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Corinne Dupuy - One of the best experts on this subject based on the ideXlab platform.

  • Conformation of the N-Terminal Ectodomain Elicits Different Effects on DUOX Function: A Potential Impact on Congenital HypoThyroidism Caused by a H2O2 Production Defect.
    Thyroid, 2018
    Co-Authors: Ruy A. N. Louzada, Rabii Ameziane-el-hassani, Raphaël Corre, Fabio Hecht, Juliana M. Cazarin, Camille Buffet, Denise P. Carvalho, Corinne Dupuy
    Abstract:

    Background: Dual oxidases (DUOX1 and DUOX2) were initially identified as H2O2 sources involved in Thyroid Hormone Synthesis. Congenital hypoThyroidism (CH) resulting from inactivating mutations in ...

  • NADPH oxidases: new actors in Thyroid cancer?
    Nature Reviews Endocrinology, 2016
    Co-Authors: Rabii Ameziane-el-hassani, Martin Schlumberger, Corinne Dupuy
    Abstract:

    The NADPH oxidase family of enzymes produce hydrogen peroxide (H_2O_2), a critical substrate for Thyroid Hormone Synthesis. However, H_2O_2is also a potent oxidant that can cause DNA damage, which might lead to Thyroid carcinogenesis. Here, the authors discuss the physiological attributes of Thyroid NADPH oxidases and their pathological involvement in Thyroid cancer. Hydrogen peroxide (H_2O_2) is a crucial substrate for Thyroid peroxidase, a key enzyme involved in Thyroid Hormone Synthesis. However, as a potent oxidant, H_2O_2 might also be responsible for the high level of oxidative DNA damage observed in Thyroid tissues, such as DNA base lesions and strand breakages, which promote chromosomal instability and contribute to the development of tumours. Although the role of H_2O_2 in Thyroid Hormone Synthesis is well established, its precise mechanisms of action in pathological processes are still under investigation. The NADPH oxidase/dual oxidase family are the only oxidoreductases whose primary function is to produce reactive oxygen species. As such, the function and expression of these enzymes are tightly regulated. Thyrocytes express dual oxidase 2, which produces most of the H_2O_2 for Thyroid Hormone Synthesis. Thyrocytes also express dual oxidase 1 and NADPH oxidase 4, but the roles of these enzymes are still unknown. Here, we review the structure, expression, localization and function of these enzymes. We focus on their potential role in Thyroid cancer, which is characterized by increased expression of these enzymes. Hydrogen peroxide (H_2O_2) is involved in both the physiology and pathology of the human Thyroid gland, with roles both in Hormone Synthesis and in oxidative DNA damage The NADPH oxidase/dual oxidase (NOX/DUOX) family are the major nonmitochondrial sources of reactive oxygen species in cells; the human Thyroid gland expresses DUOX1 , DUOX2 and NOX4 DUOX2 is the main source of H_2O_2 for Hormone Synthesis by Thyroid peroxidase; the physiological functions of DUOX1 and NOX4 in human Thyroid tissue are still unknown Both DUOXs and NOX4 are overexpressed in human Thyroid tumours, which suggests that these H_2O_2-generating enzymes might be involved in Thyroid cancer pathogenesis DUOX1 is upregulated in radiation-induced Thyroid cancer, and DUOX1-dependent production of H_2O_2 promotes persistent DNA damage after human Thyroid cells are exposed to ionizing radiation Generation of H_2O_2 by NOX4 mediates oncogene-induced DNA damage and senescence in human Thyroid cells

  • NADPH oxidases: new actors in Thyroid cancer?
    Nature Reviews Endocrinology, 2016
    Co-Authors: Rabii Ameziane-el-hassani, Martin Schlumberger, Corinne Dupuy
    Abstract:

    The NADPH oxidase family of enzymes produce hydrogen peroxide (H2O2), a critical substrate for Thyroid Hormone Synthesis. However, H2O2is also a potent oxidant that can cause DNA damage, which might lead to Thyroid carcinogenesis. Here, the authors discuss the physiological attributes of Thyroid NADPH oxidases and their pathological involvement in Thyroid cancer. Hydrogen peroxide (H2O2) is a crucial substrate for Thyroid peroxidase, a key enzyme involved in Thyroid Hormone Synthesis. However, as a potent oxidant, H2O2 might also be responsible for the high level of oxidative DNA damage observed in Thyroid tissues, such as DNA base lesions and strand breakages, which promote chromosomal instability and contribute to the development of tumours. Although the role of H2O2 in Thyroid Hormone Synthesis is well established, its precise mechanisms of action in pathological processes are still under investigation. The NADPH oxidase/dual oxidase family are the only oxidoreductases whose primary function is to produce reactive oxygen species. As such, the function and expression of these enzymes are tightly regulated. Thyrocytes express dual oxidase 2, which produces most of the H2O2 for Thyroid Hormone Synthesis. Thyrocytes also express dual oxidase 1 and NADPH oxidase 4, but the roles of these enzymes are still unknown. Here, we review the structure, expression, localization and function of these enzymes. We focus on their potential role in Thyroid cancer, which is characterized by increased expression of these enzymes.

  • Thyroid Hormone Synthesis and Secretion
    Endotext [Internet], 2015
    Co-Authors: Françoise Miot, Jacques E. Dumont, Corinne Dupuy, Bernard A Rousset
    Abstract:

    The main function of the Thyroid gland is to make Hormones, T4 and T3, which are essential for the regulation of metabolic processes throughout the body. As at any factory, effective production depends on three key components – adequate raw material, efficient machinery, and appropriate controls. Iodine is the critical raw material, because 65% of T4 weight is iodine. Ingested iodine is absorbed and carried in the circulation as iodide. The Thyroid actively concentrates the iodide across the basolateral plasma membrane of thyrocytes by the sodium/iodide symporter, NIS. Intracellular iodide is then transported in the lumen of Thyroid follicles. Meanwhile, the thyrocyte endoplasmic reticulum synthesizes two key proteins, TPO and Tg. Tg is a 660kDa glycoprotein secreted into the lumen of follicles, whose tyrosyls serve as substrate for iodination and Hormone formation. TPO sits at the apical plasma membrane, where it reduces H2O2, elevating the oxidation state of iodide to an iodinating species, and attaches the iodine to tyrosyls in Tg. H2O2 is generated at the apex of the thyrocyte by Duox, a NADPH oxydase. Initial iodination of Tg produces MIT and DIT. Further iodination couples two residues of DIT, both still in peptide linkage, to produce T4, principally at residues 5 in the Tg polypeptide chain. When Thyroid Hormone is needed, Tg is internalized at the apical pole of thyrocytes, conveyed to endosomes and lysosomes and digested by proteases, particularly the endopeptidases cathepsins B, L, D and exopeptidases. After Tg digestion, T4 and T3 are released into the circulation. Nonhormonal iodine, about 70% of Tg iodine, is retrieved intraThyroidally by DEHAL1, an iodotyrosine deiodinase and made available for recycling within the gland. TSH is the stimulator that affects virtually every stage of Thyroid Hormone Synthesis and release. Early control involves the direct activation of the cellular and enzymatic machineries while delayed and chronic controls are on gene expression of key proteins. Iodine supply, either too much or too little, impairs adequate Synthesis. AntiThyroid drugs act by interfering with iodide oxidation. Genetic abnormalities in any of the key proteins, particularly NIS, TPO, Duox and Tg, can produce goiter and hypoThyroidism.

  • Chapter 2: Thyroid Hormone Synthesis and Secretion
    Endotext, 2015
    Co-Authors: Françoise Miot, Je Dumont, Corinne Dupuy, Bernard A Rousset
    Abstract:

    3) Faculté de Médecine Lyon-Est, Site Laennec -UMR 664 Inserm, 69372 LYON Cedex 08 Fédération de Biochimie et Biologie Spécialisée, Hôpital Edouard-­‐Herriot, 69437 Lyon cedex 03, France ; Bernard.Rousset@sante.univ-lyon1.fr Revised 30 August 2015 TO DOWNLOAD OF THIS CHAPTER IN PDF OR WORD, CLICK HERE ABSTRACT The main function of the Thyroid gland is to make Hormones, T4 and T3, which are essential for the regulation of metabolic processes throughout the body. As at any factory, effective production depends on three key components -adequate raw material, efficient machinery, and appropriate controls. Iodine is the critical raw material, because 65% of T4 weight is iodine. Ingested iodine is absorbed and carried in the circulation as iodide. The Thyroid actively concentrates the iodide across the basolateral plasma membrane of thyrocytes by the sodium/iodide symporter, NIS. Intracellular iodide is then transported in the lumen of Thyroid follicles. Meanwhile, the thyrocyte endoplasmic reticulum synthesizes two key proteins, TPO and Tg. Tg is a 660kDa glycoprotein secreted into the lumen of follicles, whose tyrosyls serve as substrate for iodination and Hormone formation. TPO sits at the apical plasma membrane, where it reduces H 2 O 2 , elevating the oxidation state of iodide to an iodinating species, and attaches the iodine to tyrosyls in Tg. H 2 O 2 is generated at the apex of the thyrocyte by Duox, a NADPH oxydase. Initial iodination of Tg produces MIT and DIT. Further iodination couples two residues of DIT, both still in peptide linkage, to produce T4, principally at residues 5 in the Tg polypeptide chain. When Thyroid Hormone is needed, Tg is internalized at the apical pole of thyrocytes, conveyed to endosomes and lysosomes and digested by proteases, particularly the endopeptidases cathepsins B, L, D and exopeptidases. After Tg digestion, T4 and T3 are released into the circulation. Nonhormonal iodine, about 70% of Tg iodine, is retrieved intraThyroidally by DEHAL1, an iodotyrosine deiodinase and made available for recycling within the gland. TSH is the stimulator that affects virtually every stage of Thyroid Hormone Synthesis

G J Beckett - One of the best experts on this subject based on the ideXlab platform.

Pierre Carayon - One of the best experts on this subject based on the ideXlab platform.

  • production of immunoreactive thyroglobulin c terminal fragments during Thyroid Hormone Synthesis
    Endocrinology, 2000
    Co-Authors: Christine Duthoit, Bernard Mallet, Valerie Estienne, Frederic Delom, Joseemartine Durandgorde, Pierre Carayon
    Abstract:

    Here, we studied the fragmentation of the proThyroid Hormone, thyroglobulin (Tg), which occurs during Thyroid Hormone Synthesis, a process which involves iodide, thyroperoxidase, and the H2O2-generating system, consisting of glucose and glucose oxidase. Various peptides were found to be immunoreactive to autoantibodies to Tg from patients and monoclonal antibodies directed against the immunodominant region of Tg. The smallest peptide (40 kDa) bore Thyroid Hormones and was identified at the C-terminal end of the Tg molecule, which shows homologies with acetylcholinesterase. Similar peptides were obtained by performing metal-mediated oxidation of Tg via a Fenton reaction. It was concluded that the oxidative stress induced during Hormone Synthesis generates free radicals, which, in turn, cleave Tg into immunoreactive peptides.

  • dityrosine bridge formation and Thyroid Hormone Synthesis are tightly linked and are both dependent on n glycans
    FEBS Letters, 1996
    Co-Authors: Nathalie Baudry, Pierrejean Lejeune, Patricia Niccoli, Liliane Vinet, Pierre Carayon, Bernard Mallet
    Abstract:

    Formation of dityrosine bridges is a ubiquitous process mainly attributed to oxidative stress leading to protein degradation and cellular damages. Here we show that dityrosine formation is involved in a physiological process, Thyroid Hormone Synthesis, and is strictly dependent on structural characteristics, namely N-glycans, presented by the protein acting as the proThyroid Hormone. We used two isoforms of the N-terminal Thyroid Hormone forming domain (NTD) of human thyroglobulin: one without N-glycan (19 kDa isoform) and the other with high mannose type structures (25 kDa isoform). Both isoforms were able to form iodotyrosines after in vitro iodination. However, iodotyrosine coupling to form thyroxine did not occur with the unglycosylated 19 kDa NTD. In contrast, the 25 kDa isoform formed thyroxine. Strikingly, thyroxine Synthesis was accompanied by dimerization of the 25 kDa isoform and formation of a dityrosine bridge; none of this was observed with the 19 kDa isoform. Taken as a whole, our results indicate that dimerization through dityrosine bridging accompanies and could have a role in Thyroid Hormone Synthesis.

