Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.8 (thyroid peroxidase)
3,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Radioiodide is an effective therapy for thyroid cancer. This treatment modality exploits the thyroid-specific expression of the sodium iodide symporter (NIS) gene, which allows rapid internalization of iodide into thyroid cells. To test whether a similar treatment strategy could be exploited in nonthyroid malignancies, we transfected non-small cell lung cancer (NSCLC) cell lines with the NIS gene. Although the expression of NIS allowed significant radioiodide uptake in the transfected NSCLC cell lines, rapid radioiodide efflux limited tumor cell killing. Because thyroperoxidase (TPO) catalyzes iodination of proteins and subsequently causes iodide retention within thyroid cells, we hypothesized that coexpression of both NIS and TPO genes would overcome this deficiency. Our results show that transfection of NSCLC cells with both human NIS and TPO genes resulted in an increase in radioiodide uptake and retention and enhanced tumor cell apoptosis. These findings suggest that single gene therapy with only the NIS gene may have limited efficacy because of rapid efflux of radioiodide. In contrast, the combination of NIS and TPO gene transfer, with resulting TPO-mediated organification and intracellular retention of radioiodide, may lead to more effective tumor cell death. Thus, TPO could be used as a therapeutic strategy to enhance the NIS-based radioiodide concentrator gene therapy for locally advanced lung cancer.
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PMID:Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non-small cell lung cancer. 1157 39

Iodination of thyroglobulin, the key event in the synthesis of thyroid hormone, is an extracellular process that takes place inside the thyroid follicles at the apical membrane surface that faces the follicular lumen. The supply of iodide involves two steps of TSH-regulated transport, basolateral uptake and apical efflux, that imprint the polarized phenotype of the thyroid cell. Iodide uptake is generated by the sodium/iodide symporter present in the basolateral plasma membrane. A candidate for the apical iodide-permeating mechanism is pendrin, a chloride/iodide transporting protein recently identified in the apical membrane. In physiological conditions, transepithelial iodide transport occurs without intracellular iodination, despite the presence of large amounts of thyroglobulin and thyroperoxidase inside the cells. The reason is that hydrogen peroxide, serving as electron acceptor in iodide-protein binding and normally produced at the apical cell surface, is rapidly degraded by cytosolic glutathione peroxidase once it enters the cells. Iodinated thyroglobulin in the lumen stores not only thyroid hormone but iodine incorporated in iodotyrosine residues as well. After endocytic uptake and degradation of thyroglobulin, intracellular deiodination provides a mechanism for recycling of iodide to participate in the synthesis of new thyroid hormone at the apical cell surface.
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PMID:Iodide handling by the thyroid epithelial cell. 1157 32

Presence, functional activity and clinical relevance of autoantibodies directed against the human sodium iodide symporter (NIS) in thyroid autoimmune diseases have become the subject of much controversy in recent years. Earlier reports have claimed that NIS may represent a major thyroid autoantigen that elicits formation of functionally relevant autoantibodies in a significant proportion of patients with Graves' disease (GD) and Hashimoto's thyroiditis (HT). Moreover, a recent study has extended this notion by reporting detection of NIS-autoantibodies in 22% and 24% of a small number of patients with GD and HT, respectively, but not in patients with other autoimmune diseases. However, in striking contrast to these reports, two independent groups of investigators have now presented convincing evidence that NIS-directed autoantibodies occur with low frequency among a large sample of patients with autoimmune thyroid diseases. Moreover, no evidence of specific iodide uptake inhibiting activity was obtained once sera had been subjected to dialysis and/or IgG extraction. Thus, although the controversy has not been definitively resolved, hNIS does not appear to be a major functionally relevant antigen in autoimmune thyroid diseases. Moreover, when detected in addition to TPO and TSH receptor autoantibodies, NIS-directed autoantibodies do not appear to contribute any diagnostic power for GD and HT.
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PMID:Autoimmunity involving the human sodium/iodide symporter: fact or fiction? 1157 37

Autoimmune thyroid diseases occur in subjects with genetic predisposition, and are responsible for a large spectrum of clinical manifestations. They have in common the presence of intra-thyroid lymphocytic infiltrate and serum antibodies against thyroid constituents. The main thyroid antigens are thyroglobulin (Tg), thyroperoxidase (TPO), thyrotropin receptor (RTSH) and sodium/iodide symporter (NIS) which has been recently cloned. The assays for antiTg and antiTPO antibodies have high specificity and sensitivity, but standardisation problems still exist. Second generation antiRTSH assays are now available. The discrimination between the stimulating and the blocking activities can been studied using cellular culture. The antiTPO antibodies are the more sensitive and the more specific diagnostic markers for autoimmune thyroid diseases but their use for therapeutic decision is limited. They are good predictive factors for a thyroid dysfunction during pregnancy, during amiodaron, lithium, and cytokines treatments. The antiTg antibodies search enables the validation of a Tg assay. The antiRTSH antibodies are precious tools for the diagnostic and the follow-up of Graves' diseases and fetal pathologies caused by the antibodies crossing over the placental barrier. The utility of antiNIS antibodies determination is not yet proved.
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PMID:[Analysis for the diagnosis of auto-immune thyroid disease: contribution of the laboratory]. 1171 16

