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)

Transformation of the thyroid cell line FRTL-5 results in loss or reduction of differentiation as measured by the expression of thyroglobulin and thyroperoxidase, two proteins whose genes are exclusively expressed in thyroid follicular cells. The biochemical mechanisms leading to this phenomenon were investigated in three cell lines obtained by transformation of FRTL-5 cells with Ki-ras, Ha-ras, and polyomavirus middle-T oncogenes. With the ras oncogenes, transformation leads to undetectable expression of the thyroglobulin and thyroperoxidase genes. However, the mechanisms responsible for the extinction of the differentiated phenotype seem to be different for the two ras oncogenes. In Ki-ras-transformed cells, the mRNA encoding TTF-1, a transcription factor controlling thyroglobulin and thyroperoxidase gene expression, is severely reduced. On the contrary, nearly wild-type levels of TTF-1 mRNA are detected in Ha-ras-transformed cells. Furthermore, overexpression of TTF-1 can activate transcription of the thyroglobulin promoter in Ki-ras-transformed cells, whereas it has no effect on thyroglobulin transcription in the Ha-ras-transformed line. Expression of polyoma middle-T antigen in thyroid cells leads to only a reduction of differentiation and does not severely affect either the activity or the amount of TTF-1. Another thyroid cell-specific transcription factor, TTF-2, is more sensitive to transformation, since it disappears in all three transformed lines, and probably contributes to the reduced expression of the differentiated phenotype.
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PMID:Multiple mechanisms of interference between transformation and differentiation in thyroid cells. 144 6

A 420-bp fragment from the 5' end of the rat thyroperoxidase (TPO) gene was fused to a luciferase reporter and shown to direct cell-type-specific expression when transfected into rat thyroid FRTL-5 cells. Analysis of this DNA fragment revealed four regions of the promoter which interact with DNA-binding proteins present in FRTL-5 cells. Mutation of the DNA sequence within any of these regions reduced TPO promoter activity. The trans-acting factors binding to these sequences were compared with thyroid transcription factor 1 (TTF-1) and TTF-2, previously identified as transcriptional activators of another thyroid-specific gene, the thyroglobulin (Tg) gene. Purified TTF-1 binds to three regions of TPO which are protected by FRTL-5 proteins. Two of the binding sites overlap with recognition sites for other DNA-binding proteins. One TTF-1 site can also bind a protein (UFB) present in the nuclei of both expressing and nonexpressing cells. TTF-1 binding to the proximal region overlaps with that for a novel protein present in FRTL-5 cells which can also recognize the promoter-proximal region of Tg. Using a combination of techniques, the factor binding to the fourth TPO promoter site was shown to be TTF-2. We conclude, therefore, that the FRTL-5-specific expression of two thyroid restricted genes, encoding TPO and Tg, relies on a combination of the same trans-acting factors present in thyroid cells.
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PMID:Cell-type-specific expression of the rat thyroperoxidase promoter indicates common mechanisms for thyroid-specific gene expression. 173 32

Thyroid transcription factor 2 binds to the promoters of both thyroglobulin and thyroperoxidase genes, two markers of thyroid tissue differentiation, and its binding modulates the activity of both promoters. In this paper we describe the purification of thyroid transcription factor 2 essentially to homogeneity and demonstrate that it is a thyroid-specific DNA-binding protein. Furthermore, we provide a biochemical characterization suggesting that thyroid transcription factor 2 binds to DNA as a dimer and that it is a zinc-finger DNA-binding protein regulated in vitro by the redox state.
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PMID:Purification and characterization of thyroid transcription factor 2. 781 5

TPO is the key enzyme involved in the thyroid hormone synthesis. The human TPO (hTPO) gene locates on chromosome 2 and consists of 17 exons and 16 introns. Compared with other peroxidases, hTPO is 42% homologous with granulocyte myeloperoxidase. Thyroid cells contain multiple TPO mRNA transcripts of various size. However, the reason is unknown. TTF-1 and TTF-2 are known to regulate TPO gene expression. Moreover, the other factors are becoming clear to regulate it. Congenital TPO defects result in hypothyroidism and goiter. Recent studies clarify a human mutation causing TPO deficiency.
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PMID:[Thyroid peroxidase (TPO) gene and pathogenic TPO mutation]. 819 71

The mechanism for hormonal regulation of rat thyroperoxidase (rTPO) gene transcription in rat FRTL-5 thyroid cells has been investigated. Transient transfection experiments demonstrate that the minimal rTPO promoter that confers thyroid-specific expression also confers responsiveness to TSH and insulin. TSH induces a 7-fold increase in promoter activity, and the induction is detected almost immediately after the addition of the hormone. Insulin also stimulates TPO promoter activity, but the effect of this hormone is weaker and slower than that of TSH. The effect of TSH in increasing TPO promoter activity is mimicked by the cAMP agonist forskolin. The calcium-protein kinase C pathway is also involved in the regulation of the rTPO promoter activity, since a calcium ionophore (A23187) and phorbol esters [12-O-tetradecanoyl-phorbol-13-acetate (TPA)] inhibit it quickly. These data indicate that the region of the rTPO promoter used here contains the DNA signals necessary for its hormonal regulation. Protein-DNA binding studies show that the thyroid-specific nuclear protein TTF-2, which binds to the rTPO promoter, is induced by TSH and forskolin, and this effect is clearly observable as early as 5 h post induction. Moreover, the DNA binding activity of TTF-2 is inhibited by both A23187 and TPA. Heterologous promoter constructs containing four, eight, or 12 tandem repeats of an oligonucleotide that includes the TTF-2 binding site increase their activity in response to TSH, forskolin, and insulin, while the the presence of A23187 or TPA inhibits their activity. These data indicate that the TTF-2 protein plays an important role in the hormonal control of thyroid-specific transcription.
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PMID:Identification of a cis-regulatory element and a thyroid-specific nuclear factor mediating the hormonal regulation of rat thyroid peroxidase promoter activity. 826 61

