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Masatomo Mori - One of the best experts on this subject based on the ideXlab platform.
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A novel mechanism for the inhibition of type 2 Iodothyronine Deiodinase by tumor necrosis factor α: involvement of proteasomal degradation
Endocrine journal, 2013Co-Authors: Takayuki Ogiwara, Osamu Araki, Masatomo Mori, Tadashi Morimura, Katsuhiko Tsunekawa, Masami MurakamiAbstract:Thyroxine (T₄) needs to be converted to 3,5,3'-triIodothyronine (T₃) by Iodothyronine Deiodinase to exert its biological activity. Recent studies revealed the presence of type 2 Iodothyronine Deiodinase (D2) in human thyroid tissue, human skeletal muscle and other tissues, suggesting that D2 is involved in maintaining plasma T₃ level in human. Tumor necrosis factor α (TNFα) is an inflammatory cytokine of which production is elevated in patients with nonthyroidal illness. Although several lines of evidence suggest the causal role of TNFα in nonthyroidal illness, detailed nature of the effect of TNFα on D2 remains unclear. In the present study, we identified D2 activity and D2 mRNA in TCO-1 cells, which were derived from human anaplastic thyroid carcinoma, and studied the mechanisms involved in the regulation of D2 expression by TNFα. The characteristics of the deiodinating activity in TCO-1 cells were compatible with those of D2 and Northern analysis demonstrated that D2 mRNA was expressed in TCO-1cells. D2 activity and D2 mRNA expression were rapidly increased by dibutyryl cAMP ((Bu)₂cAMP). TNFα showed an inhibitory effect on (Bu)₂cAMP-stimulated D2 activity in spite of little effect on (Bu)₂cAMP-stimulated D2 mRNA expression. MG132, a proteasome inhibitor abolished TNFα suppression of D2 activity whereas BAY11-7082 or 6-amino-4-(4-phenoxyphenylethylamino) quinazoline, inhibitors of nuclear factor-κB (NF-κB) failed to attenuate the effect of TNFα on D2 activity. These data suggest that a posttranslational mechanism through proteasomal degradation but not NF-κB activation is involved in the suppression of D2 by TNFα.
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Regulation of Iodothyronine Deiodinase and roles of thyroid hormones in human coronary artery smooth muscle cells.
Atherosclerosis, 2005Co-Authors: Takayuki Kasahara, Katsuhiko Tsunekawa, Masatomo Mori, Koji Seki, Masami MurakamiAbstract:Thyroid hormones have been reported to have significant effects on the peripheral vascular system, including relaxation of vascular smooth muscle cells and prevention of atherosclerosis. To exert its biological activity, thyroxine (T4) needs to be converted to 3,5,3'-triIodothyronine (T3) by type 1 and type 2 Iodothyronine Deiodinases. We have previously identified type 2 Iodothyronine Deiodinase (D2) expression in cultured human coronary artery smooth muscle cells (hCASMCs). In the present study, we have characterized the regulation of D2 expression in hCASMCs by stable prostacyclin analogue beraprost sodium (BPS) and platelet derived growth factor (PDGF), and the roles of thyroid hormones in the functions of hCASMCs. BPS increased D2 expression, whereas PDGF suppressed BPS stimulated D2 expression without affecting cAMP production in hCASMCs. PDGF increased DNA synthesis, while BPS, T3 or T4 suppressed PDGF stimulated DNA synthesis in hCASMCs. Inhibition of D2 activity by 3,3',5'-triIodothyronine (rT3) partially restored T4 suppression of PDGF stimulated DNA synthesis in hCASMCs. PDGF increased migration activity, whereas BPS, T3 or T4 suppressed PDGF stimulated migration activity of hCASMCs. These results suggest that D2 expression is increased by BPS and suppressed by PDGF in hCASMCs, and that intracellular thyroid hormone activation may be involved in the suppression of DNA synthesis and migration activity of hCASMCs.
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Expression of type 2 Iodothyronine Deiodinase in human osteoblast is stimulated by thyrotropin.
Endocrinology, 2005Co-Authors: Tadashi Morimura, Takayuki Ogiwara, Masatomo Mori, Katsuhiko Tsunekawa, Takayuki Kasahara, Koji Seki, Masami MurakamiAbstract:Thyroid hormones play important roles in bone growth, development, and turnover. To exert its biological activity, T(4) needs to be converted to T(3) by Iodothyronine Deiodinase. In human thyroid gland as well as rat brown adipose tissue, type 2 Iodothyronine Deiodinase (D2) expression is regulated by a TSH receptor-cAMP-mediated mechanism. TSH receptor knockout mice demonstrated the direct effects of TSH on bone via TSH receptors found on osteoblast and osteoclast precursors. In the present study we investigated the possible expression and function of Iodothyronine Deiodinase and TSH receptors in human osteoblast-like osteosarcoma (SaOS-2) cells and normal human osteoblast (NHOst) cells. Iodothyronine Deiodinase activity was detected in SaOS-2 cells and NHOst cells, and all of the characteristics of deiodinating activity were compatible with those of D2. Northern analysis demonstrated D2 mRNA expression in SaOS-2 cells and NHOst cells. D2 mRNA levels as well as D2 activities were rapidly increased by dibutyryl cAMP or forskolin in SaOS-2 cells and NHOst cells. TSH receptor mRNA was demonstrated in SaOS-2 cells and NHOst cells, and D2 mRNA and D2 activity were stimulated by TSH in both cells. In addition, all T(3) receptor isoforms were detected by RT-PCR in SaOS-2 cells and NHOst cells. The present results indicate the expression of functional TSH receptors and D2 in human osteoblasts and suggest previously unrecognized roles of TSH receptors and local T(3) production by D2 in the pathophysiology of human osteoblasts.