  • n glycans modulate in vivo and in vitro Thyroid Hormone Synthesis study at the n terminal domain of thyroglobulin
    Journal of Biological Chemistry, 1995
    Co-Authors: Bernard Mallet, Nathalie Baudry, Pierrejean Lejeune, Patricia Niccoli, Pierre Carayon, Jeanlouis Franc
    Abstract:

    Abstract Thyroglobulin (Tg) is the substrate for Thyroid Hormone bioSynthesis, which requires tyrosine iodination and iodotyrosine coupling and occurs at the apical membrane of the thyrocytes. Tg glycoconjugates have been shown to play a major role in Tg routing through cellular compartments and recycling after endocytosis. Here we show that glycoconjugates also play a direct role in hormonoSynthesis. The N-terminal domain (NTD; Asn1-Met) of human Tg, which bears the preferential hormonogenic site, brings two N-glycans (Asn and Asn). NTD preparations were purified from Tg with low and mild iodine content in vivo and from poorly iodinated Tg after in vitro iodination and coupling. NTD separated from poorly iodinated Tg was also submitted to iodination and coupling after desialylation and deglycosylation. The various NTD isoforms were analyzed for their N-glycan structures and Hormone contents. Our results show that 1) in vivo as well as in vitro unglycosylated isoforms did not synthesize Hormones, whereas fully or partially (at Asn) glycosylated isoforms did; 2) high mannose type structures enhanced the Hormone content; and 3) desialylation did not affect in vitro Hormone Synthesis. Evidence of a direct involvement in hormonoSynthesis adds to the role of N-glycans in Tg function and opens the way to new mechanisms for regulation (e.g. TSH modulation of N-glycan) or alteration (e.g. Asn mutation) of Thyroid Hormone Synthesis.

Klaus Eder - One of the best experts on this subject based on the ideXlab platform.

  • endoplasmic reticulum stress inhibits expression of genes involved in Thyroid Hormone Synthesis and their key transcriptional regulators in frtl 5 thyrocytes
    PLOS ONE, 2017
    Co-Authors: Robert Ringseis, Klaus Eder
    Abstract:

    Endoplasmic reticulum (ER) stress is characterized by the accumulation of misfolded proteins due to an impairment of ER quality control pathways leading to the activation of a defense system, called unfolded protein response (UPR). While thyrocytes are supposed to be highly susceptible to environmental conditions that cause ER stress due to the Synthesis of large amounts of secretory proteins required for Thyroid Hormone Synthesis, systematic investigations on the effect of ER stress on expression of key genes of Thyroid Hormone Synthesis and their transcriptional regulators are lacking. Since the aim of the ER stress-induced UPR is to restore ER homeostasis and to facilitate cell survival through transient shutdown of ribosomal protein translation, we hypothesized that the expression of genes involved in Thyroid Hormone Synthesis and their transcriptional regulators, all of which are not essential for cell survival, are down-regulated in thyrocytes during ER stress, while sterol regulatory element-binding proteins (SREBPs) are activated during ER stress in thyrocytes. Treatment of FRTL-5 thyrocytes with the ER stress inducer tunicamycin (TM) dose-dependently increased the mRNA and/or protein levels of known UPR target genes, stimulated phosphorylation of the ER stress sensor protein kinase RNA-like ER kinase (PERK) and of the PERK target protein eukaryotic initiation factor 2α (eIF2α) and caused splicing of the ER stress-sensitive transcription factor X-box binding protein (XBP-1) (P < 0.05). The mRNA levels and/or protein levels of genes involved in Thyroid Hormone Synthesis, sodium/iodide symporter (NIS), Thyroid peroxidase (TPO) and thyroglobulin (TG), their transcriptional regulators and thyrotropin (TSH) receptor and the uptake of Na125I were reduced at the highest concentration of TM tested (0.1 μg/mL; P < 0.05). Proteolytic activation of the SREBP-1c pathway was not observed in FRTL-5 cells treated with TM, whereas TM reduced proteolytic activation of the SREBP-2 pathway at 0.1 μg TM/mL (P < 0.05). In conclusion, the expression of key genes involved in Thyroid Hormone Synthesis and their critical regulators and of the TSH receptor as well as the uptake of iodide is attenuated in thyrocytes during mild ER stress. Down-regulation of NIS, TPO and TG during ER stress is likely the consequence of impaired TSH/TSHR signaling in concert with reduced expression of critical transcriptional regulators of these genes.

