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)

Thyroglobulin (TG), the primary synthetic product of the thyroid, is the macromolecular precursor of thyroid hormones. TG synthesis, iodination, storage in follicles, and degradation control thyroid hormone formation and secretion into the circulation. Thyrotropin (TSH), via its receptor (TSHR), increases thyroid hormone levels by up-regulating expression of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does this by modulating the expression and activity of several thyroid-specific transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, which coordinately regulate NIS, TPO, TG, and the TSHR. Major histocompatibility complex class I gene expression, which also is regulated by TTF-1 and Pax-8 in the thyroid, is decreased simultaneously. This helps maintain self-tolerance in the face of TSH-increased gene products necessary for thyroid hormone formation. In this report we show that follicular TG counter-regulates TSH-increased, thyroid-specific gene transcription by suppressing expression of the TTF-1, TTF-2, and Pax-8 genes. This decreases expression of the TG, TPO, NIS, and TSHR genes, but increases class I expression. TG acts transcriptionally, targeting, for example, a sequence within 1.15 kb of the 5' flanking region of TTF-1. TG does not affect ubiquitous transcription factors regulating TG, TPO, NIS, and/or TSHR gene expression. The inhibitory effect of TG on gene expression is not duplicated by thyroid hormones or iodide and may be mediated by a TG-binding protein on the apical membrane. We hypothesize that TG-initiated, transcriptional regulation of thyroid-restricted genes is a normal, feedback, compensatory mechanism that limits follicular function and contributes to follicular heterogeneity.
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PMID:Autoregulation of thyroid-specific gene transcription by thyroglobulin. 965 73

There are several thyroid antigens including human sodium iodide symporter (hNIS), thyrotropin receptor (TSH-R), thyroid peroxidase (TPO), and thyroglobulin (Tg) that have been considered to be thyroid-specific proteins involved in the pathogenesis of autoimmune thyroid diseases. We examined the expression of these thyroid-tolerance related genes in normal human thymus, the lymphoid organ responsible for the induction of central T-cell self. Reverse transcription-polymerase chain reaction (RT-PCR) amplifications were performed with 4 pairs of oligonucleotide primers specific for the hNIS, TSH-R, TPO, and Tg genes, respectively. Gene-specific transcripts were confirmed by Southern hybridization using digoxigenin-labeled internal oligonucleotide probes. To monitor cDNA integrity and quantity, all samples were coamplified with a pair of intron-spanning human beta-actin-specific oligonucleotide primers. Furthermore, using a highly sensitive immunostaining technique and antibodies specific for these 4 antigens, we examined whether NIS-, TSH-R-, TPO-, and Tg-specific immunoreactivity can be detected and localized in normal human thymus. RT-PCR and Southern hybridization revealed expression of each of these 4 thyroid-related genes in normal human thymus. In addition, immunohistochemical analysis of frozen tissue sections derived from normal human thymus showed marked immunoreactivity for NIS, TSH-R, and Tg as well as weaker staining for TPO. Control reactions using isotype matched nonimmune immunoglobulins were consistently negative. Taken together, our results suggest that NIS-, TSH-R-, TPO-, and Tg-RNA are present and actively processed to immunoreactive NIS-, TSH-R-, TPO-, and Tg-like protein in human thymus. These data support the concept that pre-T lymphocytes may be educated to recognize thyroid-related epitopes expressed in thymus, and, thus, to generate self-tolerance against these thyroid-related antigens.
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PMID:Expression of thyroid-related genes in human thymus. 1009 Mar 12

Thyroglobulin (TG) is the primary synthetic product of the thyroid and the macromolecular precursor of thyroid hormones. TG synthesis, iodination, storage in follicles, and lysosomal degradation can each modulate thyroid hormone formation and secretion into the circulation. Thyrotropin (TSH), via its receptor (the TSHR), increases thyroid hormone levels by upregulating expression of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does this by modulating the expression and activity of the thyroid-specific transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, which coordinately regulate NIS, TPO, TG, and the TSHR. Major histocompatibility complex (MHC) class I gene expression, which is also regulated by TTF-1 and Pax-8 in the thyroid, is simultaneously decreased; this maintains self tolerance in the face of TSH-increased gene products necessary for thyroid hormone formation. We now show that follicular TG, 27S > 19S > 12S, counter-regulates TSH-increased thyroid-specific gene transcription by suppressing the expression of the TTF-1, TTF-2, and Pax-8 genes. This decreases expression of the TG, TPO, NIS and TSHR genes, but increases class I expression. TG action involves an apical membrane TG-binding protein; however, it acts transcriptionally, targeting, for example, a sequence within 1.15 kb of the start of TTF-1 transcription. TG does not affect ubiquitous transcription factors regulating TG, TPO, NIS and/or TSHR gene expression. TG activity is not duplicated by thyroid hormones or iodide. We hypothesize that TG-initiated, transcriptional regulation of thyroid-restricted genes is a normal, feedback, compensatory mechanism which regulates follicular function, regulates thyroid hormone secretion, and contributes to follicular heterogeneity.
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PMID:Thyroglobulin regulates follicular function and heterogeneity by suppressing thyroid-specific gene expression. 1040 66

