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Gene Review

TXN  -  thioredoxin

Homo sapiens

Synonyms: ADF, ATL-derived factor, SASP, Surface-associated sulphydryl protein, TRDX, ...
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Disease relevance of TXN

  • Nuclear factor kappaB transactivation is increased but is not involved in the proliferative effects of thioredoxin overexpression in MCF-7 breast cancer cells [1].
  • Moreover, analysis of subcellular localization of TRX and the chimeric protein harboring herpes simplex viral protein 16 transactivation domain and the GR DBD indicated that the interaction might take place in the nucleus under oxidative conditions [2].
  • Cells from patients with the cancer-prone disease Fanconi anemia (FA) exhibit reduced Trx levels [3].
  • Also the mammalian Trx system was inhibited by GS-Pt with similar efficiency (IC(50) = 325 microM), whereas neither the E. coli Trx system nor glutathione reductase were inhibited [4].
  • Together, these data suggest that, although TR is protective against Abeta-mediated toxicity, the increase observed in AD brain offers no protection due to the significant decrease in Trx levels [5].
  • The pathopysiological role of TRX in hypertension and other cardiovascular diseases is addressed [6].

Psychiatry related information on TXN


High impact information on TXN

  • TRX is a small multifunctional protein that has a redox-active disulfide/dithiol within the conserved active site sequence: Cys-Gly-Pro-Cys [8].
  • Extracellularly, TRX/ADF shows a cytoprotective activity against oxidative stress-induced apoptosis and a growth-promoting effect as an autocrine growth factor [8].
  • Adult T cell leukemia-derived factor (ADF), which we originally defined as an IL-2 receptor alpha-chain/Tac inducer produced by human T cell lymphotrophic virus-I (HTLV-I)-transformed T cells, has been identified as human TRX [8].
  • Intracellularly, TRX/ADF is involved in the regulation of protein-protein or protein-nucleic acid interactions through the reduction/oxidation of protein cysteine residues [8].
  • The thin, flat FTR molecule makes the two-electron reduction possible by forming on one side a mixed disulfide with thioredoxin and by providing on the opposite side access to ferredoxin for delivering electrons [9].

Chemical compound and disease context of TXN


Biological context of TXN

  • In this study, we demonstrated that either antisense TRX expression or cellular treatment with H2O2 negatively modulates GR function and decreases glucocorticoid-inducible gene expression [15].
  • The evidence that Trx is a negative regulator of ASK1 suggests possible mechanisms for redox regulation of the apoptosis signal transduction pathway as well as the effects of antioxidants against cytokine- and stress-induced apoptosis [16].
  • These experiments suggest that a redox-sensitive signaling pathway leading from TRX to Ref-1 to the AP-1 complex participates in the up-regulation of DNA binding activity in response to ionizing radiation [17].
  • Trx is overexpressed by a number of human tumors, and experimental studies have shown that Trx contributes to the growth and to the transformed phenotype of some human cancer cells [18].
  • Trx mRNA and protein levels and Trx mRNA stability were not affected by selenium [18].

Anatomical context of TXN

  • Phorbol 12-myristate 13 acetate efficiently translocated TRX into the HeLa cell nucleus where Ref-1 preexists [19].
  • Indeed, Trx80 appears to be the first endogenous substance shown to have the capacity on its own to induce IL-10 production by monocytes [20].
  • In this study, the role of TRX and Ref-1 in the activation of the AP-1 complex was examined in HeLa and Jurkat cell lines exposed to ionizing radiation (IR) [17].
  • Treatment of HL-60 cells with 1alpha, 25-dihydroxyvitamin D(3) caused an increase of TBP-2/VDUP1 expression and down-regulation of the expression and the reducing activity of TRX [21].
  • The Trx1 substrate, redox factor-1 (Ref-1), was also oxidized in cytosol but was reduced in nuclei [22].