The promoters of the thyroglobulin (Tg) and thyroperoxidase (TPO) genes both contain sequences that match the consensus recognized by the fork-head family of transcription factors. The fork-head recognition element in the TPO promoter is recognized by two proteins, one of which is the transcription factor HNF-3beta, a member of the hepatocyte nuclear factor 3 (HNF-3) family, and the other is a thyroid-specific binding activity previously described as thyroid transcription factor 2 (TTF-2). Differently, only TTF-2 is capable of recognizing the fork-head recognition element in the thyroglobulin promoter, HNF-3beta protein is present in cultured thyroid cells and in the adult thyroid gland, suggesting that it does indeed have a role in modulating thyroid-specific gene expression. The transcriptional activities of TPO promoter mutants impaired in either TTF-2 or HNF-3beta binding suggest that both factors participate in regulating transcription from the TPO promoter.
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PMID:Hepatocyte nuclear factor 3beta participates in the transcriptional regulation of the thyroperoxidase promoter. 860 63

Expression of thyroglobulin (Tg) and thyroperoxidase (TPO) genes in thyroid follicular cells occurs in the mouse at embryonic day (E)14.5. Two transcription factors, TTF-1 and Pax-8, have been implicated in transcriptional activation of Tg and TPO, even though the onset of their expression is at E9.5, suggesting that additional events are necessary for transcriptional activation of Tg and TPO genes. We report in this paper the cloning of TTF-2, a DNA binding protein that recognizes sites on both Tg and TPO promoters. TTF-2 is a new forkhead domain-containing protein whose expression is restricted to the endodermal lining of the foregut and to the ectoderm that will give rise to the anterior pituitary. TTF-2 shows transient expression in the developing thyroid and anterior pituitary. In the thyroid, TTF-2 expression is down-regulated just before the onset of Tg and TPO gene expression, suggesting that this transcription factor plays the role in development of a negative controller of thyroid-specific gene expression.
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PMID:TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. 921 35

The hormonal regulation of both thyroglobulin and thyroperoxidase promoter activity in FRTL-5 thyroid cells takes place, at least in part, through a hormone-responsive element to which the thyroid transcription factor TTF-2 binds. The TTF-2 cDNA, encoded by the titf2 locus, has recently been cloned and classified as a member of the forkhead transcription factor family. Here, we demonstrate that TTF-2 mRNA levels become undetectable in FRTL-5 thyroid cells cultured for 4 days in 0.2% serum and in the absent of thyrotropin (TSH) and insulin. Addition of TSH, insulin or insulin-like growth factor I (IGF-I) to the culture medium increases the levels of this transcription factor in a dose- and time- dependent manner and requires ongoing protein synthesis. The TSH effect is greater than that produced by insulin or IGF-I and is similar to the effect produced by the cAMP analog forskolin. The TSH and insulin effects are additive. In all cases, the mRNA levels increase is accompanied by an increase in transcription rate, as demonstrated by run-off assays. These data demonstrate that the TTF-2 mRNA is under tight hormonal control. This is consistent with an important role for TTF-2 as a mediator of the transcriptional activation of thyroid-specific genes (thyroglobulin and thyroperoxidase) by TSH via cAMP and by insulin through the IGF-I receptor.
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PMID:Transcriptional control of the forkhead thyroid transcription factor TTF-2 by thyrotropin, insulin, and insulin-like growth factor I. 928 45

TTF-2 is a thyroid-specific winged-helix transcription factor which has been proposed to play a key role in the hormonal control of thyroglobulin and thyroperoxidase genes transcription in FRTL-5 cells. We have analyzed TTF-2 DNA-binding activity in primary cultures of dog thyrocytes maintained in control condition or in the presence of the cAMP agonist forskolin. Binding of 35S-labelled nuclear proteins to the TTF-2 recognition sequence identified the presence of two molecular species of 41.5 and 42.5 kDa. TTF-2 DNA-binding activity was clearly detectable in nuclear extracts from unstimulated cells and appeared increased in forskolin-treated cells. Thus, the presence of TTF-2 DNA-binding activity does not correlate with the cAMP-dependent activity of thyroglobulin and thyroperoxidase genes in this cell system. In addition, the mutation of the TTF-2 binding site in the thyroglobulin promoter resulted in a very reduced but still clearly cAMP-dependent promoter activity when assayed by transient expression in the same cells. These results do not support a dominant role for TTF-2 in the cAMP-dependent control of thyroglobulin gene transcription in primary cultured thyrocytes.
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PMID:TTF-2 does not appear to be a key mediator of the effect of cyclic AMP on thyroglobulin gene transcription in primary cultured dog thyrocytes. 944 94

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


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