Selenium is an essential micronutrient in the diet of humans and other mammals. Many health benefits have been attributed to selenium that include preventing various forms of cancer (e.g., colon, prostate, lung and liver cancers), heart disease and other cardiovascular and muscle disorders. Numerous human clinical trials have been undertaken in recent years to assess the role of this element in cancer prevention, delaying the progression of AIDS, etc., at a cost of hundreds of millions of dollars, but little is known about the mechanism of how selenium acts at the metabolic level in mammals to exert these many health benefits. We have proposed that the health benefits of selenium are due largely to its presence in selenoproteins as the selenium-containing amino acid, selenocysteine (Sec). Our program therefore focuses on developing mouse models to assess the role of all selenium-containing proteins, of two subclasses of selenium-containing proteins, designated housekeeping and stress-related selenoproteins, and on individual selenoproteins in preventing and promoting cancer and in mammalian development. In the past year, we completed and published several projects involving these mouse models as follows: 1) with our mouse model involving the targeted loss of stress-related selenoproteins (TrsptG37), we published a dietary study using varying levels of selenium in the diets and a liver cancer driver gene, TGF-alpha. We observed that the bitransgenic mouse had a greater incidence of tumor formation compared to other mice lacking the TGF-alpha trangene and that selenium levels in the diet did not influence tumor formation. TrsptG37 mice on selenium-deficient diets developed a neurological phenotype and widespread disseminated pyogranulomatous inflammation resulting in early morbidity and mortality;2) in collabotative study involving the TrsptG37mouse model, the effects of diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice were examined with varying levels of selenium in the diet. Our analysis showed that tumorigenesis in TrspA37G mice maintained on the adequate Se diet was increased, whereas in control, wild-type mice, both Se deficiency and high Se levels protected against tumorigenesis. Surprisingly, a similar neuorlogical phenotype could be induced in these mice at high dietary Se intake. Overall, our results revealed a complex role of Se in chemically induced hepatocarcinogenesis, which involved interaction among selenoproteins, selenocompounds and toxins, and depended on genotype and genetic background of the animals;3) we had previously demonstrated that total knockout of selenoprotein expression in mouse keratinocytes produced progeny with gross abnormalities of skin and hair, retarded growth and premature death. In the present investigation, we examined two individual selenoproteins, TR1 and GPx4, that might account for these abnormalities. TR1 knockout mice did not exhibit any apparent phenotypic changes, while GPx4 loss in keratinocytes altered epidermal differentiation and disturbed hair follicle morphogenesis;though mice ablated for GPx4 have a normal lifespan. The lack of GPx4 altered keratinocyte adhesion and proliferation in culture, increased lipid peroxidation and elevated COX-2 levels in cultured keratinocytes, which could underlie the altered skin and hair phenotype in vivo. Our data depict for the first time, an in vivo correlation between GPx4 and COX-2 expression in skin and indicated the importance of GPx4 during early stages of hair follicle morphogenesis;4) in studies with mammalian cells in culture, we investigated whether the thioredoxin system protects against TNF-alpha-induced cancer cell death by examining the role of TR1/Trx1 status on TNF-alpha-induced apoptosis in EMT6 murine breast cancer cells. TR1-deficient cells were more sensitive to TNF-alpha than control cells. Increased sensitivity to TNF-alpha was most pronounced in Trx1-deficient cells. Our data suggested that the thioredoxin system plays a critical role in protecting against TNF-alpha-induced apoptosis by regulating the levels of nuclear p-ERK 1/2 in a PI3K-dependent manner;and 5) in another study involving mammalian cells in culture, we examined the role of TR1 and the thioredoxin, Txn1) system in cells exposed to hypoxic conditions. By examining the effects of Txn1 overexpression on hypoxia-inducible factors (HIFs and specifically, HIF-1a) in HeLa, HT-29, MCF-7 and EMT6 cell lines, we found that this oxidoreductase did not stabilize HIF-1a, yet increased its activity. These effects were dependent on the redox function of Txn1. However, Txn1 deficiency did not affect HIF-1a hypoxic-stabilization and activity, and overexpression of thioredoxin reductase 1 (TR1), the natural Txn1 reductase, had no influence on HIF-1a activity. Moreover, overexpression of Txn1 in TR1 deficient HeLa and EMT6 cells was still able to increase HIF-1a hypoxic activity. These results indicate that Txn1 is not essential for HIF-1a hypoxic stabilization or activity, that its overexpression can increase HIF-1a hypoxic activity, and that this effect is observed regardless of TR1 status. Thus, regulation of HIF-1a by the thioredoxin system depends on the specific levels of this system's major components.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC005317-30
Application #
8762991
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
30
Fiscal Year
2013
Total Cost
$530,623
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Seeher, Sandra; Carlson, Bradley A; Miniard, Angela C et al. (2014) Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice. Biochem J 462:67-75
Turanov, Anton A; Shchedrina, Valentina A; Everley, Robert A et al. (2014) Selenoprotein S is involved in maintenance and transport of multiprotein complexes. Biochem J 462:555-65
Hatfield, Dolph L; Tsuji, Petra A; Carlson, Bradley A et al. (2014) Selenium and selenocysteine: roles in cancer, health, and development. Trends Biochem Sci 39:112-20
Kasaikina, Marina V; Turanov, Anton A; Avanesov, Andrei et al. (2013) Contrasting roles of dietary selenium and selenoproteins in chemically induced hepatocarcinogenesis. Carcinogenesis 34:1089-95
Sengupta, Aniruddha; Lichti, Ulrike F; Carlson, Bradley A et al. (2013) Targeted disruption of glutathione peroxidase 4 in mouse skin epithelial cells impairs postnatal hair follicle morphogenesis that is partially rescued through inhibition of COX-2. J Invest Dermatol 133:1731-41
Naranjo-Suarez, Salvador; Carlson, Bradley A; Tobe, Ryuta et al. (2013) Regulation of HIF-1α activity by overexpression of thioredoxin is independent of thioredoxin reductase status. Mol Cells 36:151-7
Moustafa, Mohamed E; Carlson, Bradley A; Anver, Miriam R et al. (2013) Selenium and selenoprotein deficiencies induce widespread pyogranuloma formation in mice, while high levels of dietary selenium decrease liver tumor size driven by TGFα. PLoS One 8:e57389
Patterson, Andrew D; Carlson, Bradley A; Li, Fei et al. (2013) Disruption of Thioredoxin Reductase 1 Protects Mice from Acute Acetaminophen-Induced Hepatotoxicity through Enhanced NRF2 Activity. Chem Res Toxicol :
Yoo, Min-Hyuk; Carlson, Bradley A; Gladyshev, Vadim N et al. (2013) Abrogated thioredoxin system causes increased sensitivity to TNF-α-induced apoptosis via enrichment of p-ERK 1/2 in the nucleus. PLoS One 8:e71427
Carlson, Bradley A; Yoo, Min-Hyuk; Tobe, Ryuta et al. (2012) Thioredoxin reductase 1 protects against chemically induced hepatocarcinogenesis via control of cellular redox homeostasis. Carcinogenesis 33:1806-13

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