Structural and functional differences in the dio1 gene in mice with inherited type 1 deiodinase deficiency.

Maia, Ana Luiza Silva; Berry, Marla J.; Sabbag, Rachel V.; Harney, John W.; Larsen, P. Reed

doi:10.1210/mend.9.8.7476994

Cited by 44 publications

(35 citation statements)

References 34 publications

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“…The INR sequences of the mouse and human genes are identical, and mdio1 also has the SP1-binding site. The human and mouse promoters have 72% identity over the 260 bp 5Ј to the TSS (41). The hdio1 mRNA is T3 responsive in HepG2 cells and the increase of both rat dio1 and hdio1 mRNAs is not blocked by 30 min of preincubation with cycloheximide, indicating that this response does not require protein synthesis or the presence of short-lived proteins.…”

Section: Discussionmentioning

confidence: 99%

“…The mouse dio1 gene (mdio1) consists of four exons and a TATA-less promoter which is GC rich and contains an SP1-binding site (41). No TREs in the 5Ј-flanking region of that gene have yet been identified despite the fact that mdio1 mRNA increases rapidly after T3 administration in vivo (41).…”

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confidence: 99%

“…No TREs in the 5Ј-flanking region of that gene have yet been identified despite the fact that mdio1 mRNA increases rapidly after T3 administration in vivo (41).…”

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A Novel Retinoid X Receptor-Independent Thyroid Hormone Response Element Is Present in the Human Type 1 Deiodinase Gene

Toyoda

Zavacki

Maia

et al. 1995

Molecular and Cellular Biology

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130

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We identified two thyroid hormone response elements (TREs) in the 2.5-kb, 5-flanking region of the human gene encoding type 1 iodothyronine deiodinase (hdio1), an enzyme which catalyses the activation of thyroxine to 3,5,3-triiodothyronine (T3). Both TREs contribute equally to T3 induction of the homologous promoter in transient expression assays. The proximal TRE (TRE1), which is located at bp ؊100, has an unusual structure, a direct repeat of the octamer YYRGGTCA hexamer that is spaced by 10 bp. The pyrimidines in the ؊2 position relative to the core hexamer are both essential to function. In vitro binding studies of TRE1 showed no heterodimer formation with retinoid X receptor (RXR) ␤ or JEG nuclear extracts (containing RXR␣) and bacterially expressed chicken T3 receptor ␣1 (TR␣) can occupy both half-sites although the 3 half-site is dominant. T3 causes dissociation of TR␣ from the 5 half-site but increases binding to the 3 half-site. Binding of a second TR to TRE1 is minimally cooperative; however, no cooperativity was noted for a functional mutant in which the half-sites are separated by 15 bp, implying that TRs bind as independent monomers. Nonetheless, T3 still causes TR dissociation from the DR؉15, indicating that dissociation occurs independently of TR-TR contact and that rebinding of a T3-TR complex to the 3 half-site occurs because of its slightly higher affinity. A distal TRE (TRE2) is found at bp ؊700 and is a direct repeat of a PuGGTCA hexamer spaced by 4 bp. It has typical TR homodimer and TR-RXR heterodimer binding properties. The TRE1 of hdio1 is the first example of a naturally occurring TRE consisting of two relatively independent octamer sequences which do not require the RXR family of proteins for function.Type 1 iodothyronine deiodinase (D1), the product of the dio1 gene, catalyzes both the first step in thyroid hormone activation, which is outer ring deiodination of thyroxine (T4) to form 3,5,3Ј-triiodothyronine (T3), and the inactivation of T4 or T3 by removal of an inner-ring iodine from the iodothyronine nucleus (48). In the rat, T3 produced by D1 activity provides ϳ60 to 70% of the circulating hormone (35,52). D1 is one of a very small group of selenoenzymes in which selenocysteine, which is encoded by UGA, is present in the active center (8, 9). Thyroid hormone markedly increases dio1 mRNA in liver and kidney in vivo and in rat FRTL-5 and pituitary tumor cells as well as in hepatocytes in primary culture (6,7,42,47,51,67). This increase is a consequence of a direct interaction of T3 with the thyroid hormone receptor and does not require new protein synthesis as does the T3-induced increase in rat growth hormone (rGH) or spot 14 mRNA (59, 63).Triiodothyronine induction of gene expression requires the interaction of ligand with the T3 receptor (TR), which is bound to specific sequences of DNA termed thyroid hormone response elements (TREs) and usually found in the 5Ј-flanking region of T3-responsive genes. A common TRE conformation consists of two core hexamers, termed half-sites, beari...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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A Novel Retinoid X Receptor-Independent Thyroid Hormone Response Element Is Present in the Human Type 1 Deiodinase Gene

Toyoda

Zavacki

Maia

et al. 1995

Molecular and Cellular Biology

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130

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“…The main thyroid gland hormonal secretion is thyroxine (T 4 ), which is then deiodinated to generate tri-iodothyronine (T 3 ), the most active thyroid hormone (Maia et al 1995, Yen 2001. Types I, II, and III iodothyronine deiodinases (D1, D2, and D3 respectively) regulate T 3 production and clearance via removal of specific iodine atoms from the precursor molecule T 4 or T 3 itself.…”

