Disease relevance of TXNRD2

• For TXNRD2 A66S [AS versus AA: odds ratio (OR), 1.05; 95% confidence intervals (95% CI), 0.96-1.15; SS versus AA: OR, 1.12; 95% CI, 0.98-1.29], there are bioinformatics data to suggest that it is functional but confirmation in independent data sets is required before they can be regarded as definitive breast cancer susceptibility alleles [1].
• The antitumor quinones diaziquone and doxorubicin have been shown to produce a time- and concentration-dependent inhibition of TR when incubated for up to 24 hr with intact A204 human rhabdomyosarcoma cells [2].
• This mode of action for anthralin was confirmed by using pure TR from Escherichia coli [3].
• These competitive relations apparently have behavioral consequences, as thyroid hormones will reduce lordosis, and a TRbeta gene knockout will increase it [4].
• Autoantibodies against recombinant TR were not found in our 100 patients with systemic autoimmune diseases [5].

Psychiatry related information on TXNRD2

• MEASUREMENTS: Thyroid, cardiovascular, psychometric, hearing, speech, and growth testing; thyroid tests done at baseline and after TSH-releasing hormone stimulation; and DNA analysis for detection of mutations in the thyroid hormone receptor beta (TR beta) gene (exons 9 and 10) [6].
• Neuron-specific localisation of the TR3 death receptor in Alzheimer's disease [7].

High impact information on TXNRD2

• Natural mutations expected to occur in the cold region of TR beta should fail to manifest as RTH (group A) or should escape detection (group B) since the serum thyroid hormone levels required to compensate for the reduced binding affinity should be inferior to those found in subjects with R320H [8].
• Furthermore, when several clinical parameters of THR were compared in several affected members from two kindreds with GRTH, we found that two cases in one kindred exhibited a high mutant-to-normal hTR beta ratio and had considerably more bone resistance during their development [9].
• 28 different point mutations in the human thyroid hormone receptor beta (TR beta) gene have been associated with GRTH [10].
• Primers containing the normal sequences amplified exons 7 and 8 of the TR beta gene in all subjects except affected members of one family [11].
• The expression level of MDM2 is negatively regulated by orphan receptor TR3 that mainly acts as a transcriptional factor to regulate gene expression [12].

Chemical compound and disease context of TXNRD2

• The causal routes by which two genes contribute to the control of lordosis behavior, the classical estrogen receptor gene (ER-alpha) and a thyroid hormone (TH) receptor gene (TR-beta), have been delineated [13].
• Azelaic acid has been shown to inhibit thioredoxin reductase (TR) at the surface of guinea pig and human skin, on cultures of human keratinocytes, melanocytes, melanoma cells, murine melanoma cells (Cloudman S91), and on purified enzymes from Escherichia coli, rat liver, and human melanoma [14].
• 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 [15].
• The increase in TR activity produced by 1 microM Se compared to medium with no added selenium was: for MCF-7 breast cancer cells, 37-fold; for HT-29 colon cancer cells, 19-fold; and for A549 lung cancer cells, 8-fold [16].
• Defective biliary excretion of epinephrine metabolites in mutant (TR-) rats: relation to the pathogenesis of black liver in the Dubin-Johnson syndrome and Corriedale sheep with an analogous excretory defect [17].

Biological context of TXNRD2

• Multiple transcription start sites within TR genes may be relevant to complex regulation of expression and/or organelle- and cell type-specific location of animal thioredoxin reductases [18].
• Further truncations and point mutations suggest that TRAP interacts with the ligand-binding domain of TR and with an independent region which overlaps a conserved sequence adjacent to the second Zn2+ finger (amino acids 120-149 in rTR alpha-1) [19].
• TR bound to the estrogen response element is unable to respond to TRAP and unable to stimulate transcription, possibly due to the absence of TRAP in the TR-estrogen response element complex [19].
• Antisense-mediated inhibition of TR abrogates cell death [20].
• The coding region of hTR spans over 13 kb and is organized into five exons separated by four introns which were 60% sequenced [21].

Anatomical context of TXNRD2

• Thioredoxin reductase 2 (TrxR2), thioredoxin II (Trx II) and peroxiredoxin III (Prx III) are specifically localized in mitochondria and believed to play important roles in the regulation of cellular redox status by serving as a primary line of defense against H2O2 produced during respiration [22].
• We report here the design and construction of several gene vectors for expression in mammalian cells of membrane-bound and soluble human T cell receptors (TR) [23].
• Both hTR alpha 1 and hTR alpha 2 were strongly expressed in brain, prostate, and thyroid and much less in other tissues [24].
• Human autoantibodies affinity-purified with bacterial recombinant TR reacted to approximately 60-kDa polypeptide in HeLa extract in immunoblotting analysis and strongly stained around chromosome of metaphase of HeLa cells in immunofluorescence studies [5].
• Keratinocyte cell cultures, grown from normal and psoriatic skin of one donor, revealed 24% and 42% inhibition of cell surface TR activity, respectively, in the presence of 2 X 10(-5)M anthralin [3].

