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About the Authors:
Min-Hyuk Yoo
Affiliation: Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America
Bradley A. Carlson
Affiliation: Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America
Vadim N. Gladyshev
Affiliation: Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
Dolph L. Hatfield
* E-mail: [email protected]
Affiliation: Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America
Introduction
The thioredoxin system is one of the most important cellular redox regulatory systems. Thioredoxin (Trx) and thioredoxin reductase 1 (TR1) are the principal components of this system. The thioredoxin system regulates the redox state of protein thiols and controls many cellular processes, including proliferation, defense against oxidative stress, and apoptosis [1–3]. Trx was first identified as a reductant for ribonucleotide reductase and a regulator of DNA synthesis [4,5]. However, Trx is now known to regulate many proteins in a variety of pathways. The molecular and biological targets of Trx include methionine sulfoxide reductase, which is involved in protein repair [6,7], nuclear factor-kappa B (NF-κB) and apoptosis signal-regulating kinase 1 (ASK1), which regulate apoptosis [8,9], and peroxiredoxin, which regulates levels of reactive oxygen species (ROS) [10].
Mammalian TR1 is a selenium-containing protein that has selenocysteine (Sec), the 21st amino acid, at its catalytic site. Sec is essential for the activity of TR1 [11,12]. TR1 is primarily known for its ability to catalyze the transfer of reducing potentials to thioredoxin from NADPH. However, TR1 has additional substrates, including selenocompounds, ascorbate, lipoate, and oxidized lipids. Thus, TR1 may regulate multiple cellular processes in addition to reducing Trx and, through function, regulate the cellular redox status [13–15]. Importantly, TR1 has been shown to be over-expressed in many human tumors and cancer cell lines. Numerous inhibitors of TR1 have been reported to impede tumor growth, suggesting that this selenoprotein may be a target for cancer therapy [16,17]. Indeed, knockdown of TR1 with small interfering RNA (siRNA) technology reversed many cancer phenotypes, providing further evidence that this antioxidant enzyme plays...