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Dolph L. Hatfield, Ph.D.
Role of Selenium in Cancer and Human Health
The major aims of the section of the Molecular Biology of Selenium are to understand 1) the molecular mechanisms by which selenium and selenium-containing proteins (selenoproteins) provide essential roles in development, cancer prevention and human health and 2) the means by which selenium is incorporated into protein as selenocysteine, 21st amino acid in the genetic code.
Selenium has been shown to have roles in preventing cancer and heart disease, delaying the aging process and the onset of AIDS in HIV positive patients, inhibiting viral expression and supporting mammalian development, male reproduction and immune function. A detailed understanding of how selenium makes its way into protein and how it functions in cellular metabolism will elucidate the molecular mechanisms by which this element and selenoproteins provide their many health benefits.
We devised various mouse model systems to examine the role of selenium and selenoproteins in health and development. Since the removal of the Sec tRNA gene is embryonic lethal, loxP/Cre technology is being used to generate a conditional knockout of this gene in targeted mouse tissues and organs. Thus far, we have targeted liver, breast, T cells, macrophages, epidermal and dermal tissues, endothelial cells and cardiac muscle. In these models, selenoprotein expression is specifically altered providing a means of assessing the biological roles of selenium-containing proteins in numerous diseases and in development. Our studies have shown that the targeted removal of selenoprotein expression in heart muscle results in cardiac failure at 10-12 days after birth providing the first evidence that this protein class has a role in preventing heart disease. Furthermore, studies from this laboratory have shown that both low molecular weight selenocompounds and selenoproteins have a role in colon cancer prevention. Ongoing studies are examining the role of selenium and selenoproteins in immune function, liver cancer prevention and skin development.
We have also generated a mouse line that carries mutant Sec tRNA transgenes which produce Sec tRNA lacking the highly modified base isopentenyladenosine in its anticodon loop. The mutant mice manifest reduced translation of numerous selenoproteins in a protein- and tissue-specific manner. This study provided the first example of mice engineered to produce functional tRNA transgenes. The response of these selenoprotein-deficient mice to variety of stress conditions such as viral infection, specific cancer driver genes, or selenium-deficient diets are expected to yield important insights into the roles of selenoproteins in health, including their ability to serve as anticarcinogenic agents.
We recently determined the entire biosynthetic pathway of selenocysteine in eukaryotes and archaea. Selenocysteine was the last known amino acid in the genetic code in eukaryotes whose biosynthesis had not been resolved. We are currently examining several of the factors involved in the selenocysteine biosynthetic and protein-insertion machinery in mice to understand the regulation of these processes.
We have also targeted the knockdown of thioredoxin reductase 1 (TR1) in a mouse lung cancer cell line and found that many of the malignant phenotypes were reversed in the resulting TR1 deficient cells and similar to those of normal cells. We have recently shown that knockdown of TR1 in a number of mouse and human cancer cell lines alter malignant phenotypes and that the resulting TR1 deficient cells have a defect in DNA replication. Our program is actively pursuing the role of TR1 in malignancy in breast and liver cancers and as a target for cancer therapy.
In addition, we are exploring the role of selenoprotein 15 (Sep15) in colon cancer and this selenoprotein, like that of TR1, appears to act as a double edged sword in both preventing and promoting cancer.
Our collaborators are Melinda Beck, University of North Carolina; Marla Berry, University of Hawaii; Marcus Conrad, Institute of Clinical Molecular Biology and Tumor Genetics, GSF, Munich, Germany; Cindy Davis, Nutritional Science Research Group, NCI, NIH; Vadim Gladyshev, Center for Redox Medicine
Division of Genetics, Department of Medicine,
Brigham & Women's Hospital, Harvard Medical School; Jeffrey Green, Laboratory of Cell Regulation and Carcinogenesis, NCI, NIH; Byeong Jae Lee, Seoul National University, Korea; and Ulrich Schweizer, Neuroscience Research Center, Charite Universitatsmedizin, Berlin, Germany.
This page was last updated on 6/7/2013.