Disease relevance of TXNRD1

• Thioredoxin reductase 1 expression in colon cancer: discrepancy between in vitro and in vivo findings [1].
• Hemolysate thioredoxin reductase and glutathione peroxidase activities correlate with serum selenium in a group of New Zealand men at high prostate cancer risk [2].
• Exposure of HT-20 colon cancer cells to hypoxia resulted in a 14-fold increase in thioredoxin mRNA by 16 hours, and a transient 4-fold increase in thioredoxin reductase mRNA at 1 hour that had returned to control levels by 8 hours [3].
• We found that serum stimulation of growth arrested MCF-7 breast cancer cells caused a 59% increase in thioredoxin mRNA and a 62% increase in thioredoxin reductase mRNA by 24 hours [3].
• Thioredoxin reductase protein and activity were increased an average of 2-fold in human colorectal tumors compared to normal mucosa [3].

High impact information on TXNRD1

• An example of two related enzymes that catalyse similar reactions but possess different active sites is provided by comparing the structure of Escherichia coli thioredoxin reductase with glutathione reductase [4].
• The mammalian thioredoxins are a family of small (approximately 12 kDa) redox proteins that undergo NADPH-dependent reduction by thioredoxin reductase and in turn reduce oxidized cysteine groups on proteins [5].
• The chaperonin heat shock protein (Hsp) 90 and thioredoxin reductase were identified by mass spectrometry sequencing in CTF complexes purified from both human T cell and yeast [6].
• The deficient ATP-dependent conjugate transport in canalicular membranes from TR- mutant rat hepatocytes was associated with a lack of amplification of one of the mrp cDNA fragments and with a selective loss of Mrp on immunoblots of canalicular membranes [7].
• Reduction of thioredoxins in chloroplasts is catalyzed by an iron-sulfur disulfide enzyme, ferredoxin-thioredoxin reductase, that receives photosynthetic electrons from ferredoxin, thereby providing a link between light and enzyme activity [8].

Chemical compound and disease context of TXNRD1

• Heparin-binding properties of selenium-containing thioredoxin reductase from HeLa cells and human lung adenocarcinoma cells [9].
• Cell cycle inhibition of HTLV-I transformed T cell lines by retinoic acid: the possible therapeutic use of thioredoxin reductase inhibitors [10].
• The mechanism of thioredoxin reductase from human placenta is similar to the mechanisms of lipoamide dehydrogenase and glutathione reductase and is distinct from the mechanism of thioredoxin reductase from Escherichia coli [11].
• Thus, alloxan showed an apparent Km of 70 microM in the presence of 3.4 microM E. coli thioredoxin, 0.2 microM thioredoxin reductase, and 0.4 mM NADPH [12].
• Thioredoxin from Anabaena sp. has been purified 800-fold with an assay based on the reduction of insulin disulfides by NADPH and the heterologous calf thymus thioredoxin reductase [13].

Biological context of TXNRD1

• Furthermore, extensive alternative splicing occured in the 5' region of TXNRD1 [14].
• In this study, we have further characterized the recently identified core promoter region of TXNRD1 [14].
• Rapid induction of cell death by selenium-compromised thioredoxin reductase 1 but not by the fully active enzyme containing selenocysteine [15].
• However, several recent studies have suggested that TrxR1 may promote apoptosis, and the enzyme was identified as GRIM-12 (gene associated with retinoid interferon-induced mortality 12) [15].
• Transient transfection with GRIM-12/TrxR1 was also shown to directly induce cell death [15].

Anatomical context of TXNRD1

• Moreover, the HeLa cells transfected with an antisense TRXR RNA expression vector to reduce the intracellular enzyme activity displayed an enhanced sensitivity to CDDP [16].
• HeLa, a human cervical carcinoma cell line, cultured with CDDP showed a time- and dose-dependent reduction of intracellular TRXR activity, which was well correlated with the decrease in cell viability after exposure to CDDP [16].
• In a cell-free system, CDDP was found to directly inactivate the reduced form of purified human TRXR [16].
• Transcriptional regulation of thioredoxin reductase 1 expression by cadmium in vascular endothelial cells: role of NF-E2-related factor-2 [17].
• A number of human hematologic and solid tumor cell lines were studied and showed a 10-fold range of thioredoxin mRNA and a 23-fold range of thioredoxin reductase mRNA [3].