Associations of TXN with chemical compounds

  • To prove the direct active site-mediated association between TRX and Ref-1, we generated a series of substitution-mutant cysteine residues of TRX [19].
  • Thioredoxin and glutathione systems are the major thiol-dependent redox systems in animal cells [23].
  • Redox potential of human thioredoxin 1 and identification of a second dithiol/disulfide motif [24].
  • Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination [25].
  • A second repair enzyme, thioredoxin (TRx), which is NADPH-dependent, is widely found in many lower and higher life forms of life [26].
  • Chemical modification of Trx1 by common environmental and endogenously generated reactive aldehydes can contribute to atherosclerosis development by interfering with antioxidant and redox signaling functions of Trx1 [27].
  • These findings suggest that the cysteine at the active site of TRX plays a key role in the internalization and signal transduction of extracellular TRX into the cells [28].
  • Treatment of a two-disulfide form of Trx1 with S-nitrosoglutathione resulted in nitrosylation of Cys(73), which can act as a trans-nitrosylating agent as observed by others to control caspase 3 activity (Mitchell, D. A., and Marletta, M. A. (2005) Nat. Chem. Biol. 1, 154-158) [29].

Physical interactions of TXN


Enzymatic interactions of TXN


Regulatory relationships of TXN

  • AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1 [19].
  • Deficiency of TRP14 or Trx1 enhanced TNF-alpha-induced activation of caspases and subsequent apoptosis by a similar extent [40].
  • Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation [41].
  • The treatment of cells with reduced human Trx stimulated the synthesis of GAPDH mRNA [3].
  • Taken together, our results suggest that Trx may regulate cell cycle and growth through a novel modulation of Jab1-mediated proliferation signals, further indicating that Trx may have the ability to control tumor progression [42].

Other interactions of TXN

  • Moreover, not only the ligand binding domain but the DNA binding domain of the GR is also suggested to be a direct target of TRX [15].
  • We here report the molecular cascade of redox regulation of AP-1 mediated by TRX and Ref-1 [19].
  • Based on these experimental results, a catalytic mechanism is proposed to explain the Grx- and Trx-dependent activities of poplar Prx [43].
  • These results suggested that TBP-2/VDUP1 serves as a negative regulator of the biological function and expression of TRX [21].
  • Modulation of p53 dependent gene expression and cell death through thioredoxin-thioredoxin reductase by the Interferon-Retinoid combination [44].
  • We confirm that Trx1 affects CD30-dependent changes in lymphocyte effector function [45].