Thyroid-specific transcription factors TTF-1 and Pax-8 play a decisive role in the determination and maintenance of cellular phenotype activating thyroglobulin (Tg), thyroperoxidase (TPO), thyrotropin receptor (TSH-R) and the sodium/iodide symporter (NIS) gene transcription. In the present work, we have studied the expression of TTF-1 and Pax-8 and their target genes in samples derived from thyroid neoplasms of follicular origin, as well as in medullary carcinoma (MTC), obtained from surgery or from fine needle aspiration (FNA) biopsies. The results show that TTF-1 and Pax-8 are expressed in well differentiated adenomas and that their expression decreases in less differentiated papillary and follicular carcinomas and is lost in undifferentiated anaplastic carcinomas. Parallel levels of Tg, TPO and TSH-R expression were found in the same neoplasm samples. Interestingly TSH-R and TTF-1 gene expression was found in MTC samples. Furthermore, the expression of the thyroid-specific genes and their transcription factors is lost in thyroid cells derived from follicular, papillary and anaplastic human carcinomas. In these cells, Tg, TPO and TSH-R promoter activities were absent. Cotransfection with expression vectors for TTF-1 and Pax-8 resulted in the stimulation of transcription to a different extent for each promoter. These results may be clinically relevant for the evaluation and prognosis of thyroid cancer since the loss of specific markers correlates with the degree of tumor differentiation.
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PMID:Thyroid-specific gene expression in the multi-step process of thyroid carcinogenesis. 1040 74

In 1948, Wolff and Chaikoff reported that organic binding of iodide in the thyroid was decreased when plasma iodide levels were elevated (acute Wolff-Chaikoff effect), and that adaptation or escape from the acute effect occurred in approximately 2 days, in the presence of continued high plasma iodide concentrations. We later demonstrated that the escape is attributable to a decrease in iodide transport into the thyroid, lowering the intrathyroidal iodine content below a critical inhibitory threshold and allowing organification of iodide to resume. We have now measured the rat thyroid sodium/iodide symporter (NIS) messenger RNA (mRNA) and protein levels, in response to both chronic and acute iodide excess, in an attempt to determine the mechanism responsible for the decreased iodide transport. Rats were given 0.05% NaI in their drinking water for 1 and 6 days in the chronic experiments, and a single 2000-microg dose of NaI i.p. in the acute experiments. Serum was collected for iodine and hormone measurements, and thyroids were frozen for subsequent measurement of NIS, TSH receptor, thyroid peroxidase (TPO), thyroglobulin, and cyclophilin mRNAs (by Northern blotting) as well as NIS protein (by Western blotting). Serum T4 and T3 concentrations were significantly decreased at 1 day in the chronic experiments and returned to normal at 6 days, and were unchanged in the acute experiments. Serum TSH levels were unchanged in both paradigms. Both NIS mRNA and protein were decreased at 1 and 6 days after chronic iodide ingestion. NIS mRNA was decreased at 6 and 24 h after acute iodide administration, whereas NIS protein was decreased only at 24 h. TPO mRNA was decreased at 6 days of chronic iodide ingestion and 24 h after acute iodide administration. There were no iodide-induced changes in TSH receptor and thyroglobulin mRNAs. These data suggest that iodide administration decreases both NIS mRNA and protein expression, by a mechanism that is likely to be, at least in part, transcriptional. Our findings support the hypothesis that the escape from the acute Wolff-Chaikoff effect is caused by a decrease in NIS, with a resultant decreased iodide transport into the thyroid. The observed decrease in TPO mRNA may contribute to the iodine-induced hypothyroidism that is common in patients with Hashimoto's thyroiditis.
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PMID:Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. 1043 93