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Expression of type 2 Iodothyronine Deiodinase in corticotropin-secreting mouse pituitary tumor cells is stimulated by glucocorticoid and corticotropin-releasing hormone.
Endocrinology, 2003Co-Authors: Osamu Araki, Takayuki Ogiwara, Haruo Mizuma, Masatomo Mori, Tadashi Morimura, Masami MurakamiAbstract:We identified the presence of Iodothyronine Deiodinase in AtT-20 mouse pituitary tumor cells that secrete corticotropin. IodothyroninedeiodinatingactivityinAtT-20cellsfulfillsallthe characteristics of type 2 Iodothyronine Deiodinase (D2), including the inhibition by thyroid hormones, the insensitivity to inhibition by 6-propyl-2-thiouracil, and the low Michaelis-Menten constant value for T4. Northern analysis using mouse D2 cRNA probe demonstrated the hybridization signal of approximately 7.0 kb in size in AtT-20 cells. D2 activity and D2 mRNA were stimulated by glucocorticoid in a dose-dependent manner but were not stimulated by testosterone or -estradiol. D2 expression was stimulated by (Bu)2cAMP, and CRH in a dosedependent manner in the presence of dexamethasone. These resultssuggestthepreviouslyunrecognizedroleoflocalthyroid hormone activation by D2 in the regulation of pituitary corticotrophs. (Endocrinology 144: 4459–4465, 2003)
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Expression and regulation of type II Iodothyronine Deiodinase in human thyroid gland.
Endocrinology, 2001Co-Authors: Masami Murakami, Yuji Kamiya, Osamu Araki, Yasuhiro Hosoi, Takayuki Ogiwara, Haruo Mizuma, Tadashi Morimura, Masatomo MoriAbstract:We have studied the expression of type II Iodothyronine Deiodinase (DII) in human thyroid tumors and cultured human thyroid cells to elucidate the mechanisms involved in the regulation of DII expression in human thyroid gland. Three cases with hyperfunctioning thyroid adenoma, including a case that showed an activating mutation of Gsα with a constitutive activation of cAMP production in cultured cells, and six cases with papillary thyroid carcinoma were analyzed in the present study. Free T3 was increased, whereas free T4 was within the normal range in all patients with hyperfunctioning thyroid adenoma. Thyroid tumor tissue and surrounding nontumor tissue were obtained at the time of surgery, and DII expression was compared between tumor tissue and nontumor tissue in each case. Northern analysis demonstrated the presence of DII messenger RNA (mRNA) approximately 7.5 kb in size in all of the tumor and nontumor tissues. DII mRNA and DII activity in hyperfunctioning thyroid adenoma were significantly increas...
Theo J. Visser - One of the best experts on this subject based on the ideXlab platform.
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Induction of type 1 Iodothyronine Deiodinase expression inhibits proliferation and migration of renal cancer cells.
Molecular and Cellular Endocrinology, 2016Co-Authors: Piotr Popławski, Theo J. Visser, Beata Rybicka, Joanna Boguslawska, Katarzyna Rodzik, Alicja Nauman, Agnieszka Piekiełko-witkowskaAbstract:Abstract Type 1 Iodothyronine Deiodinase (DIO1) regulates peripheral metabolism of thyroid hormones that control cellular proliferation, differentiation and metabolism. The significance of DIO1 in cancer is unknown. In this study we hypothesized that diminished expression of DIO1, observed in renal cancer, contributes to the carcinogenic process in the kidney. Here, we demonstrate that ectopic expression of DIO1 in renal cancer cells changes the expression of genes controlling cell cycle, including cyclin E1 and E2F5, and results in inhibition of proliferation. The expression of genes encoding collagens (COL1A1, COL4A2, COL5A1), integrins (ITGA4, ITGA5, ITGB3) and transforming growth factor-β-induced (TGFBI) is significantly altered in renal cancer cells with induced expression of DIO1. Finally, we show that overexpression of DIO1 inhibits migration of renal cancer cells. In conclusion, we demonstrate for the first time that loss of DIO1 contributes to renal carcinogenesis and that its induced expression protects cells against cancerous proliferation and migration.
