Alternative titles; symbols
HGNC Approved Gene Symbol: TXN
Cytogenetic location: 9q31.3 Genomic coordinates (GRCh38): 9:110,243,810-110,256,507 (from NCBI)
Thioredoxin is a 12-kD oxidoreductase enzyme containing a dithiol-disulfide active site. It is ubiquitous and found in many organisms from plants and bacteria to mammals. Multiple in vitro substrates for thioredoxin have been identified, including ribonuclease, choriogonadotropins, coagulation factors, glucocorticoid receptor, and insulin. Reduction of insulin is classically used as an activity test (summary by Wollman et al., 1988).
Wollman et al. (1988) identified a full-length cDNA clone encoding human thioredoxin. The open reading frame codes for a protein of 104 amino acids, excluding the initial methionine. This protein possesses the highly conserved enzymatic active site common to plant and bacterial thioredoxins: trp-cys-gly-pro-cys (amino acids 30 to 34).
By yeast 2-hybrid analysis of a human brain cDNA library, Saitoh et al. (1998) identified TRX and ASK1 (MAP3K5; 602448) as interacting partners. TRX associated with the N-terminal portion of ASK1 in vitro and in vivo, and the interaction between TRX and ASK1 was highly dependent on the redox status of TRX. Expression of TRX inhibited ASK1 kinase activity and ASK1-dependent apoptosis. Inhibition of TRX resulted in activation of endogenous ASK1 activity. Saitoh et al. (1998) concluded that TRX is a physiologic inhibitor of ASK1 and may be involved in redox regulation of the apoptosis signal transduction pathway.
Junn et al. (2000) found that the C-terminal half of mouse Vdup1 (TXNIP; 606599) interacted with the redox-active center of Trx. Mutation of 2 critical cysteines in the Trx active center abrogated the interaction with Vdup1. Transfection of mouse Vdup1 into human embryonic kidney cells reduced the endogenous reducing activity of TRX or the activity of cotransfected TRX. Overexpression of Vdup1 inhibited interaction between Trx and a thiol-specific antioxidant, Pag (PRDX1; 176763), and it inhibited interaction between Trx and Ask1. Treatment of mouse fibroblasts and T-cell hybridoma cells with various stress stimuli, such as hydrogen peroxide or heat shock, induced Vdup1 expression. Exposure of mouse fibroblasts overexpressing Vdup1 to stress resulted in reduced cell proliferation and elevated apoptotic cell death. Junn et al. (2000) concluded that VDUP1 functions as an oxidative stress mediator by inhibiting TRX activity.
Wang et al. (2002) found that biomechanical strain or hydrogen peroxide downregulated expression of Vdup1, but not Trx, in rat cardiomyocytes. The rapid response occurred through transcriptional control and led to increased Trx activity. Adenovirus-mediated overexpression of Vdup1 suppressed Trx activity and induced cardiomyocyte apoptosis. Furthermore, Vdup1 overexpression sensitized cells to hydrogen peroxide-induced apoptosis, whereas Trx overexpression protected cells against injury. Wang et al. (2002) concluded that VDUP1 is a key stress-responsive inhibitor of thioredoxin activity in cardiomyocytes.
Adriamycin (ADR) is an anticancer drug that causes severe cardiac toxicity by generating free radicals. Shioji et al. (2002) found that Trx1 was dose-dependently increased concomitant with formation of hydroxyl radicals in ADR-treated neonatal rat cardiomyocytes. Treatment with recombinant human TRX1 suppressed cardiomyocyte injury in ADR-treated cells. Electron microscopy revealed better maintenance of cardiac mitochondria and cellular architecture in ADR-treated TRX1-expressing transgenic mice than in ADR-treated wildtype mice. Formation of hydroxyl radicals following ADR treatment was reduced in transgenic mice compared with wildtype mice, and transgenic mice showed significantly increased survival.
Yoshioka et al. (2004) overexpressed thioredoxin in rat cardiomyocytes and observed the induction of protein synthesis; overexpression of TXNIP reduced protein synthesis in response to mechanical strain, phenylephrine, and angiotensin II (see 106150). In vivo, myocardial TXN activity increased 3.5-fold compared to sham controls after transverse aortic constriction; however, aortic constriction did not increase TXN expression but reduced TXNIP expression by 40%. Gene transfer studies revealed that cells overexpressing TXNIP developed less hypertrophy after aortic constriction than control cells in the same animals. Yoshioka et al. (2004) concluded that TXN has a dual function as both an antioxidant and a signaling protein involved in the development of pressure-overload cardiac hypertrophy, and suggested that TXNIP is a critical regulator of biomechanical signaling.
