Selenium is an essential trace element in the diets of mammals because of its presence in selenocysteine- containing proteins. Clinical trials and animal studies have demonstrated the potent cancer prevention activity of selenium;however, mechanisms by which it decreases cancer incidence are not understood. This deficiency precludes identification of subsets of the human population that benefit from dietary selenium supplementation, as well as those who do not. At optimal concentrations of selenium in the diet, selenoproteins account for the major pool of this trace element in mammalian organs and tissues. Functionally characterized selenoproteins exhibit redox activities, and imbalance in the levels of these proteins affects redox homeostasis. The PI recently identified a full set of selenoproteins in mammals, many of which are redox proteins. Among them, the 15 kDa selenoprotein (Sep15) emerged as the major candidate for mediating the cancer prevention effect of dietary Se. In the previous funding cycle, the PI's research team carried out initial functional and structural characterization of Sep15, its homologs and interacting partners, and developed Sep15 mouse models. The role of selenoproteins and selenocompounds in the development of hepatic tumors in mice was also addressed. The research team is now poised to benefit from this foundation and proposes to characterize in detail the functions of Sep15 and members of its protein family and to use novel mouse models of hepatic selenoprotein deficiency to directly determine the role of selenoproteins in cancer prevention. This work will be guided by three questions (specific aims): 1) What is the role of Sep15 in oxidative protein folding? 2) What is the biological function of Sep15? and 3) What roles do selenoproteins play in cancer prevention? These questions will be addressed using a combination of biochemical and cell biology studies and animal models. Relevance to the public health: The trace element selenium protects against prostate, colon, lung, and liver cancer, but the mechanism of this effect and forms of selenium that contribute most to this protection are unknown. This research will examine selenoproteins implicated in cancer prevention and the factors affecting their functions. This research may have direct implications for human studies and may lead to the ability to identify segments of the human population at risk of developing cancers that can be prevented by selenium.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080946-12
Application #
8080365
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (02))
Program Officer
Perloff, Marjorie
Project Start
2001-04-01
Project End
2013-03-31
Budget Start
2011-06-01
Budget End
2013-03-31
Support Year
12
Fiscal Year
2011
Total Cost
$284,449
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Podolskiy, Dmitriy I; Lobanov, Alexei V; Kryukov, Gregory V et al. (2016) Analysis of cancer genomes reveals basic features of human aging and its role in cancer development. Nat Commun 7:12157
Tobe, Ryuta; Carlson, Bradley A; Huh, Jang Hoe et al. (2016) Selenophosphate synthetase 1 is an essential protein with roles in regulation of redox homoeostasis in mammals. Biochem J 473:2141-54
Mariotti, Marco; Lobanov, Alexei V; Manta, Bruno et al. (2016) Lokiarchaeota Marks the Transition between the Archaeal and Eukaryotic Selenocysteine Encoding Systems. Mol Biol Evol 33:2441-53
Podolskiy, Dmitriy I; Gladyshev, Vadim N (2016) Intrinsic Versus Extrinsic Cancer Risk Factors and Aging. Trends Mol Med 22:833-834
Gladyshev, Vadim N; Arnér, Elias S; Berry, Marla J et al. (2016) Selenoprotein Gene Nomenclature. J Biol Chem 291:24036-24040
Ma, Siming; Lee, Sang-Goo; Kim, Eun Bae et al. (2015) Organization of the Mammalian Ionome According to Organ Origin, Lineage Specialization, and Longevity. Cell Rep 13:1319-1326
Tobe, Ryuta; Carlson, Bradley A; Tsuji, Petra A et al. (2015) Differences in Redox Regulatory Systems in Human Lung and Liver Tumors Suggest Different Avenues for Therapy. Cancers (Basel) 7:2262-76
Cornelis, Marilyn C; Fornage, Myriam; Foy, Millennia et al. (2015) Genome-wide association study of selenium concentrations. Hum Mol Genet 24:1469-77
Tian, Xiao; Azpurua, Jorge; Ke, Zhonghe et al. (2015) INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform. Proc Natl Acad Sci U S A 112:1053-8
Tsuji, Petra A; Carlson, Bradley A; Yoo, Min-Hyuk et al. (2015) The 15kDa selenoprotein and thioredoxin reductase 1 promote colon cancer by different pathways. PLoS One 10:e0124487

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