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

• Decreased thioredoxin and increased thioredoxin reductase levels in Alzheimer's disease brain [5].
• Thioredoxin is a small ubiquitous protein with multiple biological functions, including cellular defense mechanisms against oxidative stress [7].

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

• Here we show a dynamic change of glutathione homeostasis in lung cancer A549 cells and an up-regulation of Prx I and Trx following hypoxia [10].
• In 140-day animals given lesser O2 concentrations (as needed) who do not develop chronic lung disease, lung TRX and TR mRNAs were also increased on days 1 and 6 but not significantly on day 10 [11].
• Apparent Km values for DTNB, Escherichia coli Trx, and rat Trx were 116, 34, and 3.7 microM, respectively [12].
• Recombinant human thioredoxin, expressed in Escherichia coli, possesses a dithiol-reducing enzymatic activity as assayed on mammalian and plant substrates [13].
• Using models of serum deprivation and 1-methyl-4-phenylpyridinium (MPP(+)), we investigated the mechanism by which thioredoxin (Trx) exerts its antiapoptotic protection in human neuroblastoma cells (SH-SY5Y) and preconditioning-induced neuroprotection [14].

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

• These results showed that p40phox interacts with TRX and indicated the possibility of TRX-dependent regulation of phagocyte oxidase activity [30].
• Cys-250 and Cys-30 in the N-terminal domain of ASK1 are critical for binding of Trx1 and Trx2, respectively [31].
• Electrophoretic mobility shift assay showed that TRX augmented the DNA binding activity of p53 and also further potentiated Ref-1-enhanced p53 activity [32].
• Solution structure of human thioredoxin in a mixed disulfide intermediate complex with its target peptide from the transcription factor NF kappa B [33].
• C-propeptide region of human pro alpha 1 type 1 collagen interacts with thioredoxin [34].

Enzymatic interactions of TXN

• Thioredoxin reductase (TRX) is a selenoprotein that reduces oxidized protein substrates in an NADPH-dependent process (cf. Fig. 1). The thioredoxins (TX) are a family of small redox active proteins that undergo reversible oxidation/reduction and help to maintain the redox state of cells [35].
• Thioredoxin reductase (TrxR) is the homodimeric flavoenzyme that catalyzes reduction of thioredoxin disulfide (Trx) [36].
• We have determined by X-ray crystallography the structure of AtErv1, an ERV/ALR enzyme that contains a Cys-X(4)-Cys shuttle disulfide and oxidizes thioredoxin in vitro, and compared it to ScErv2, which has a Cys-X-Cys shuttle and does not oxidize thioredoxin at an appreciable rate [37].
• Tryparedoxin, a thioredoxin-related protein from Crithidia fasciculata with a molecular mass of 16 kDa catalyses the reduction of a peroxiredoxin-type peroxidase, Cf21, at the expense of trypanothione [Nogoceke, E., Gommel, D. U., Kiess, M., Kalisz, H. M. & Flohé, L. E. (1997) Biol. Chem. Hoppe-Seyler 378, 827-836] [38].
• Two kinetically and thermodynamically distinct thiol/disulfide redox changes are observed during the reversible thioredoxin fb-catalyzed reduction and oxidation of spinach chloroplast fructose-1,6-bisphosphatase by dithiothreitol [39].

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

• In both an in vitro diamide-induced cross-linking study and an in vivo mammalian two-hybrid assay we proved that TRX can associate directly with Ref-1 in the nucleus; also, we demonstrated the requirement of cysteine residues in the TRX catalytic center for the potentiation of AP-1 activity [19].
• Trx treatment of cells and subsequent analysis of the differential gene expression by human cDNA arrays containing about 50 000 different PCR products resulted in more than 300 up- or downregulated genes [3].
• Fluorescence resonance energy transfer and co-immunoprecipitation studies revealed that Trx and Jab1 colocalize and directly interact with each other [42].
• GSH/GSSG redox states were determined by HPLC, and Trx1 and Trx2 redox states were determined by Redox Western blot methods [46].
• Competitive enzyme-linked immunosorbent assays (ELISA) showed that plasma levels (mean +/- SD) of Grx and Trx in healthy volunteers (n = 41) were 456 +/- 284 ng/ml and 28.5 +/- 12.6 ng/ml, respectively [47].

References