Analytical, diagnostic and therapeutic context of TXN


  1. Nuclear factor kappaB transactivation is increased but is not involved in the proliferative effects of thioredoxin overexpression in MCF-7 breast cancer cells. Freemerman, A.J., Gallegos, A., Powis, G. Cancer Res. (1999) [Pubmed]
  2. Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function. Makino, Y., Yoshikawa, N., Okamoto, K., Hirota, K., Yodoi, J., Makino, I., Tanaka, H. J. Biol. Chem. (1999) [Pubmed]
  3. Thioredoxin, a regulator of gene expression. Kontou, M., Will, R.D., Adelfalk, C., Wittig, R., Poustka, A., Hirsch-Kauffmann, M., Schweiger, M. Oncogene (2004) [Pubmed]
  4. Analysis of the inhibition of mammalian thioredoxin, thioredoxin reductase, and glutaredoxin by cis-diamminedichloroplatinum (II) and its major metabolite, the glutathione-platinum complex. Arnér, E.S., Nakamura, H., Sasada, T., Yodoi, J., Holmgren, A., Spyrou, G. Free Radic. Biol. Med. (2001) [Pubmed]
  5. Decreased thioredoxin and increased thioredoxin reductase levels in Alzheimer's disease brain. Lovell, M.A., Xie, C., Gabbita, S.P., Markesbery, W.R. Free Radic. Biol. Med. (2000) [Pubmed]
  6. Thioredoxin in vascular biology: role in hypertension. Ebrahimian, T., Touyz, R.M. Antioxid. Redox Signal. (2008) [Pubmed]
  7. Redox control of resistance to cis-diamminedichloroplatinum (II) (CDDP): protective effect of human thioredoxin against CDDP-induced cytotoxicity. Sasada, T., Iwata, S., Sato, N., Kitaoka, Y., Hirota, K., Nakamura, K., Nishiyama, A., Taniguchi, Y., Takabayashi, A., Yodoi, J. J. Clin. Invest. (1996) [Pubmed]
  8. Redox regulation of cellular activation. Nakamura, H., Nakamura, K., Yodoi, J. Annu. Rev. Immunol. (1997) [Pubmed]
  9. Redox signaling in chloroplasts: cleavage of disulfides by an iron-sulfur cluster. Dai, S., Schwendtmayer, C., Schürmann, P., Ramaswamy, S., Eklund, H. Science (2000) [Pubmed]
  10. Preferential elevation of Prx I and Trx expression in lung cancer cells following hypoxia and in human lung cancer tissues. Kim, H.J., Chae, H.Z., Kim, Y.J., Kim, Y.H., Hwangs, T.S., Park, E.M., Park, Y.M. Cell Biol. Toxicol. (2003) [Pubmed]
  11. Induction of thioredoxin and thioredoxin reductase gene expression in lungs of newborn primates by oxygen. Das, K.C., Guo, X.L., White, C.W. Am. J. Physiol. (1999) [Pubmed]
  12. A new selenoprotein from human lung adenocarcinoma cells: purification, properties, and thioredoxin reductase activity. Tamura, T., Stadtman, T.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  13. Cloning and expression of a cDNA for human thioredoxin. Wollman, E.E., d'Auriol, L., Rimsky, L., Shaw, A., Jacquot, J.P., Wingfield, P., Graber, P., Dessarps, F., Robin, P., Galibert, F. J. Biol. Chem. (1988) [Pubmed]
  14. The roles of thioredoxin in protection against oxidative stress-induced apoptosis in SH-SY5Y cells. Andoh, T., Chock, P.B., Chiueh, C.C. J. Biol. Chem. (2002) [Pubmed]
  15. Thioredoxin: a redox-regulating cellular cofactor for glucocorticoid hormone action. Cross talk between endocrine control of stress response and cellular antioxidant defense system. Makino, Y., Okamoto, K., Yoshikawa, N., Aoshima, M., Hirota, K., Yodoi, J., Umesono, K., Makino, I., Tanaka, H. J. Clin. Invest. (1996) [Pubmed]
  16. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. Saitoh, M., Nishitoh, H., Fujii, M., Takeda, K., Tobiume, K., Sawada, Y., Kawabata, M., Miyazono, K., Ichijo, H. EMBO J. (1998) [Pubmed]
