Abstract
The intracellular generation of reactive oxygen species, together with the thioredoxin and glutathione systems, is thought to participate in redox signaling in mammalian cells. The activity of thioredoxin is dependent on the redox status of thioredoxin reductase (TR), the activity of which in turn is dependent on a selenocysteine residue. Two mammalian TR isozymes (TR2 and TR3), in addition to that previously characterized (TR1), have now been identified in humans and mice. All three TR isozymes contain a selenocysteine residue that is located in the penultimate position at the carboxyl terminus and which is encoded by a UGA codon. The generation of reactive oxygen species in a human carcinoma cell line was shown to result in both the oxidation of the selenocysteine in TR1 and a subsequent increase in the expression of this enzyme. These observations identify the carboxyl-terminal selenocysteine of TR1 as a cellular redox sensor and support an essential role for mammalian TR isozymes in redox-regulated cell signaling.
Highlights
The intracellular generation of reactive oxygen species, together with the thioredoxin and glutathione systems, is thought to participate in redox signaling in mammalian cells
The redox state of essential thiol groups is controlled by two cellular redox systems: the thioredoxin (thioredoxin, thioredoxin reductase, and thioredoxin peroxidase) and glutathione (glutathione, glutathione reductase, glutaredoxin, and glutathione peroxidase (GPX)) systems [9]
Several proteins, including apoptosis signal-regulating kinase 1 (ASK1; this protein belongs to a family of mitogenactivated protein kinase kinase kinases) [12], protein-tyrosine phosphatase 1B (PTP1B) [13], and thioredoxin peroxidase [14], have been identified as components of redox signaling pathways that act downstream of the generation of intracellular Reactive oxygen species (ROS)
Summary
Vol 274, No 35, Issue of August 27, pp. 24522–24530, 1999 Printed in U.S.A. Redox Regulation of Cell Signaling by Selenocysteine in Mammalian Thioredoxin Reductases*. The intracellular generation of reactive oxygen species, together with the thioredoxin and glutathione systems, is thought to participate in redox signaling in mammalian cells. The generation of reactive oxygen species in a human carcinoma cell line was shown to result in both the oxidation of the selenocysteine in TR1 and a subsequent increase in the expression of this enzyme These observations identify the carboxyl-terminal selenocysteine of TR1 as a cellular redox sensor and support an essential role for mammalian TR isozymes in redox-regulated cell signaling. Several proteins, including apoptosis signal-regulating kinase 1 (ASK1; this protein belongs to a family of mitogenactivated protein kinase kinase kinases) [12], protein-tyrosine phosphatase 1B (PTP1B) [13], and thioredoxin peroxidase [14], have been identified as components of redox signaling pathways that act downstream of the generation of intracellular ROS. The data suggest that the selenocysteine residue in thioredoxin reductases serves as a cellular redox sensor
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