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knockdown of type 3 Iodothyronine Deiodinase severely perturbs both embryonic and early larval development in zebrafish
Endocrinology, 2014Co-Authors: Marjolein Heijlen, Theo J. Visser, Anne M Houbrechts, Enise Bagci, Stijn Van Herck, Simone Kersseboom, Camila V Esguerra, Ronny Blust, Dries Knapen, Veerle DarrasAbstract:Exposure to appropriate levels of thyroid hormones (THs) at the right time is of key importance for normal development in all vertebrates. Type 3 Iodothyronine Deiodinase (D3) is the prime TH-inactivating enzyme, and its expression is highest in the early stages of vertebrate development, implying that it may be necessary to shield developing tissues from overexposure to THs. We used antisense morpholino knockdown to examine the role of D3 during early development in zebrafish. Zebrafish possess 2 D3 genes, dio3a and dio3b. Here, we show that both genes are expressed during development and both contribute to in vivo D3 activity. However, dio3b mRNA levels in embryos are higher, and the effects of dio3b knockdown on D3 activity and on the resulting phenotype are more severe. D3 knockdown induced an overall delay in development, as determined by measurements of otic vesicle length, eye and ear size, and body length. The time of hatching was also severely delayed in D3-knockdown embryos. Importantly, we also...
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Regulation of type III Iodothyronine Deiodinase expression in human cell lines.
Endocrinology, 2006Co-Authors: Monique H. A. Kester, George G. J. M. Kuiper, Rogier Versteeg, Theo J. VisserAbstract:Type I Iodothyronine Deiodinase (D1) and type II Iodothyronine Deiodinase (D2) catalyze the activation of the prohormone T4 to the active hormone T3; type III Iodothyronine Deiodinase (D3) catalyzes the inactivation of T4 and T3. D3 is highly expressed in brain, placenta, pregnant uterus, and fetal tissues and plays an important role in regulating thyroid hormone bioavailability during fetal development. We examined the activity of the different Deiodinases in human cell lines and investigated the regulation of D3 activity and mRNA expression in these cell lines, as well as its possible coexpression with neighboring genes Dlk1 and Dio3os, which may also be especially important during development. D1 activity and mRNA were only found in HepG2 hepatocarcinoma cells, and D2 activity was observed in none of the cell lines. D3 activity and mRNA was found in ECC-1 endometrium carcinoma cells, MCF-7 mammacarcinoma cells, WRL-68 embryonic liver cells, and SH-SY5Y neuroblastoma cells, but not in the HepG2 hepatocarcinoma cell line or in any choriocarcinoma or astrocytoma cell line. We demonstrated that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate increased D3 activity 2- to 9-fold in ECC-1, MCF-7, WRL-68, and SH-SY5Y cells. Estradiol increased D3 activity 3-fold in ECC-1, but not in any other cells. Dexamethasone decreased D3 activity in WRL-68 cells only in the absence of fetal calf serum. Incubation with retinoids increased D3 activity 2- to 3-fold in ECC-1, WRL-68, and MCF-7 cells but decreased D3 activity in SH-SY5Y cells. D3 expression in the different cells was not affected by cAMP or thyroid hormone. Interestingly, D3 mRNA expression in the different cell lines strongly correlated with Dio3os mRNA expression and in a large set of neuroblastoma cell lines also with Dlk1 expression. In conclusion, we identified different human D3-expressing cell lines, in which the regulation of D3 expression is cell type-specific. Our data suggest that estradiol may be one of the factors contributing to the induction of D3 activity in the pregnant uterus and that in addition to gene-specific regulatory elements, more distant common regulatory elements also may be involved in the regulation of D3 expression.
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Molecular basis for the substrate selectivity of cat type I Iodothyronine Deiodinase.
Endocrinology, 2003Co-Authors: George G. J. M. Kuiper, Ellen Kaptein, Frank W. J. S. Wassen, Willem Klootwijk, Hans Van Toor, Theo J. VisserAbstract:The type I Iodothyronine Deiodinase (D1) catalyzes the activation of T4 to T3 as well as the degradation of T3 (rT3) and sulfated Iodothyronines. A comparison of the catalytic activities of D1 in liver microsomal preparations from several species revealed a remarkable difference between cat D1 on one hand and rat/human D1 on the other hand. The Michaelis constant (Km) of cat D1 for rT3 (11 μm) is 30-fold higher than that of rat and human D1 (0.2–0.5 μm). Deiodination of rT3 by cat D1 is facilitated by sulfation [maximal velocity (Vmax)/Km rT3 = 3 and Vmax/Km rT3S = 81]. To understand the molecular basis for the difference in substrate interaction the cat D1 cDNA was cloned, and the deduced amino acid sequence was compared with rat/human D1 protein. In the region between amino acid residues 40 and 70 of cat D1, various differences with rat/human D1 are concentrated. By site-directed mutagenesis of cat D1 it was found that a combination of mutations was necessary to improve the deiodination of rT3 by cat D1...