Section: Introductionmentioning

confidence: 99%

The effect of acute exercise session on thyroid hormone economy in rats

Fortunato

Ignacio²,

Padrón³

et al. 2008

Journal of Endocrinology

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The hypothalamic-pituitary-thyroid axis is affected by acute exercise, but the mechanisms underlying thyroid function changes after exercise remain to be defined. The aim of this study was to elucidate the effects of a session of acute exercise on the treadmill at 75% of maximum oxygen consumption on thyroid function of rats. Male Wistar rats were divided into five groups: control (without exercise), and killed immediately after (0 min) or 30, 60, and 120 min after the end of the exercise session. A significant increase in serum tri-iodothyronine (T 3 ) occurred immediately after the exercise, with a gradual decrease thereafter, so that 120 min after the end of the exercise, serum T 3 was significantly lower than that in controls. Total thyroxine (T 4 ) increased progressively reaching values significantly higher than that in the control group at 120 min. T 3 /T 4 ratio was significantly decreased 60 and 120 min after the exercise, indicating impaired T 4 -to-T 3 conversion. Liver type 1 deiodinase activity (D1) significantly decreased at 60 and 120 min, while pituitary D1 increased progressively from 30 to 120 min after the exercise, and thyroid D1 was increased only immediately after the end of the exercise. Brown adipose tissue (BAT) type 2 deiodinase activity (D2) was significantly lower at 30 min, but pituitary D2 remained unchanged. No change in serum thyrotropin was detected, while serum corticosterone was significantly higher 30 min after the exercise. Our results demonstrate that decreased liver D1 and BAT D2 might be involved in the decreased T 4 -to-T 3 conversion detected after an exercise session on the treadmill.

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“…Previous studies reported that T 3 and retinoids induce the expression of the Dio1 gene via two complex thyroid hormone response-retinoic acid response elements located in the promoter region of the human Dio1 gene (66). Although both the rat and mouse liver Dio1 mRNAs are markedly increased by T 3 , canonical thyroid hormone response elements (TREs) have not yet been identified in the available 5Ј-flanking regions (5Ј-FR) of these genes (9,35,36).…”

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Hepatocyte Nuclear Factor 4α Contributes to Thyroid Hormone Homeostasis by Cooperatively Regulating the Type 1 Iodothyronine Deiodinase Gene with GATA4 and Krüppel-Like Transcription Factor 9

Ohguchi

Tanaka

Uchida

et al. 2008

Molecular and Cellular Biology

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Type 1 iodothyronine deiodinase (Dio1), a selenoenzyme catalyzing the bioactivation of thyroid hormone, is highly expressed in the liver. Dio1 mRNA and enzyme activity levels are markedly reduced in the livers of hepatocyte nuclear factor 4␣ (HNF4␣)-null mice, thus accounting for its liver-specific expression. Consistent with this deficiency, serum T 4 and rT 3 concentrations are elevated in these mice compared with those in HNF4␣-floxed control littermates; however, serum T 3 levels are unchanged. Promoter analysis of the mouse Dio1 gene demonstrated that HNF4␣ plays a key role in the transactivation of the mouse Dio1 gene. Deletion and substitution mutation analyses demonstrated that a proximal HNF4␣ site (direct repeat 1 [TGGACAAA GGTGC]; HNF4␣-RE) is crucial for transactivation of the mouse Dio1 gene by HNF4␣. Mouse Dio1 is also stimulated by thyroid hormone signaling, but a direct role for thyroid hormone receptor action has not been reported. We also showed that thyroid hormone-inducible Krüppel-like factor 9 (KLF9) stimulates the mouse Dio1 promoter very efficiently through two CACCC sequences that are located on either side of HNF4␣-RE. Furthermore, KLF9 functions together with HNF4␣ and GATA4 to synergistically activate the mouse Dio1 promoter, suggesting that Dio1 is regulated by thyroid hormone in the mouse through an indirect mechanism requiring prior KLF9 induction. In addition, we showed that physical interactions between the C-terminal zinc finger domain (Cf) of GATA4 and activation function 2 of HNF4␣ and between the basic domain adjacent to Cf of GATA4 and a C-terminal domain of KLF9 are both required for this synergistic response. Taken together, these results suggest that HNF4␣ regulates thyroid hormone homeostasis through transcriptional regulation of the mouse Dio1 gene with GATA4 and KLF9.Thyroid hormone plays important roles in growth, development, differentiation, and the basal metabolic rate in vertebrates. Synthesis of thyroid hormone occurs exclusively in the thyroid gland, whose predominant secretory product is the prohormone thyroxin (T 4 ) and which produces only a small amount of the biologically active hormone 3,5,3Ј-triiodothyronine (T 3 ) (29). The majority of plasma T 3 derives from extrathyroid tissues via outer-ring deiodination of T 4 (9). This activation is catalyzed by two different deiodinases, type 1 iodothyronine deiodinase (Dio1) and type 2 iodothyronine deiodinase (Dio2). Dio1 is one of a family of selenoenzymes extensively expressed in the liver, kidney, thyroid, and pituitary in mammals (5, 6). Unlike Dio2, Dio1 can catalyze both activation of T 4 by outer-ring deiodination (5ЈD) to generate T 3 and inactivation of T 4 by inner-ring deiodination to produce 3,3Ј,5Ј-triiodothyronine (rT 3 ) (5D) (9). The expression and activity of Dio1 are modulated by a variety of hormonal, nutritional, and developmental factors, the most potent being thyroid hormone. Thyroid hormone-induced Dio1 expression contributes to the T 3 excess commonly found in hyperthyroidism. Propylthiour...

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Structural and functional differences in the dio1 gene in mice with inherited type 1 deiodinase deficiency.

Cited by 44 publications

References 34 publications

A Novel Retinoid X Receptor-Independent Thyroid Hormone Response Element Is Present in the Human Type 1 Deiodinase Gene

A Novel Retinoid X Receptor-Independent Thyroid Hormone Response Element Is Present in the Human Type 1 Deiodinase Gene

The effect of acute exercise session on thyroid hormone economy in rats

Hepatocyte Nuclear Factor 4α Contributes to Thyroid Hormone Homeostasis by Cooperatively Regulating the Type 1 Iodothyronine Deiodinase Gene with GATA4 and Krüppel-Like Transcription Factor 9

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