Associations of TXNRD2 with chemical compounds

• With TXN, TXNPx, trypanothione and TR, T. cruzi possesses all components constituting the crithidial peroxidase system [25].
• Tumors expressing the vector or wild-type TR were readily suppressed by the IFN/RA combination [20].
• All these also inhibited CysR and GR from the trophozoites other than mepacrine which inhibited only CysR and TR [26].
• Deletion of six amino acids(451-456) in the extreme COOH terminus of TRbeta resulted in a receptor that retained the ability to bind thyroid hormone but failed to inhibit progesterone-dependent transcription [27].
• In this case, 15-HPETE was catalytically reduced by the selenol amino acid, selenocysteine, generated from the diselenide by the HP-TR/NADPH system [28].

Physical interactions of TXNRD2

• We further studied the abilities of wild-type and the mutant TR beta 1s and alpha 1s on RXR and co-repressor binding by a two-hybrid interference assay. beta F451X had significantly stronger abilities to bind to RXR and SMRT than did wild-type TR beta 1 and beta E449X [29].
• In contrast, equimolar amounts of hPPAR completely inhibited the DNA-binding of hTR beta 1:RXR heterodimers, but not of TR:TR homodimers, suggesting that hPPAR has a higher RXR-binding affinity and is therefore a potent competitor for intranuclear RXR [30].
• Here, we show that hTR beta interacts specifically with the human basal transcription factor TFIIB [31].
• This TRbeta variant (TRbeta2spl) lacked thyroid hormone binding and had impaired T3-dependent negative regulation of both TSHbeta and glycoprotein hormone alpha-subunit genes in cotransfection studies [32].
• Thus, these structural analyses provide mechanistic insight into the etiology of RTH disease in human TRbeta mutants that exhibit hormone binding with decreased ligand-dependent corepressor release [33].

Regulatory relationships of TXNRD2

• Thus, developmental and tissue-specific expression of human thyroid hormone receptor beta1 5'-UTR mRNAs may regulate T3-responsiveness in target tissues by modulating TRbeta protein translation and thereby controlling the ratio of expressed TRalpha and -beta proteins [34].
• These results indicate that hTR beta 1 expression is directly regulated by hTR alpha 1, beta 1, and their ligand through two TREs [35].
• In support of this hypothesis it was demonstrated that the presence of N-CoR can enhance TRbeta-mediated transcriptional activation [36].
• Thyroid hormone receptors TRalpha1 and TRbeta differentially regulate gene expression of Kcnq4 and prestin during final differentiation of outer hair cells [37].
• To dissect the role of the LBD in receptor-mediated silencing, we used a cell-free transcription system containing HeLa nuclear extracts in which exogenously added unliganded TRbeta repressed the basal level of RNA polymerase II-driven transcription from a thyroid hormone response element-linked template [38].

Other interactions of TXNRD2

• We then used carboxyl-terminal truncations of rat TR alpha-1 and human TR beta in the avidin-biotin complex DNA-binding assay to identify regions that are important for interaction with TRAP [19].
• There was borderline evidence for association of variants in CAT g27168a {P [2 degrees of freedom (df)] = 0.05}, TXN t2715c [P (2 df) = 0.007], and TXNRD2 A66S and TXNRD2 g23524a (P(trend) = 0.074 and 0.046, respectively) [1].
• One such gene, GRIM-12, encodes the redox enzyme thioredoxin reductase (TR) [20].
• Using large random and focused (centered on the LXXLL motif) recombinant peptide diversity libraries, we have obtained novel peptide sequences that interact specifically with ERbeta or with TRbeta in a ligand-dependent manner [39].
• For example, by nongenomic mechanisms, estrogen and thyroid hormone can promote serine phosphorylation, respectively, of nuclear ER and TR [40].

Analytical, diagnostic and therapeutic context of TXNRD2

• The approaches we used here for manipulation of a human tumor-specific TR can be useful for other investigators interested in TR-based immunotherapy [23].
• The molecular size of native TR was determined to be 160 kDa by gel filtration chromatography whereas migration on a sucrose gradient gave a molecular mass of 130 kDa [41].
• Circular dichroism (CD) spectra of TR indicated that the secondary structural changes at 60 degrees C were only partly reversible at 28 degrees C. CD studies showed the flavoenzyme had a TM of 63 degrees C and above 45 degrees C began to exhibit changes in the secondary structure [41].
• Southern blot analysis revealed the presence of TL and TR genes in different mammalian species [42].
• Binding of hTR protein to the promoter region of the hTR beta 1 gene was confirmed by gel mobility shift assay [43].

References