Using RNA interference with HeLa cells, Jeong et al. (2004) found that depletion of TRP14 (TXNDC17; 616967) or TRX1 enhanced TNF-alpha (TNF; 191160)-induced activation of caspases (see CASP3, 600636) and NF-kappa-B (see 164011). Depletion of TRP14, but not TRX1, augmented TNF-alpha-induced activation of JNK (MAPK8; 601158) and p38 MAPK (MAPK14; 600289). In contrast, the reduced form of TRX1, but not TRP14, bound and inhibited ASK1, which activates the JNK and p38 pathways.
Nitric oxide (see 163731) acts substantially in cellular signal transduction through stimulus-coupled S-nitrosylation of cysteine residues. Benhar et al. (2008) searched for denitrosylase activities, and focused on caspase-3, an exemplar of stimulus-dependent denitrosylation, and identified thioredoxin and thioredoxin reductase (see TXNRD1, 601112) in a biochemical screen. In resting human lymphocytes, thioredoxin-1 actively denitrosylated cytosolic caspase-3 and thereby maintained a low steady-state amount of S-nitrosylation. Upon stimulation of Fas, thioredoxin-2 (609063) mediated denitrosylation of mitochondria-associated caspase-3, a process required for caspase-3 activation, and promoted apoptosis. Inhibition of thioredoxin-thioredoxin reductases enabled identification of additional substrates subject to endogenous S-nitrosylation. These substrates included caspase-9 (602234) and protein tyrosine phosphatase-1B (176885). Thus, Benhar et al. (2008) concluded that specific enzymatic mechanisms may regulate basal and stimulus-induced denitrosylation in mammalian cells.
Im et al. (2012) found that DJ1 (602533) protected HeLa cells and human neuroblastoma cell lines from oxidative stress by inducing expression of TRX1. Studies with Dj1-null mice confirmed the findings. DJ1 increased protein expression and nuclear accumulation of the transcription factor NRF2 (NFE2L2; 600492) and enhanced binding of NRF2 to the antioxidant response element (ARE) in the TRX1 promoter.
Pader et al. (2014) found that both TRP14 and TRX1 functioned as S-denitrosylases in catalyzing TRXR1 (TXNRD1)-dependent denitrosylation of S-nitrosylated glutathione or HEK293 cell-derived S-nitrosoproteins. TRP14 and TRX1 reactivated caspase-3 and lysosomal cathepsin B (CTSB; 116810) that had been inactivated via nitrosylation.
Tonissen and Wells (1991) determined that the TRX gene extends over 13 kb and has 5 exons.
Kaghad et al. (1994) also cloned the TXN gene and identified 5 exons. They determined the +1 transcription start point by primer extension. The +1 site is located 22 bp downstream from a TATAA box and defines a 5-prime untranslated region of 74 bp.
Im et al. (2012) reported that the TXN promoter region contains binding sites for FOXO3 (602681), NRF2, CREB (123810), and SP1 (189906).
Using in situ chromosomal hybridization with a human TXN cDNA probe, Lafage-Pochitaloff-Huvale et al. (1989) localized the gene to chromosome 3p12-p11. However, Heppell-Parton et al. (1995) concluded that the correct chromosomal localization of the transcribed thioredoxin gene is 9q31. They discovered this both by analysis of a somatic cell hybrid panel and by fluorescence in situ hybridization of a YAC encoding the transcribed gene. The localization to chromosome 9 was confirmed by PCR amplification from a human/hamster somatic cell hybrid containing chromosome 9 as its only human chromosome. No amplification signals were detected in any of the other monochromosome hybrid cells. The location of the mouse thioredoxin gene on chromosome 4 is noteworthy because part of that chromosome shares homology with human chromosome 9.
Taketo et al. (1994) found that the homologous gene in mouse is located on chromosome 4 and that there is a processed Txn pseudogene in the proximal region of mouse chromosome 1.
Southern analysis by Tonissen and Wells (1991) demonstrated the presence of several TXN genes in the human genome, at least one of which is a pseudogene. By Southern hybridization of genomic DNAs from several donors, Kaghad et al. (1994) detected only 1 active TXN gene.