Congenital hypothyroidism is a common preventable cause of mental retardation. The overall incidence is approximately 1:4000; females are affected about twice as often as males. Approximately 85% of cases are sporadic, while 15% are hereditary. The most common sporadic etiology is thyroid dysgenesis, with ectopic glands more common than aplasia or hypoplasia. While the pathogenesis of dysgenesis is largely unknown, some cases are now discovered to be the result of mutations in the transcription factors PAX-8 and TTF-2. Loss of function mutations in the thyrotropin (TSH) receptor have been demonstrated to cause some familial forms of athyreosis. The most common hereditary etiology is the inborn errors of thyroxine (T4) synthesis. Recent mutations have been described in the genes coding for the sodium/iodide symporter, thyroid peroxidase (TPO), and thyroglobulin. Transplacental passage of a maternal thyrotropin receptor blocking antibody (TRB-Ab) causes a transient form of familial congenital hypothyroidism. The vast majority of infants are now diagnosed after detection through newborn screening programs using a primary T4-backup TSH or primary TSH test. Screening test results must be confirmed by serum thyroid function tests. Thyroid scintigraphy, using 99mTc or 123I, is the most accurate diagnostic test to detect thyroid dysgenesis or one of the inborn errors of T4 synthesis. Thyroid sonography is nearly as accurate, but it may miss some cases of ectopic glands. If maternal antibody-mediated hypothyroidism is suspected, measurement of maternal and/or neonatal TRB-Ab will confirm the diagnosis. The goals of treatment are to raise the serum T4 as rapidly as possible into the normal range, adjust the levothyroxine dose with growth to keep the serum T4 (or free T4) in the upper half of the normal range and the TSH normal, and maintain normal growth and development while avoiding overtreatment. An initial starting dose of 10-15 microg/kg per day is recommended; this dose will decrease on a weight basis over time. Serum T4 (or free T4) and TSH should be monitored every 1-2 months in the first year of life and every 2-3 months in the second and third years.
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PMID:Congenital hypothyroidism: etiologies, diagnosis, and management. 1044 22

Follicular thyroglobulin (TG) decreases expression of the thyroid-restricted transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, thereby suppressing expression of the sodium iodide symporter, thyroid peroxidase, TG, and thyrotropin receptor genes (Suzuki, K., Lavaroni, S., Mori, A., Ohta, M., Saito, J., Pietrarelli, M., Singer, D. S., Kimura, S., Katoh, R., Kawaoi, A. , and Kohn, L. D. (1997) Proc. Natl. Acad. Sci. U. S. A. 95, 8251-8256). The ability of highly purified 27, 19, or 12 S follicular TG to suppress thyroid-restricted gene expression correlates with their ability to bind to FRTL-5 thyrocytes and is inhibited by a specific antibody to the thyroid apical membrane asialoglycoprotein receptor (ASGPR), which is related to the ASGPR of liver cells. Phosphorylating serine/threonine residues of TG, by autophosphorylation or protein kinase A, eliminates TG suppression and enhances transcript levels of the thyroid-restricted genes 2-fold in the absence of a change in TG binding to the ASGPR. Follicular TG suppression of thyroid-restricted genes is thus mediated by the ASPGR on the thyrocyte apical membrane and regulated by a signal system wherein phosphorylation of serine/threonine residues on the bound ligand is an important component. These data provide a hitherto unsuspected role for the ASGPR in transcriptional signaling, aside from its role in endocytosis. They establish a functional role for phosphorylated serine/threonine residues on the TG molecule.
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PMID:Follicular thyroglobulin (TG) suppression of thyroid-restricted genes involves the apical membrane asialoglycoprotein receptor and TG phosphorylation. 1045 90