  17. Thioredoxin nuclear translocation and interaction with redox factor-1 activates the activator protein-1 transcription factor in response to ionizing radiation. Wei, S.J., Botero, A., Hirota, K., Bradbury, C.M., Markovina, S., Laszlo, A., Spitz, D.R., Goswami, P.C., Yodoi, J., Gius, D. Cancer Res. (2000) [Pubmed]
  18. Mechanisms of the regulation of thioredoxin reductase activity in cancer cells by the chemopreventive agent selenium. Gallegos, A., Berggren, M., Gasdaska, J.R., Powis, G. Cancer Res. (1997) [Pubmed]
  19. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Hirota, K., Matsui, M., Iwata, S., Nishiyama, A., Mori, K., Yodoi, J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  20. Truncated thioredoxin (Trx80) induces differentiation of human CD14+ monocytes into a novel cell type (TAMs) via activation of the MAP kinases p38, ERK, and JNK. Pekkari, K., Goodarzi, M.T., Scheynius, A., Holmgren, A., Avila-Cariño, J. Blood (2005) [Pubmed]
  21. Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. Nishiyama, A., Matsui, M., Iwata, S., Hirota, K., Masutani, H., Nakamura, H., Takagi, Y., Sono, H., Gon, Y., Yodoi, J. J. Biol. Chem. (1999) [Pubmed]
  22. Selective protection of nuclear thioredoxin-1 and glutathione redox systems against oxidation during glucose and glutamine deficiency in human colonic epithelial cells. Go, Y.M., Ziegler, T.R., Johnson, J.M., Gu, L., Hansen, J.M., Jones, D.P. Free Radic. Biol. Med. (2007) [Pubmed]
  23. Alternative mRNAs arising from trans-splicing code for mitochondrial and cytosolic variants of Echinococcus granulosus thioredoxin Glutathione reductase. Agorio, A., Chalar, C., Cardozo, S., Salinas, G. J. Biol. Chem. (2003) [Pubmed]
  24. Redox potential of human thioredoxin 1 and identification of a second dithiol/disulfide motif. Watson, W.H., Pohl, J., Montfort, W.R., Stuchlik, O., Reed, M.S., Powis, G., Jones, D.P. J. Biol. Chem. (2003) [Pubmed]
  25. Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination. Ma, X., Karra, S., Lindner, D.J., Hu, J., Reddy, S.P., Kimchi, A., Yodoi, J., Kalvakolanu, D.V., Kalvakolanu, D.D. Oncogene (2001) [Pubmed]
  26. Redox regulation in the lens. Lou, M.F. Progress in retinal and eye research. (2003) [Pubmed]
  27. Reactive aldehyde modification of thioredoxin-1 activates early steps of inflammation and cell adhesion. Go, Y.M., Halvey, P.J., Hansen, J.M., Reed, M., Pohl, J., Jones, D.P. Am. J. Pathol. (2007) [Pubmed]
  28. Lipid raft-mediated uptake of cysteine-modified thioredoxin-1: apoptosis enhancement by inhibiting the endogenous thioredoxin-1. Kondo, N., Ishii, Y., Kwon, Y.W., Tanito, M., Sakakura-Nishiyama, J., Mochizuki, M., Maeda, M., Suzuki, S., Kojima, M., Kim, Y.C., Son, A., Nakamura, H., Yodoi, J. Antioxid. Redox Signal. (2007) [Pubmed]
  29. Regulation of the catalytic activity and structure of human thioredoxin 1 via oxidation and S-nitrosylation of cysteine residues. Hashemy, S.I., Holmgren, A. J. Biol. Chem. (2008) [Pubmed]
  30. Demonstration of the interaction of thioredoxin with p40phox, a phagocyte oxidase component, using a yeast two-hybrid system. Nishiyama, A., Ohno, T., Iwata, S., Matsui, M., Hirota, K., Masutani, H., Nakamura, H., Yodoi, J. Immunol. Lett. (1999) [Pubmed]
  31. Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. Zhang, R., Al-Lamki, R., Bai, L., Streb, J.W., Miano, J.M., Bradley, J., Min, W. Circ. Res. (2004) [Pubmed]
  32. Thioredoxin-dependent redox regulation of p53-mediated p21 activation. Ueno, M., Masutani, H., Arai, R.J., Yamauchi, A., Hirota, K., Sakai, T., Inamoto, T., Yamaoka, Y., Yodoi, J., Nikaido, T. J. Biol. Chem. (1999) [Pubmed]