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placental Iodothyronine Deiodinase expression in normal and growth restricted human pregnancies
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Shiao-yng Chan, S. Kachilele, E. Hobbs, Judith N. Bulmer, Kristien Boelaert, Christopher Mccabe, P. M. Driver, Arthur R. Bradwell, Monique H. A. Kester, Theo J. VisserAbstract:We have described the expression of specific Iodothyronine Deiodinase mRNAs (using quantitative RT-PCR) and activities in normal human placentas throughout gestation and compared our findings to those in placentas from pregnancies affected by intrauterine growth restriction (IUGR). The predominant Deiodinase expressed in placenta was type III (D3); type II (D2) was also present. In general terms, the activities of the enzymes D2 and D3 (and mRNAs encoding these enzymes) were higher earlier in gestation (<28 wk) than at term and displayed an inverse relationship with the duration of gestation (P < 0.05). Comparison of the relative expressions of mRNAs encoding D2 and D3 as well as their activities in placentas associated with IUGR (early and late gestational groups) with findings from normal placentas of similar gestational ages revealed no significant differences. Immunolocalization of D2 and D3 in syncytiotrophoblast (including syncytial sprouts) and cytotrophoblast of human placentas was demonstrated at both early and late gestation. Treatment of primary cultures of term cytotrophoblast cells in vitro with increasing doses of T3 (1, 10, and 100 nM) resulted in increased expression of mRNAs encoding both D2 and D3 at 100-nM concentrations (P < 0.01) compared with control. Experiments with JEG-3 choriocarcinoma cells demonstrated a similar effect on D3 mRNA at 10 and 100 nM T3 (P < 0.01). The demonstrated changes in Iodothyronine Deiodinase expression in the placenta across pregnancy are likely to contribute to regulation of the thyroid hormone supply to the developing fetus. The lack of difference in Deiodinase expression in normal placentas and those found in IUGR argues against placental Deiodinases being responsible for the hypothyroxemia in circulating fetal thyroid hormones observed in this condition. (J Clin Endocrinol Metab 88: 4488 – 4495, 2003)
Masami Murakami - One of the best experts on this subject based on the ideXlab platform.
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A novel mechanism for the inhibition of type 2 Iodothyronine Deiodinase by tumor necrosis factor α: involvement of proteasomal degradation
Endocrine journal, 2013Co-Authors: Takayuki Ogiwara, Osamu Araki, Masatomo Mori, Tadashi Morimura, Katsuhiko Tsunekawa, Masami MurakamiAbstract:Thyroxine (T₄) needs to be converted to 3,5,3'-triIodothyronine (T₃) by Iodothyronine Deiodinase to exert its biological activity. Recent studies revealed the presence of type 2 Iodothyronine Deiodinase (D2) in human thyroid tissue, human skeletal muscle and other tissues, suggesting that D2 is involved in maintaining plasma T₃ level in human. Tumor necrosis factor α (TNFα) is an inflammatory cytokine of which production is elevated in patients with nonthyroidal illness. Although several lines of evidence suggest the causal role of TNFα in nonthyroidal illness, detailed nature of the effect of TNFα on D2 remains unclear. In the present study, we identified D2 activity and D2 mRNA in TCO-1 cells, which were derived from human anaplastic thyroid carcinoma, and studied the mechanisms involved in the regulation of D2 expression by TNFα. The characteristics of the deiodinating activity in TCO-1 cells were compatible with those of D2 and Northern analysis demonstrated that D2 mRNA was expressed in TCO-1cells. D2 activity and D2 mRNA expression were rapidly increased by dibutyryl cAMP ((Bu)₂cAMP). TNFα showed an inhibitory effect on (Bu)₂cAMP-stimulated D2 activity in spite of little effect on (Bu)₂cAMP-stimulated D2 mRNA expression. MG132, a proteasome inhibitor abolished TNFα suppression of D2 activity whereas BAY11-7082 or 6-amino-4-(4-phenoxyphenylethylamino) quinazoline, inhibitors of nuclear factor-κB (NF-κB) failed to attenuate the effect of TNFα on D2 activity. These data suggest that a posttranslational mechanism through proteasomal degradation but not NF-κB activation is involved in the suppression of D2 by TNFα.
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Regulation of Iodothyronine Deiodinase and roles of thyroid hormones in human coronary artery smooth muscle cells.