Transforming growth factor (TGF)-beta1-decreased major histocompatibility complex (MHC) class I gene expression in thyrocytes is transcriptional; it involves trans factors and cis elements important for hormone- as well as iodide-regulated thyroid growth and function. Thus, in rat FRTL-5 thyrocytes, TGF-beta1 regulates two elements within -203 bp of the transcription start site of the MHC class I 5'-flanking region: Enhancer A, -180 to -170 bp, and a downstream regulatory element (DRE), -127 to -90 bp, that contains a cAMP response element (CRE)-like sequence. TGF-beta1 reduces the interaction of a NF-kappaB p50/fra-2 heterodimer (MOD-1) with Enhancer A while increasing its interaction with a NF-kappaB p50/p65 heterodimer. Both reduced MOD-1 and increased p50/p65 suppresses class I expression. Decreased MOD-1 and increased p50/p65 have been separately associated with the ability of autoregulatory (high) concentrations of iodide to suppress thyrocyte growth and function, as well as MHC class I expression. TGF-beta1 has two effects on the downstream regulatory element (DRE). It increases DRE binding of a ubiquitously expressed Y-box protein, termed TSEP-1 (TSHR suppressor element binding protein-1) in rat thyroid cells; TSEP-1 has been shown separately to be an important suppressor of the TSH receptor (TSHR) in addition to MHC class I and class II expression. It also decreases the binding of a thyroid-specific trans factor, thyroid transcription factor-1 (TTF-1), to the DRE, reflecting the ability of TGF-beta1 to decrease TTF-1 RNA levels. TGF-beta1-decreased TTF-1 expression accounts in part for TGF-beta1-decreased thyroid growth and function, since decreased TTF-1 has been shown to decrease thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR gene expression, coincident with decreased MHC class I. Finally, we show that TGF-beta1 increases c-jun RNA levels and induces the formation of new complexes involving c-jun, fra-2, ATF-1, and c-fos, which react with Enhancer A and the DRE. TGF-beta1 effects on c-jun may be a pivotal fulcrum in the hitherto unrecognized coordinate regulation of Enhancer A and the DRE.
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PMID:Transforming growth factor-beta1 down-regulation of major histocompatibility complex class I in thyrocytes: coordinate regulation of two separate elements by thyroid-specific as well as ubiquitous transcription factors. 1077 Apr 87

Transformation of rat thyroid cells with polyoma virus middle T antigen results in loss of the thyroid-differentiated phenotype, measured as the expression of the thyroglobulin (Tg), thyroperoxidase (TPO), and sodium/iodide symporter (NIS) genes. Among the transcription factors involved in the regulation of these genes, TTF-1 and TTF-2 were still detected at nearly wild-type levels, while a specific loss of the paired domain transcription factor Pax8 was observed. In this study, we used the PCPy cell line as a model system to study the role of Pax8 in thyroid differentiation. We demonstrate that the reintroduction of Pax8 in PCPy cells is sufficient to activate expression of the endogenous genes encoding thyroglobulin, thyroperoxidase, and sodium/iodide symporter. Thus, this cell system provides direct evidence for the ability of Pax8 to activate transcription of thyroid-specific genes at their chromosomal locus and strongly suggests a fundamental role of this transcription factor in the maintenance of functional differentiation in thyroid cells. Moreover, we show that Pax8 and TTF-1 cooperate in the activation of the thyroglobulin promoter and that additional thyroid-specific mechanism(s) are involved in such a cooperation. To identify the Pax8 domain able to mediate the specific activation of the thyroglobulin promoter, we transfected in PCPy cells three different Pax8 isoforms. The results of such experiments indicate that for the transcriptional activation of thyroid-specific genes, Pax8 uses an as yet unidentified functional domain.
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PMID:Pax8 has a key role in thyroid cell differentiation. 1106 1

Thyroid transcription factor 1 (TTF-1) is essential for thyroid differentiation and regulates expression of thyroglobulin, thyroid peroxidase, sodium/iodide symporter, and thyrotropin receptor (TSH-R) genes. Because thyrotropin (TSH) upregulates these same genes, we hypothesized TSH-R activation might increase TTF-1 and that TTF-1 might be differentially expressed in benign and malignant thyroid disease. TTF-1 expression and sub-cellular localization were determined by immunohistochemistry in 62 thyroid carcinomas, 15 benign lesions, and 2 normal thyroids. Nuclear TTF-1 was detected in benign (77%) and malignant lesions (69%), with similar intensity in both (1.1+/-0.19 versus 1.0+/-0.10). Nuclear TTF-1 staining correlated with the effective serum TSH level (p = 0.02) and patient age (p < 0.05). Nuclear TTF-1 was detected in 35 papillary thyroid carcinomas (PTC), of which 23% developed recurrent or persistent disease, and was absent from 18 PTC, of which only 6% recurred (p = 0.06). We conclude that nuclear TTF-1 correlates with serum TSH activity, increases with age, and may be increased in persistent or recurrent PTC.
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PMID:Nuclear localization of thyroid transcription factor-1 correlates with serum thyrotropin activity and may be increased in differentiated thyroid carcinomas with aggressive clinical course. 1150 27


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