  33. Solution structure of human thioredoxin in a mixed disulfide intermediate complex with its target peptide from the transcription factor NF kappa B. Qin, J., Clore, G.M., Kennedy, W.M., Huth, J.R., Gronenborn, A.M. Structure (1995) [Pubmed]
  34. C-propeptide region of human pro alpha 1 type 1 collagen interacts with thioredoxin. Matsumoto, K., Masutani, H., Nishiyama, A., Hashimoto, S., Gon, Y., Horie, T., Yodoi, J. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  35. The thioredoxin reductase/thioredoxin system: novel redox targets for cancer therapy. Biaglow, J.E., Miller, R.A. Cancer Biol. Ther. (2005) [Pubmed]
  36. Mechanism-based inactivation of thioredoxin reductase from Plasmodium falciparum by Mannich bases. Implication for cytotoxicity. Davioud-Charvet, E., McLeish, M.J., Veine, D.M., Giegel, D., Arscott, L.D., Andricopulo, A.D., Becker, K., Müller, S., Schirmer, R.H., Williams, C.H., Kenyon, G.L. Biochemistry (2003) [Pubmed]
  37. Gain of Function in an ERV/ALR Sulfhydryl Oxidase by Molecular Engineering of the Shuttle Disulfide. Vitu, E., Bentzur, M., Lisowsky, T., Kaiser, C.A., Fass, D. J. Mol. Biol. (2006) [Pubmed]
  38. Catalytic characteristics of tryparedoxin. Gommel, D.U., Nogoceke, E., Morr, M., Kiess, M., Kalisz, H.M., Flohé, L. Eur. J. Biochem. (1997) [Pubmed]
  39. Thiol/disulfide exchange in the thioredoxin-catalyzed reductive activation of spinach chloroplast fructose-1,6-bisphosphatase. Kinetics and thermodynamics. Clancey, C.J., Gilbert, H.F. J. Biol. Chem. (1987) [Pubmed]
  40. Roles of TRP14, a thioredoxin-related protein in tumor necrosis factor-alpha signaling pathways. Jeong, W., Chang, T.S., Boja, E.S., Fales, H.M., Rhee, S.G. J. Biol. Chem. (2004) [Pubmed]
  41. Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation. Karimpour, S., Lou, J., Lin, L.L., Rene, L.M., Lagunas, L., Ma, X., Karra, S., Bradbury, C.M., Markovina, S., Goswami, P.C., Spitz, D.R., Hirota, K., Kalvakolanu, D.V., Yodoi, J., Gius, D. Oncogene (2002) [Pubmed]
  42. Thioredoxin modulates activator protein 1 (AP-1) activity and p27Kip1 degradation through direct interaction with Jab1. Hwang, C.Y., Ryu, Y.S., Chung, M.S., Kim, K.D., Park, S.S., Chae, S.K., Chae, H.Z., Kwon, K.S. Oncogene (2004) [Pubmed]
  43. Glutaredoxin-dependent peroxiredoxin from poplar: protein-protein interaction and catalytic mechanism. Rouhier, N., Gelhaye, E., Jacquot, J.P. J. Biol. Chem. (2002) [Pubmed]
  44. Modulation of p53 dependent gene expression and cell death through thioredoxin-thioredoxin reductase by the Interferon-Retinoid combination. Hu, J., Ma, X., Lindner, D.J., Karra, S., Hofmann, E.R., Reddy, S.P., Kalvakolanu, D.V. Oncogene (2001) [Pubmed]
  45. Selective redox regulation of cytokine receptor signaling by extracellular thioredoxin-1. Schwertassek, U., Balmer, Y., Gutscher, M., Weingarten, L., Preuss, M., Engelhard, J., Winkler, M., Dick, T.P. EMBO J. (2007) [Pubmed]
  46. Differential oxidation of thioredoxin-1, thioredoxin-2, and glutathione by metal ions. Hansen, J.M., Zhang, H., Jones, D.P. Free Radic. Biol. Med. (2006) [Pubmed]
  47. Measurements of plasma glutaredoxin and thioredoxin in healthy volunteers and during open-heart surgery. Nakamura, H., Vaage, J., Valen, G., Padilla, C.A., Björnstedt, M., Holmgren, A. Free Radic. Biol. Med. (1998) [Pubmed]
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