Atherosclerosis, 2005Co-Authors: Takayuki Kasahara, Katsuhiko Tsunekawa, Masatomo Mori, Koji Seki, Masami MurakamiAbstract:Thyroid hormones have been reported to have significant effects on the peripheral vascular system, including relaxation of vascular smooth muscle cells and prevention of atherosclerosis. To exert its biological activity, thyroxine (T4) needs to be converted to 3,5,3'-triIodothyronine (T3) by type 1 and type 2 Iodothyronine Deiodinases. We have previously identified type 2 Iodothyronine Deiodinase (D2) expression in cultured human coronary artery smooth muscle cells (hCASMCs). In the present study, we have characterized the regulation of D2 expression in hCASMCs by stable prostacyclin analogue beraprost sodium (BPS) and platelet derived growth factor (PDGF), and the roles of thyroid hormones in the functions of hCASMCs. BPS increased D2 expression, whereas PDGF suppressed BPS stimulated D2 expression without affecting cAMP production in hCASMCs. PDGF increased DNA synthesis, while BPS, T3 or T4 suppressed PDGF stimulated DNA synthesis in hCASMCs. Inhibition of D2 activity by 3,3',5'-triIodothyronine (rT3) partially restored T4 suppression of PDGF stimulated DNA synthesis in hCASMCs. PDGF increased migration activity, whereas BPS, T3 or T4 suppressed PDGF stimulated migration activity of hCASMCs. These results suggest that D2 expression is increased by BPS and suppressed by PDGF in hCASMCs, and that intracellular thyroid hormone activation may be involved in the suppression of DNA synthesis and migration activity of hCASMCs.
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Expression of type 2 Iodothyronine Deiodinase in human osteoblast is stimulated by thyrotropin.
Endocrinology, 2005Co-Authors: Tadashi Morimura, Takayuki Ogiwara, Masatomo Mori, Katsuhiko Tsunekawa, Takayuki Kasahara, Koji Seki, Masami MurakamiAbstract:Thyroid hormones play important roles in bone growth, development, and turnover. To exert its biological activity, T(4) needs to be converted to T(3) by Iodothyronine Deiodinase. In human thyroid gland as well as rat brown adipose tissue, type 2 Iodothyronine Deiodinase (D2) expression is regulated by a TSH receptor-cAMP-mediated mechanism. TSH receptor knockout mice demonstrated the direct effects of TSH on bone via TSH receptors found on osteoblast and osteoclast precursors. In the present study we investigated the possible expression and function of Iodothyronine Deiodinase and TSH receptors in human osteoblast-like osteosarcoma (SaOS-2) cells and normal human osteoblast (NHOst) cells. Iodothyronine Deiodinase activity was detected in SaOS-2 cells and NHOst cells, and all of the characteristics of deiodinating activity were compatible with those of D2. Northern analysis demonstrated D2 mRNA expression in SaOS-2 cells and NHOst cells. D2 mRNA levels as well as D2 activities were rapidly increased by dibutyryl cAMP or forskolin in SaOS-2 cells and NHOst cells. TSH receptor mRNA was demonstrated in SaOS-2 cells and NHOst cells, and D2 mRNA and D2 activity were stimulated by TSH in both cells. In addition, all T(3) receptor isoforms were detected by RT-PCR in SaOS-2 cells and NHOst cells. The present results indicate the expression of functional TSH receptors and D2 in human osteoblasts and suggest previously unrecognized roles of TSH receptors and local T(3) production by D2 in the pathophysiology of human osteoblasts.
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Expression of type 2 Iodothyronine Deiodinase in corticotropin-secreting mouse pituitary tumor cells is stimulated by glucocorticoid and corticotropin-releasing hormone.
Endocrinology, 2003Co-Authors: Osamu Araki, Takayuki Ogiwara, Haruo Mizuma, Masatomo Mori, Tadashi Morimura, Masami MurakamiAbstract:We identified the presence of Iodothyronine Deiodinase in AtT-20 mouse pituitary tumor cells that secrete corticotropin. IodothyroninedeiodinatingactivityinAtT-20cellsfulfillsallthe characteristics of type 2 Iodothyronine Deiodinase (D2), including the inhibition by thyroid hormones, the insensitivity to inhibition by 6-propyl-2-thiouracil, and the low Michaelis-Menten constant value for T4. Northern analysis using mouse D2 cRNA probe demonstrated the hybridization signal of approximately 7.0 kb in size in AtT-20 cells. D2 activity and D2 mRNA were stimulated by glucocorticoid in a dose-dependent manner but were not stimulated by testosterone or -estradiol. D2 expression was stimulated by (Bu)2cAMP, and CRH in a dosedependent manner in the presence of dexamethasone. These resultssuggestthepreviouslyunrecognizedroleoflocalthyroid hormone activation by D2 in the regulation of pituitary corticotrophs. (Endocrinology 144: 4459–4465, 2003)
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Expression and regulation of type II Iodothyronine Deiodinase in human thyroid gland.