Benhar, M., Forrester, M. T., Hess, D. T., Stamler, J. S. Regulated protein denitrosylation by cytosolic and mitochondrial thioredoxins. Science 320: 1050-1054, 2008. [PubMed: 18497292] [Full Text: https://doi.org/10.1126/science.1158265]
Heppell-Parton, A., Cahn, A., Bench, A., Lowe, N., Lehrach, H., Zehetner, G., Rabbitts, P. Thioredoxin, a mediator of growth inhibition, maps to 9q31. Genomics 26: 379-381, 1995. [PubMed: 7601465] [Full Text: https://doi.org/10.1016/0888-7543(95)80223-9]
Im, J.-Y., Lee, K.-W., Woo, J.-M., Junn, E., Mouradian, M. M. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. Hum. Molec. Genet. 21: 3013-3024, 2012. [PubMed: 22492997] [Full Text: https://doi.org/10.1093/hmg/dds131]
Jeong, W., Chang, T.-S., Boja, E. S., Fales, H. M., Rhee, S. G. Roles of TRP14, a thioredoxin-related protein in tumor necrosis factor-alpha signaling pathways. J. Biol. Chem. 279: 3151-3159, 2004. [PubMed: 14607843] [Full Text: https://doi.org/10.1074/jbc.M307959200]
Junn, E., Han, S. H., Im, J. Y., Yang, Y., Cho, E. W., Um, H. D., Kim, D. K., Lee, K. W., Han, P. L., Rhee, S. G., Choi, I. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J. Immun. 164: 6287-6295, 2000. [PubMed: 10843682] [Full Text: https://doi.org/10.4049/jimmunol.164.12.6287]
Kaghad, M., Dessarps, F., Jacquemin-Sablon, H., Caput, D., Fradelizi, D., Wollman, E. E. Genomic cloning of human thioredoxin-encoding gene: mapping of the transcription start point and analysis of the promoter. Gene 140: 273-278, 1994. [PubMed: 8144037] [Full Text: https://doi.org/10.1016/0378-1119(94)90557-6]
Lafage-Pochitaloff-Huvale, M., Shaw, A., Dessarps, F., Mannoni, P., Fradelizi, D., Wollman, E. E. The gene for human thioredoxin maps on the short arm of chromosome 3 at bands 3p11-p12. FEBS Lett. 255: 89-91, 1989. [PubMed: 2676601] [Full Text: https://doi.org/10.1016/0014-5793(89)81066-x]
Pader, I., Sengupta, R., Cebula, M., Xu, J., Lundberg, J. O., Holmgren, A., Johansson, K., Arner, E. S. J. Thioredoxin-related protein of 14 kDa is an efficient L-cystine reductase and S-denitrosylase. Proc. Nat. Acad. Sci. 111: 6964-6969, 2014. [PubMed: 24778250] [Full Text: https://doi.org/10.1073/pnas.1317320111]
Saitoh, M., Nishitoh, H., Fujii, M., Takeda, K., Tobiume, K., Sawada, Y., Kawabata, M., Miyazono, K., Ichijo, H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17: 2596-2606, 1998. [PubMed: 9564042] [Full Text: https://doi.org/10.1093/emboj/17.9.2596]
Shioji, K., Kishimoto, C., Nakamura, H., Masutani, H., Yuan, Z., Oka, S., Yodoi, J. Overexpression of thioredoxin-1 in transgenic mice attenuates adriamycin-induced cardiotoxicity. Circulation 106: 1403-1409, 2002. [PubMed: 12221060] [Full Text: https://doi.org/10.1161/01.cir.0000027817.55925.b4]
Taketo, M., Matsui, M., Rochelle, J. M., Yodoi, J., Seldin, M. F. Mouse thioredoxin gene maps on chromosome 4, whereas its pseudogene maps on chromosome 1. Genomics 21: 251-253, 1994. [PubMed: 8088797] [Full Text: https://doi.org/10.1006/geno.1994.1252]
Tonissen, K. F., Wells, J. R. E. Isolation and characterization of human thioredoxin-encoding genes. Gene 102: 221-228, 1991. [PubMed: 1874447] [Full Text: https://doi.org/10.1016/0378-1119(91)90081-l]
Wang, Y., De Keulenaer, G. W., Lee, R. T. Vitamin D3-up-regulated protein-1 is a stress-responsive gene that regulates cardiomyocyte viability through interaction with thioredoxin. J. Biol. Chem. 277: 26496-26500, 2002. [PubMed: 12011048] [Full Text: https://doi.org/10.1074/jbc.M202133200]
Wollman, E. E., d'Auriol, L., Rimsky, L., Shaw, A., Jacquot, J.-P., Wingfield, P., Graber, P., Dessarps, F., Robin, P., Galibert, F., Bertoglio, J., Fradelizi, D. Cloning and expression of a cDNA for human thioredoxin. J. Biol. Chem. 263: 15506-15512, 1988. [PubMed: 3170595]
Yoshioka, J., Schulze, P. C., Cupesi, M., Sylvan, J. D., MacGillivray, C., Gannon, J., Huang, H., Lee, R. T. Thioredoxin-interacting protein controls cardiac hypertrophy through regulation of thioredoxin activity. Circulation 109: 2581-2586, 2004. [PubMed: 15123525] [Full Text: https://doi.org/10.1161/01.CIR.0000129771.32215.44]