Duox2, and probably Duox1 are glycoflavoproteins involved in the thyroid H2O2 generator functionally associated to thyroperoxidase (TPO). We investigated both DUOX1 and DUOX2 gene expressions using quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 47 thyroid carcinomas, including 10 paired normal/tumoral tissues. In carcinomas, variations of DUOX1 and DUOX2 mRNA levels were parallel, indicating that control mechanisms of both gene expressions operate in tumors as well as in normal thyroid tissues; DUOX1 expression was in the normal range in 20, was decreased up to 50-fold in 8, and increased up to 7-fold in 19 samples. DUOX2 expression was in the normal range in 15, was decreased up to 200-fold in 10, and increased up to 5-fold in 22 samples. In the 10 paired samples, variations of DUOX and TPO gene expressions were not correlated. We analyzed Duoxl/2 protein expression in 86 tumor samples using an antipeptide antiserum reacting with both Duox proteins. In normal tissue, Duox proteins are localized at the apical pole of thyrocytes, with 40% to 60% of thyrocytes being stained. In the 86 cancer tissues, immunostaining was absent in 19 samples, was low in 32, and normal or even slightly increased in the other 35 samples. The expression of Duox proteins was related to tumor differentiation, being more frequently found in neoplastic tissues that were able to pick up radioiodine, and in those with a detectable expression of sodium iodide symporter (NIS), pendrin and TPO.
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PMID:Expression of nicotinamide adenine dinucleotide phosphate oxidase flavoprotein DUOX genes and proteins in human papillary and follicular thyroid carcinomas. 1176 10

Radioactive iodine (131I) is routinely used for the treatment of differentiated thyroid cancers. Attempts have been made to enlarge this therapeutic strategy to nonthyroid tumors by coupling radioactive iodide administration with transfer of the sodium iodide symporter (NIS) gene into target cells, for example with an adenoviral vector (AdNIS). Although efficient iodide uptake was achieved in the tumors treated with AdNIS, no therapeutic effect could be observed with 131I, most probably because the iodide retention time in the target cells was short. To circumvent this problem, we propose to organify the iodide taken up, as it occurs in the thyroid. We constructed a recombinant adenovirus encoding the human thyroperoxidase (TPO) gene under the control of the cytomegalovirus early promoter (AdTPO). Infection of nonthyroid tumor cells with this virus led to production of an enzymatically active protein. A significant increase in iodide organification could be observed in cells coinfected with both AdNIS and AdTPO in the presence of exogenous hydrogen peroxide. However, the levels of iodide organification obtained were too low to significantly increase the iodide retention time in the target cells.
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PMID:Transposition of the thyroid iodide uptake and organification system in nonthyroid tumor cells by adenoviral vector-mediated gene transfers. 1183 26

The aim of the study was to investigate the incidence of thyroid abnormalities in neck irradiated lymphoma patients. Of the 298 patients who had irradiation to the neck for lymphoma between 1966-1988, 174 were found to be alive and free of disease. These patients were invited to participate in the study. From the 174, 93 were able to participate (group 1). Two control groups were recruited; both were sex and aged matched. One group (group 2) consisted of lymphoma patients who were treated with chemotherapy (n=39) or irradiation to areas other than the neck (n=16). The other group (group 3) consisting of healthy volunteers (n=35) recruited from hospital staff and minor surgery attendees, had never had lymphoma or radiotherapy. All participants were required to complete a past medical history and thyroid symptom questionnaire, had blood taken for assays of thyroid stimulating hormone (TSH), thyroglobulin antibodies, thyroid peroxidase antibodies, sodium iodide symporter antibodies and TSH receptor antibodies and underwent ultrasound and clinical examination of the neck. A significant percentage of patients who had been irradiated in the neck had abnormalities on ultrasound, compared to groups 2 and 3 (77% vs 42% vs 24%). Abnormal TSH levels were found to be significantly more common in neck irradiated patients compared to the other groups (50% vs 9% vs 5%). There is a clear difference between neck irradiated patients and control groups. The importance of screening irradiated patients for thyroid abnormalities is re-emphasised.
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PMID:The incidence of thyroid abnormalities in adults irradiated for lymphoma. 1195 5