Endocrinology, 2001Co-Authors: Masami Murakami, Yuji Kamiya, Osamu Araki, Yasuhiro Hosoi, Takayuki Ogiwara, Haruo Mizuma, Tadashi Morimura, Masatomo MoriAbstract:We have studied the expression of type II Iodothyronine Deiodinase (DII) in human thyroid tumors and cultured human thyroid cells to elucidate the mechanisms involved in the regulation of DII expression in human thyroid gland. Three cases with hyperfunctioning thyroid adenoma, including a case that showed an activating mutation of Gsα with a constitutive activation of cAMP production in cultured cells, and six cases with papillary thyroid carcinoma were analyzed in the present study. Free T3 was increased, whereas free T4 was within the normal range in all patients with hyperfunctioning thyroid adenoma. Thyroid tumor tissue and surrounding nontumor tissue were obtained at the time of surgery, and DII expression was compared between tumor tissue and nontumor tissue in each case. Northern analysis demonstrated the presence of DII messenger RNA (mRNA) approximately 7.5 kb in size in all of the tumor and nontumor tissues. DII mRNA and DII activity in hyperfunctioning thyroid adenoma were significantly increas...
Reed P Larsen - One of the best experts on this subject based on the ideXlab platform.
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BRIEF REPORT Brief Report SEVERE HYPOTHYROIDISM CAUSED BY TYPE 3 Iodothyronine Deiodinase IN INFANTILE HEMANGIOMAS
2011Co-Authors: Stephen A Huang, John W Harney, M Venihaki, Atul J Butte, Harry P W Kozakewich, Steven J Fishman, Ph. D, Reed P LarsenAbstract:EMANGIOMAS are the most common tumors of infancy, with a prevalence of 5 to 10 percent among one-year-olds. They are characterized by rapid growth in the first year of life, followed by involution and gradual regression by adolescence. 1,2 H We recently treated a three-month-old infant with massive hepatic hemangiomas and primary hypothyroidism who needed very high doses of thyroid hormone to restore euthyroidism and normal thyrotropin secretion. This finding suggested that the rate of degradation of thyroid hormone was accelerated. We subsequently identified high levels of type 3 Iodothyronine Deiodinase activity in the hemangioma tissue. This selenoenzyme, normally present in the brain and placenta, catalyzes the conversion of thyroxine to reverse triIodothyronine and the conversion of triIodothyronine to 3,3'-diIodothyronine, both of which are biologically inactive. We then retrospectively analyzed other patients with hemangiomas and identified additional patients with similar histories and other hemangiomas with type 3 Iodothyronine Deiodinase activity. CASE REPORT A full-term baby boy was delivered at home after a normal pregnancy. The parents declined to have him undergo thyroid screening. At six weeks of age, he was brought to medical attention because of abdominal distention. Liver biopsy revealed a hepatic hemangioma. The serum thyrotropin concentration was 156 µU per milliliter (normal range, 0.3 to 6.2), and the serum fre
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transforming growth factor β promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 Iodothyronine Deiodinase
Molecular Endocrinology, 2005Co-Authors: Stephen A Huang, John W Harney, Alessandra Crescenzi, Michelle A Mulcahey, Mirra Chung, Brian W Kim, Carmen M Barnes, Wichert Kuijt, Helen Turano, Reed P LarsenAbstract:Thyroid hormone is a critical mediator of cellular metabolism and differentiation. Precise tissue-specific regulation of the concentration of the active ligand, T3, is achieved by Iodothyronine monodeiodination. Type 3 Iodothyronine Deiodinase (D3) is the major inactivating pathway, preventing activation of the prohormone T4 and terminating the action of T3. Using nontransformed human cells, we show that TGF-β stimulates transcription of the hDio3 gene via a Smad-dependent pathway. Combinations of Smad2 or Smad3 with Smad4 stimulate hDio3 gene transcription only in cells that express endogenous D3 activity, indicating that Smads are necessary but not sufficient for D3 induction. TGF-β induces endogenous D3 in diverse human cell types, including fetal and adult fibroblasts from several tissues, hemangioma cells, fetal epithelia, and skeletal muscle myoblasts. Maximum stimulation of D3 by TGF-β also requires MAPK and is synergistic with phorbol ester and several mitogens known to signal through transmembran...
