Regulation of the Mammalian Selenoprotein Thioredoxin Reductase 1 in Relation to Cellular Phenotype, Growth, and Signaling Events

Abstract

Reactive oxygen species (ROS) are generated as toxic by-products of aerobic metabolism, but are also essential biomolecules in cell signaling. The thioredoxin (Trx) system is a major enzymatic system modulating ROS levels and is important for redox regulation of cellular function. It consists of Trx and thioredoxin reductase (TrxR), which reduces Trx using NADPH. Most, if not all, of the functions of Trx depend on the activity of TrxR. Mammalian TrxR enzymes are selenoproteins with broad substrate specificities, and alteration of cytosolic TrxR1 expression and activity is likely to be an important determinant for the control of cellular redox regulation. TrxR1 activity in cells seems to be modulated by an intricate interplay, involving a housekeeping type promoter in combination with alternative splice variants and transcriptional start sites, posttranscriptional regulation through AU-rich elements, inactivation by electrophilic agents and by itself modulating the effects of several key signaling molecules. TrxR1 activity is also intimately linked with several aspects of selenium metabolism, and hence selenoprotein function in general. Here, we summarize the current knowledge of these different levels of TrxR1 regulation in diverse cell types and in response to growth and signaling events.

Selenoproteins: Molecular Pathways and Physiological Roles

“…Among other physiological roles, TR1 has been implicated in DNA repair, maintaining redox homeostasis and regulation of cell signaling (12,266,297). In addition, this selenoprotein is known to activate the p53 tumor suppressor (251).…”

Spermatocyte/Spermatid-specific Thioredoxin-3, a Novel Golgi Apparatus-associated Thioredoxin, Is a Specific Marker of Aberrant Spermatogenesis

“…Thus, the TrxR-1 gene has been reported to produce at least 21 different mRNAs, whose conceptual trans- lation would result in proteins targeting the cytoplasm, mitochondria, and nucleus (10). Likewise, TrxR-2 gene could code potential mitochondrial and cytosolic variants, depending on whether the N-terminal exon coding for the mitochondrial targeting sequence is present or not (11,12).…”

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“…Transcriptional regulation of additional GPx family members extends beyond the Nrf2/Keap1 system and has been recently reviewed (45). A complex transcriptional regulation pattern involving interplay between several transcription factors, such as Oct-1, Sp1, and Sp3, and multiple transcription start sites in a cell-and stimuli-specific manner has been reported for the TrxR1 gene (reviewed in (270). Characterization of the promoter region and transcriptional regulation of the GPx4 gene also has been reported (157,219).…”

“…The thioredoxin system plays a central role in the regulation of gene expression via redox control of transcription factors including NF-B, Ref-1, AP-1, P53, glucocorticoid receptor, and apoptosis-regulating kinase (ASK1), thus indirectly regulating cellular activities such as cell proliferation, cell death, and immune-response activation (270). Conversely, several studies have now reported that TrxR is transcriptionally regulated via an antioxidant-response element (ARE) (137,304).…”