Associations of TXNRD1 with chemical compounds

• Here we report that methylseleninate does not act as an inhibitor of mammalian thioredoxin reductase but is in fact an excellent substrate (K(m) of 18 microm, k(cat) of 23 s(-1)), which is reduced by the enzyme according to the equation 2 NADPH + 2 H(+) + CH(3)SeO(2)H --> 2 NADP(+) + 2 H(2)O + CH(3)SeH [18].
• Thioredoxin reductase modified by DNCB lacked reducing activity with oxidized thioredoxin, 5,5'-dithiobis-(2-nitrobenzoic acid), or sodium selenite [19].
• 1-Chloro-2,4-dinitrobenzene is an irreversible inhibitor of human thioredoxin reductase. Loss of thioredoxin disulfide reductase activity is accompanied by a large increase in NADPH oxidase activity [19].
• Human TR1 has three major structural domains, the FAD binding domain, the NADPH binding domain, and an interface domain (ID) [20].
• An alternative splicing variant of the selenoprotein thioredoxin reductase is a modulator of estrogen signaling [21].

Physical interactions of TXNRD1

• Human thioredoxin reductase contains the redox-active cysteines in the putative FAD binding domain and has a dimer interface domain not previously seen with prokaryote and lower eukaryote thioredoxin reductases [22].

Enzymatic interactions of TXNRD1

• Thioredoxin reductase (TrxR) is the homodimeric flavoenzyme that catalyzes reduction of thioredoxin disulfide (Trx) [23].
• Human thioredoxin reductase is a dimeric enzyme that catalyzes reduction of the disulfide in oxidized thioredoxin by a mechanism involving transfer of electrons from NADPH via FAD to a redox-active disulfide [19].

Regulatory relationships of TXNRD1

• Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation [24].
• Interestingly, recent work has indicated that thioredoxin reductase can regulate the activity of transcription factors such as p53, hypoxia-inducible factor, and AP-1 [21].
• The most effective derivatives are the (4'-chloro-2, 2':6',2"-terpyridine)platinum(II) ammine and the (4-picoline)(4'-p-bromophenyl-2,2':6',2" -terpyridine)platinum(II) complexes which in the presence of NADPH inhibit TR with second-order rate constants of about 1.3 x 10(4) M(-1) s(-1) [25].
• A mutation in a thioredoxin reductase homolog suppresses p53-induced growth inhibition in the fission yeast Schizosaccharomyces pombe [26].

Other interactions of TXNRD1

• Expression of the thioredoxin-thioredoxin reductase system in the inflamed joints of patients with rheumatoid arthritis [27].
• Mutational analysis of human thioredoxin reductase 1. Effects on p53-mediated gene expression and interferon and retinoic acid-induced cell death [20].
• Thioredoxin, thioredoxin reductase, and alpha-crystallin revive inactivated glyceraldehyde 3-phosphate dehydrogenase in human aged and cataract lens extracts [28].
• GCLM and TXNRD1 exhibited 13- and 9-fold increases, respectively at 24 h [29].
• Exposure of rabbits to iAsV in drinking water (5 mg/L) for 18 weeks caused a significant suppression of hepatic TR and GR activities, of approximately 30% and 20%, respectively, below controls [30].

Analytical, diagnostic and therapeutic context of TXNRD1

• A genetic technique permitted the isolation of human thioredoxin reductase (TR) as a critical regulator of IFN/all-trans-retinoic acid-induced cell death [20].
• Thioredoxin reductase protein levels measured by western blotting using an antibody to human thioredoxin reductase were decreased in rats fed the selenium-deficient diet and did not increase in rats fed the high selenium diet [31].
• Analysis of the expression and localization of TR1 in different normal and cancer cell lines and in colon tissues (normal, neoplastic, or inflamed) was performed using reverse transcription-PCR and in situ hybridization [1].
• We have also determined the relative tissue distribution of thioredoxin reductase mRNA as well as thioredoxin mRNA by probing a Northern blot of several human normal tissues [32].
• Removal of Trx or TR1 by immunoprecipitation diminished these changes in proMMP-2 activity [33].

References