The thyroid-stimulating hormone/thyrotropin (TSH) is the most relevant hormone in the control of thyroid gland physiology in adulthood. TSH effects on the thyroid gland are mediated by the interaction with a specific TSH receptor (TSHR). We studied the role of TSHTSHR signaling on gland morphogenesis and differentiation in the mouse embryo using mouse lines deprived either of TSH (pit(dw)pit(dw)) or of a functional TSHR (tshr(hyt)tshr(hyt) and TSHR-knockout lines). The results reported here show that in the absence of either TSH or a functional TSHR, the thyroid gland develops to a normal size, whereas the expression of thyroperoxidase and the sodium/iodide symporter are reduced greatly. Conversely, no relevant changes are detected in the amounts of thyroglobulin and the thyroid-enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that the major role of the TSH/TSHR pathway is in controlling genes involved in iodide metabolism such as sodium/iodide symporter and thyroperoxidase. Furthermore, our data indicate that in embryonic life TSH does not play an equivalent role in controlling gland growth as in the adult thyroid.
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PMID:Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland. 1243 93

We evaluated the potential of radioiodide therapy in human sodium iodide symporter (hNIS)-defective thyroid cancer cells via exogenous hNIS expression. Three human thyroid cancer cells (ARO, FRO and NPA) of different origin were transduced by a recombinant adenovirus encoding hNIS expression cassette (Rad-hNIS). The cells were efficiently transduced by a recombinant adenovirus in a virus dose-dependent manner. Consequently, the hNIS protein could be readily detected by Western blot analysis 48-h post-infection at 10 infectious virus particles per cell. These hNIS-transduced cells actively transported iodide into the cytoplasm at the level of 11635.3, 61571.6, and 19367.5 pmoles/10(6) cells in ARO, FRO, and NPA, respectively. However, a significant amount of iodide was eluted to an iodide-free media within 60 min in all the cell lines. RT-PCR analysis revealed that the expression of genes related to iodide trapping (Tg, TSHR and TPO) was dramatically downregulated in these cells. The present study indicates that functional hNIS can be efficiently expressed and is responsible for active transport of iodide in hNIS-negative human thyroid cancer cells by a recombinant adenovirus. However, the human thyroid cancer cells, along with downregulation of iodide metabolism-related gene expression, lose the ability to maintain iodide. Therefore, these kinetic characteristics of iodide uptake and efflux may limit the therapeutic potential of hNIS/radioiodide-based treatment following exogenous hNIS expression in human thyroid cancer.
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PMID:Kinetics of iodide uptake and efflux in various human thyroid cancer cells by expressing sodium iodide symporter gene via a recombinant adenovirus. 1279 33

Humans expressing one allele of the thyroid transcription factor 1 (TTF1) gene have neurological symptoms and increased serum TSH with variable degrees of hypothyroidism. Ttf1+/- mice have also poor coordination and increased serum TSH concentration (205 +/- 22 vs. 92 +/- 12 mU/liter; P < 0.001) and slightly lower T4 (46 +/- 3 vs. 63 +/- 6 nmol/liter; P < 0.02) as compared with Ttf1+/+ mice. To determine whether the hypothyroidism is of central or primary origin, we examined the bioactivity of TSH, thyroidal response to exogenous TSH and the expression of genes regulated by TTF1. TSH bioactivity was normal, but T4 response to a low but not high dose of TSH was significantly reduced in the Ttf1+/- mice (5.5 +/- 2.2 vs. 15.3 +/- 4.1 nmol/liter; P < 0.03), indicating a reduced thyroidal response. Thyroid mRNAs were measured by real-time PCR (Ttf1+/+ littermates = 100%). Ttf1+/- mice had half the levels of TTF1 mRNA (54 +/- 9; P < 0.01) and protein, confirming their haploinsufficiency. Significantly lower levels of mRNAs were observed for two of the three genes with TTF1 cis elements: TSH receptor (TSHr, 57 +/- 4%; P < 0.002), thyroglobulin (63 +/- 7%; P < 0.005), but not thyroid peroxidase (81 +/- 12%; P > 0.05). No significant difference between the two genotypes was found for Pax8, sodium iodide symporter, and iodothyronine deiodinase 1. These results show that Ttf1 haploinsufficiency causes a reduction in the expression of TSHr and thyroglobulin, genes with TTF1 binding sites in their promoter regions. The low TSHr is only partially compensated by an increase in TSH secretion because T4 remains mildly reduced. However, administration of a larger amount of TSH obliterates the response differences by saturating a reduced amount of receptor.
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PMID:Hypothyroidism in thyroid transcription factor 1 haploinsufficiency is caused by reduced expression of the thyroid-stimulating hormone receptor. 1290 60


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