Selenoprotein W in Embryonic Development and Oxidative Stress
Chrissa Kioussi, Ph.D.
Selenium is an essential element for human health. There are places in the world, such as China, where selenium deficiency is still a problem. In lambs and calves, selenium deficiency can cause white muscle disease and, in humans, Keshan cardiomyopathy, deforming arthritis in Kashim-Beck disease, and myxedematous cretinism. Selenium-deficient diets in animals can modify the course of viral infections and can cause mutations within the virus that create new, more virulent strains. Additionally, many studies have demonstrated that selenium supplementation has anticancer effects when given in pharmacological amounts.
Selenium is involved is several cellular processes, including regulation of thyroid hormone metabolism, regulation of the redox state of cells, cancer prevention, and immune function. Low blood selenium levels are associated with several pathologies, including cancer, cardiovascular disease, and mental illness. It is believed that selenium exerts its protective effects by preventing oxidative damage. Neuronal and neuromuscular disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, stroke, and Duchenne Muscular Dystrophy, are diseases associated with free radicals and oxidative stress. The synthesis of the selenocysteine-containing proteins is an essential prerequisite for fetal development and a healthy life.
So far, 25 mammalian selenoproteins have been identified that contain selenium in the form of the amino acid selenocysteine. Availability of selenium is a critical, limiting factor for the synthesis of selenocysteine. Most of the selenoproteins for which an enzymatic function has been determined possess antioxidant activities, suggesting that human diseases associated with selenium deficiency may be attributed to increased oxidative stress and alterations in redox signaling.
Selenoprotein W (SePW) is a mammalian protein of 87 amino acids in length. SePW is highly conserved among mammalsit varies little between species. SePW binds to an important endogenous antioxidant, glutathione, in cells. It was originally purified in the early 1990s in the laboratory of Dr. Phil Whanger at Oregon State University and found to be missing in selenium-deficient lambs suffering from white muscle disease. Expression of SePW in the brain is preserved even in selenium-deficient animals, which suggests a crucial role in nervous system development and function. Recent studies have indicated that SePW is a molecular target of methylmercury, an environmental toxicant. Methylmercury decreases SePW and, consequently, is associated with intracellular glutathione depletion in neuronal cells. When SePW is increased in epithelial ovary and lung cancer cells, these cells exhibit a markedly reduced sensitivity to hydrogen peroxide.
We recently found that SePW is present in newly implanted embryos in mice. SePW was found in the ectodermal cells of the egg cylinder stage, which give rise to the neuroepithelium of the cephalic neural folds, which, in turn, form parts of the brain (cortex, thalamus, and hypothalamus) and spinal cord. SePW was also found in the heart and the somites, the mesodermal structures that give rise to skeletal muscles. We observed that SePW levels gradually increased during the second week of gestation in mice (equivalent to the second trimester in humans) and dramatically increased by the end of the gestation period as a result of the high proliferation rate of brain, heart, and skeletal muscle tissues. This functional profile of SePW suggests its involvement in the transition from the maternal genome to the embryonic genome and in the development of organ systems, such as brain, heart, and skeletal muscles.
In cell culture studies, we found that SePW levels were increased in the proliferating myoblasts that give rise to muscle tissue, with a subsequent decrease during further differentiation, suggesting a role in development and growth. When proliferating myoblasts were exposed to hydrogen peroxide, levels of SePW decreased after 30 minutes. After two hours, SePW levels decreased by 56%. Inhibition of glutathione synthesis in these cells also dramatically decreased SePW levels. This immediate response of SePW in cells treated with hydrogen peroxide suggests that SePW is involved in the oxidative metabolic pathways and functions as an antioxidant to maintain proper muscle function. Other investigators found that SePW is decreased by cadmium. Glutathione is implicated in the anti-cadmium defense through a transcription factor called MTF-1. MTF-1 binds to sequences in DNA that code for the SePW promoter. Given the effect of methylmercury, hydrogen peroxide, and cadmium on SePW, it appears that SePW can be used to monitor immediate oxidative and toxic stress.
Another selenoprotein, Selenoprotein N (SEPN1), is also found in muscles and linked to congenital muscular dystrophies. SEPN1 is localized in the endoplasmic reticulum in cells, which is involved in calcium sequestration and muscle contraction. Calcium sequestration is lost in the sarcoplasmic reticulum in the muscles of animals with white muscle disease, where SePW is absent. Therefore, it is likely that both forms of selenium are linked to both muscle development and disease.
Last updated May 2007