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type 1 Iodothyronine Deiodinase is a sensitive marker of peripheral thyroid status in the mouse
Endocrinology, 2005Co-Authors: Ann Marie Zavacki, Marcelo A Christoffolete, John W Harney, Reed P Larsen, Hao Ying, Goele Aerts, Sheueyann Cheng, Antonio C BiancoAbstract:Mice with one thyroid hormone receptor (TR) alpha-1 allele encoding a dominant negative mutant receptor (TR alpha1(PV/+)) have persistently elevated serum T3 levels (1.9-fold above normal). They also have markedly increased hepatic type 1 Iodothyronine Deiodinase (D1) mRNA and enzyme activity (4- to 5-fold), whereas other hepatic T3-responsive genes, such as Spot14 and mitochondrial alpha-glycerol phosphate dehydrogenase (alpha-GPD), are only 0.7-fold and 1.7-fold that of wild-type littermates (TR alpha1+/+). To determine the cause of the disproportionate elevation of D1, TR alpha1+/+ and TR alpha1(PV/+) mice were rendered hypothyroid and then treated with T3. Hypothyroidism decreased hepatic D1, Spot14, and alpha-GPD mRNA to similar levels in TR alpha1+/+ and TR alpha1(PV/+) mice, whereas T3 administration caused an approximately 175-fold elevation of D1 mRNA but only a 3- to 6-fold increases in Spot14 and alpha-GPD mRNAs. Interestingly, the hypothyroidism-induced increase in cerebrocortical type 2 Iodothyronine Deiodinase activity was 3 times greater in the TR alpha1(PV/+) mice, and these mice had no T3-dependent induction of type 3 Iodothyronine Deiodinase. Thus, the marked responsiveness of hepatic D1 to T3 relative to other genes, such as Spot14 and alpha-GPD, explains the relatively large effect of the modest increase in serum T3 in the TR alpha1(PV/+) mice, and TR alpha plays a key role in T3-dependent positive and negative regulation of the Deiodinases in the cerebral cortex.
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type 3 Iodothyronine Deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Stephen A Huang, Domenico Salvatore, David M Dorfman, David R Genest, Reed P LarsenAbstract:Type 3 Iodothyronine Deiodinase (D3) is the major physiologic inactivator of thyroid hormone. This selenoenzyme, previously identified in human placenta and brain, catalyzes the inner-ring deiodination of T4 to reverse T3 and T3 to 3, 3′-diIodothyronine, both of which are biologically inactive. We analyzed D3 expression in several human adult and fetal tissues by immunohistochemistry and correlated the results with D3 activity assays where possible. High D3 expression was present in the placental syncytiotrophoblasts and cytotrophoblasts, endothelium of fetal vessels, and maternal decidua. D3 was also present at other sites of maternal-fetal interface, including the umbilical arteries and vein and the fetal respiratory, digestive, and urinary tract epithelium. Surprisingly, D3 was also present in the endometrial glands of nonpregnant human uteri, and endometrial activity approximated that of term placenta. The presence of D3 at maternal-fetal interfaces is consistent with its role in modulating the thyroi...
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a 21 year old woman with consumptive hypothyroidism due to a vascular tumor expressing type 3 Iodothyronine Deiodinase
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Stephen A Huang, Harry P W Kozakewich, Domenico Salvatore, Stephanie A Fish, David M Dorfman, Susan J Mandel, Reed P LarsenAbstract:We present a 21-yr-old female with a large hepatic vascular tumor and subclinical hypothyroidism. A high level of the thyroid hormone inactivating enzyme type 3 Iodothyronine Deiodinase (D3) was detected in her tumor, and the TSH of 26.2 mU/liter returned to normal after surgical resection of the mass. This indicates that the vascular tumor caused this adult's hypothyroidism as has now been documented in nine infants with this syndrome. This first example of consumptive hypothyroidism in an adult indicates that the inactivation rate of thyroid hormone by D3 in a vascular tumor can stress the secretory capacity even of the TSH-stimulated normal adult thyroid gland.
Veerle Darras - One of the best experts on this subject based on the ideXlab platform.
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knockdown of type 3 Iodothyronine Deiodinase severely perturbs both embryonic and early larval development in zebrafish
Endocrinology, 2014Co-Authors: Marjolein Heijlen, Theo J. Visser, Anne M Houbrechts, Enise Bagci, Stijn Van Herck, Simone Kersseboom, Camila V Esguerra, Ronny Blust, Dries Knapen, Veerle DarrasAbstract:Exposure to appropriate levels of thyroid hormones (THs) at the right time is of key importance for normal development in all vertebrates. Type 3 Iodothyronine Deiodinase (D3) is the prime TH-inactivating enzyme, and its expression is highest in the early stages of vertebrate development, implying that it may be necessary to shield developing tissues from overexposure to THs. We used antisense morpholino knockdown to examine the role of D3 during early development in zebrafish. Zebrafish possess 2 D3 genes, dio3a and dio3b. Here, we show that both genes are expressed during development and both contribute to in vivo D3 activity. However, dio3b mRNA levels in embryos are higher, and the effects of dio3b knockdown on D3 activity and on the resulting phenotype are more severe. D3 knockdown induced an overall delay in development, as determined by measurements of otic vesicle length, eye and ear size, and body length. The time of hatching was also severely delayed in D3-knockdown embryos. Importantly, we also...