  • Sterol Regulatory Element-Binding Proteins Are Regulators of the Rat Thyroid Peroxidase Gene in Thyroid Cells
    PLOS ONE, 2014
    Co-Authors: Christine Rauer, Robert Ringseis, Susanne Rothe, Klaus Eder
    Abstract:

    Sterol regulatory element-binding proteins (SREBPs)-1c and -2, which were initially discovered as master transcriptional regulators of lipid bioSynthesis and uptake, were recently identified as novel transcriptional regulators of the sodium-iodide symporter gene in the Thyroid, which is essential for Thyroid Hormone Synthesis. Based on this observation that SREBPs play a role for Thyroid Hormone Synthesis, we hypothesized that another gene involved in Thyroid Hormone Synthesis, the Thyroid peroxidase (TPO) gene, is also a target of SREBP-1c and -2. Thyroid epithelial cells treated with 25-hydroxycholesterol, which is known to inhibit SREBP activation, had about 50% decreased mRNA levels of TPO. Similarly, the mRNA level of TPO was reduced by about 50% in response to siRNA mediated knockdown of both, SREBP-1 and SREBP-2. Reporter gene assays revealed that overexpression of active SREBP-1c and -2 causes a strong transcriptional activation of the rat TPO gene, which was localized to an approximately 80 bp region in the intron 1 of the rat TPO gene. In vitro- and in vivo-binding of both, SREBP-1c and SREBP-2, to this region in the rat TPO gene could be demonstrated using gel-shift assays and chromatin immunoprecipitation. Mutation analysis of the 80 bp region of rat TPO intron 1 revealed two isolated and two overlapping SREBP-binding elements from which one, the overlapping SRE+609/InvSRE+614, was shown to be functional in reporter gene assays. In connection with recent findings that the rat NIS gene is also a SREBP target gene in the Thyroid, the present findings suggest that SREBPs may be possible novel targets for pharmacological modulation of Thyroid Hormone Synthesis.

  • Research paper effects of 13-HPODE on expression of genes involved in Thyroid Hormone Synthesis, iodide uptake and formation of hydrogen peroxide in porcine thyrocytes.
    International Journal for Vitamin and Nutrition Research, 2006
    Co-Authors: Sebastian Luci, Anja Bettzieche, Corinna Brandsch, Klaus Eder
    Abstract:

    It has been shown that dietary oxidized fats influence Thyroid function in rats and pigs. Mechanisms underlying this phenomenon are unknown. This study was performed to investigate whether 13-hydroperoxy- 9,11-octadecadienic acid (13-HPODE), a primary oxidation product of linoleic acid, affects expression of genes involved in Thyroid Hormone Synthesis and formation of hydrogen peroxide in primary porcine thyrocytes. Thy- rocytes were treated with 13-HPODE in concentrations between 20 and 100 µM. Cells treated with vehicle alone ("control cells") or with equivalent concentrations of linoleic acid were considered as controls. Treatment of cells with 13-HPODE did not affect cell viability but increased the activities of the antioxidant enzymes super- oxide dismutase and glutathione peroxidase (p < 0.05) compared to control cells or cells treated with linoleic acid. Relative mRNA concentrations of genes involved in Thyroid Hormone Synthesis like sodium iodide sym- porter, thyrotropin receptor, and Thyroid peroxidase, as well as iodide uptake, did not differ between cells treat- ed with 13-HPODE and control cells or cells treated with linoleic acid. Treatment of cells with 13-HPODE, how- ever, reduced the relative mRNA concentrations of dual oxidase-2 and the formation of hydrogen peroxide com- pared to control cells or cells treated with linoleic acid (p < 0.05). Because the production of hydrogen perox- ide is rate-limiting for the Synthesis of Thyroid Hormones, it is suggested that 13-HPODE could have an impact on the formation of Thyroid Hormones in the Thyroid gland.

A F Howie - One of the best experts on this subject based on the ideXlab platform.