mix, Heiko et al. (2007) Biosynthesis of selenocysteine on its tRNA in eukaryotes. PLoS Biol 5:e4
de Jesus, Lucia A; Hoffmann, Peter R; Michaud, Tanya et al. (2006) Nuclear assembly of UGA decoding complexes on selenoprotein mRNAs: a mechanism for eluding nonsense-mediated decay? Mol Cell Biol 26:1795-805
Small-Howard, Andrea; Morozova, Nadya; Stoytcheva, Zoia et al. (2006) Supramolecular complexes mediate selenocysteine incorporation in vivo. Mol Cell Biol 26:2337-46

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