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type 2 Iodothyronine Deiodinase is essential for thyroid hormone dependent embryonic development and pigmentation in zebrafish
Endocrinology, 2009Co-Authors: Chaminda Walpita, Serge Van Der Geyten, Alexander D Crawford, Els Janssens, Veerle DarrasAbstract:Despite the known importance of thyroid hormones (THs) in vertebrate growth and development, the role of tissue-specific TH activation in early embryogenesis remains unclear. We therefore examined the function of type 2 Iodothyronine Deiodinase (D2), one of the two tissue-specific enzymes catalyzing the conversion of T4 to T3, in developing zebrafish embryos (Danio rerio). Microinjection of early embryos with antisense oligonucleotides targeting either the D2 translation start site or the splice junction between the first exon and intron induced delays in development and pigmentation, as determined through the measurement of otic vesicle length, head-trunk angle, and pigmentation index at 31 h after fertilization. The antisense-induced delays in developmental progression and pigmentation were reversible through treatment with T3, suggesting that these phenotypic effects may be due to the depletion of intracellular T3 levels. Additional evidence for this hypothesis was provided by quantitative RT-PCR analy...
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exposure to pcb 77 induces tissue dependent changes in Iodothyronine Deiodinase activity patterns in the embryonic chicken
General and Comparative Endocrinology, 2006Co-Authors: Veerle Beck, Simon Roelens, Veerle DarrasAbstract:PCB 77 is a dioxin-like PCB that has been shown to reduce circulating thyroid hormone (TH) levels. This may be an important factor contributing to its neurotoxicity, since THs are essential for normal brain development. In this study, we investigated the changes in TH activating and inactivating Iodothyronine Deiodinase (D) activities in liver, telencephalon and cerebellum of chicken embryos during the final stages of embryonic development and hatching. We combined these results with measurements of plasma TH levels and intracellular TH availability in the tissues mentioned above, to find out whether D activity was a factor contributing to the PCB 77-induced decrease in peripheral TH levels and/or whether it was capable of reducing the adverse effects on brain via compensatory mechanisms. PCB 77 reduced both T4 and T3 levels in plasma and brain. Its effect on hepatic D1 and D3 activity was limited and rebuts a causative role of hepatic Ds in the drop of plasma TH levels. In cerebellum, D2 increased and D3 decreased, indicating a compensatory mechanism in this brain part, mainly during the stages of pipping and hatching. The changes in telencephalon occurred at the earlier stages and included an increase in both D2 and D3 activity.
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Role of spatiotemporal expression of Iodothyronine Deiodinase proteins in cerebellar cell organization
Brain research bulletin, 2005Co-Authors: Carla Verhoelst, Simon Roelens, Veerle DarrasAbstract:Thyroid hormones (TH) play a crucial role in various developmental processes in all vertebrates. The expression of a number of thyroid hormone responsive genes is of critical importance in processes like cell maturation and migration. Since these genes are mostly regulated by binding of the receptor-active TH (T(3)) to the thyroid hormone receptor, the availability of this T(3) is indispensable for correct brain lamination. One important way to regulate local TH availability is via the ontogenetic changes in activating and inactivating Iodothyronine Deiodinases. The current study was set up to investigate the distribution of type I, type II and type III (D1, D2 and D3) Iodothyronine Deiodinase protein in the chicken cerebellum at two important developmental ages, namely embryonic day 18 when cerebellar cell migration is fully in progress, and 1 day posthatch, when cerebellar maturation is mostly finished. The results show that the Deiodinase proteins are divergently expressed in the cerebellar cell population. D1 and D3 are expressed in the granule cells at E18, whereas D2 is found mostly in the molecular layer and the Purkinje cells at that time. One day posthatch, the expression of D1 is limited to the mature granule cells and that of D3 to the Purkinje cells exclusively, whereas D2 remains clearly present in the molecular layer. Comparison of the Deiodinase protein distribution with the expression of TH-responsive proteins involved in cell migration (reelin, disabled protein 1 and tenascin-C) allows speculating about the effect of this spatiotemporal distribution pattern on cerebellar cell communicative pathways.
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Renal and hepatic distribution of type I and type III Iodothyronine Deiodinase protein in chicken
Journal of Endocrinology, 2004Co-Authors: Carla Verhoelst, S. Van Der Geyten, Veerle DarrasAbstract:Iodothyronine Deiodinase in vitro activity studies in the chicken showed the presence of type I and type III Iodothyronine Deiodinase activity in both liver and kidney. Due to the lack of a specific antiserum the cellular localization of the Deiodinase proteins could not be revealed until now. In the present study, specific antisera were used to study the renal and hepatic distribution of type I and type III Iodothyronine Deiodinase protein in the chicken. Immunocytochemical staining of liver tissue led to an immunopositive signal in the hepatocytes in general. Moreover, a zonal distribution could be detected for both enzymes. Maximum protein expression was shown in a thin layer of hepatocytes bordering the blood veins. Although pericentral localization of type I Deiodinase protein has been previously reported in the rat, no data were given concerning type III Deiodinase protein. In the present study, we report the co-localization of both enzymes in the chicken. Co-expression of the Deiodinases was also found in the kidney. Expression of both proteins was associated with the tubular epithelial cells and with the transitional epithelium, and the inner longitudinal and outer circular muscle layers of the ureter. No staining could be detected in the lamina propria or in the fat tissue surrounding the ureter.
