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PubMed1994

Two thyroid hormone response elements are present in the promoter of human thyroid hormone receptor beta 1.

Autoregulation of the human thyroid hormone receptor beta 1 (hTR beta 1) promoter was assessed by chloramphenicol acetyltransferase and luciferase reporter assays of transient transfections into COS1 and GH3 cells, DNase I footprinting, and gel shift assays. A 5'-deletional analysis of the promoter showed that the region between -906 and -839 and the sequence from -438 to -130 were positively regulated by T3 in COS1 cells cotransfected with an hTR beta 1 expression vector. We also transfected deletion constructs into GH3 cells and showed similar effects of T3 on the trans-activation of the reporters. DNase I footprinting showed a protected inverted palindromic thyroid response element (TRE) at position -890 to -866 in the distal fragment and a direct repeat at position -190 to -166 in the proximal fragment, which were protected by TRs. Mutation of each TRE significantly decreased the trans-activation of the promoter by T3. Gel mobility shift assays showed both proximal and distal TREs formed a retarded band with hTR alpha 1 or hTR beta 1 expressed in COS1 cells and reticulocyte lysates. The bands formed on the distal TRE and the proximal TRE appear to be preferentially formed by a TR homodimer and a heterodimer, respectively. Furthermore, the band formed on the distal TRE disappeared after adding T3 but that on the proximal TRE did not. These results indicate that hTR beta 1 expression is directly regulated by hTR alpha 1, beta 1, and their ligand through two TREs. The different structure of the TREs in this promoter suggests their physiological role in transcriptional regulation may be different.

Animals↗
PubMed1984

Circannual rhythms of plasma growth hormone, thyrotropin and thyroid hormones in prepuberty.

To clarify the occurrence of circannual GH, TSH, T4 and T3 rhythms in prepuberty we have been studying, for a four year period, 150 healthy subjects, aged 6-10, by cross-sectional design. Plasma samples were taken at 0800 h and all hormones were measured by RIA. The occurrence of any circannual rhythm was statistically investigated by the cosinor method. A significant rhythm was validated (P = 0.02) only in TSH secretion, with annual crest time in December; GH, T4, T3 did not show a circannual rhythm. Our results seem to strengthen the hypothesis that the thyroid hormones, at least before puberty, do not play an important role in the regulation of circannual TSH periodicity.

Child↗
PubMed1983

Response of thyroid hormones in peripheral and thyroid venous blood to TRH administration in man.

Thyroid vein and cubital vein samples were collected simultaneously in 6 moderately hypercalcemic patients and 1 eucalcemic hypothyroid patient, and thyroid hormones were measured in the serum in the basal state, as well as 30 and 60 min after intravenous administration of TRH. No gradient was detectable between peripheral and thyroid blood in the case of T4, and no significant changes were observed following TRH. The levels of T3 were higher in the thyroid venous effluent than in the periphery and a marked increase occurred following TRH. Serum thyroglobulin also increased following TRH, but there was no peripheral vs. thyroid gradient. Calcitonin demonstrated a marked positive gradient in the thyroid vein compared to the periphery, but no change was observed following TRH. It is concluded that the patterns of response of individual thyroid hormones reflect differences in their secretion and, specifically, that intrathyroid conversion of T4 to T3 occurs during the thyroid hormone secretion.

Female↗
PubMedDate not supplied

Adenohypophyseal degradation of thyrotropin releasing hormone regulated by thyroid hormones.

Thyrotropin Releasing Hormone (TRH; pyroGlu-His-Pro-NH2) is important in the regulation of adenohypophyseal hormone secretion and also serves neurotropic functions in extra-hypothalamic brain areas, indicating that it is involved in neurotransmission and other forms of cellular communication. This hypothesis is strengthened by the observation that TRH is hydrolysed at the pyroGlu-His bond by a particulate enzyme located in the synaptosomal and adenohypophyseal plasma membrane. Furthermore, this enzyme has been identified as a heterogeneously distributed ectoenzyme which has a high degree of substrate specificity like the TRH-degrading serum enzyme studied previously. In the rat, the activity of the TRH-degrading serum enzyme has been shown to be influenced by the thyroid status of the animals; here I report that the activity of the membrane-bound TRH-degrading enzyme of the anterior pituitary is stringently controlled by thyroid hormones, but that the activity of the brain enzyme is not.

Animals↗
PubMed1999

Thyroid hormone receptor-associated proteins and general positive cofactors mediate thyroid hormone receptor function in the absence of the TATA box-binding protein-associated factors of TFIID.

Coactivators previously implicated in ligand-dependent activation functions by thyroid hormone receptor (TR) include p300 and CREB-binding protein (CBP), the steroid receptor coactivator-1 (SRC-1)-related family of proteins, and the multicomponent TR-associated protein (TRAP) complex. Here we show that two positive cofactors (PC2 and PC4) derived from the upstream stimulatory activity (USA) cofactor fraction act synergistically to mediate thyroid hormone (T3)-dependent activation either by TR or by a TR-TRAP complex in an in vitro system reconstituted with purified factors and DNA templates. Significantly, the TRAP-mediated enhancement of activation by TR does not require the TATA box-binding protein-associated factors of TFIID. Furthermore, neither the pleiotropic coactivators CBP and p300 nor members of the SRC-1 family were detected in either the TR-TRAP complex or the other components of the in vitro assay system. These results show that activation by TR at the level of naked DNA templates is enhanced by cooperative functions of the TRAP coactivators and the general coactivators PC2 and PC4, and they further indicate a potential functional redundancy between TRAPs and TATA box-binding protein-associated factors in TFIID. In conjunction with earlier studies on other nuclear receptor-interacting cofactors, the present study also suggests a multistep pathway, involving distinct sets of cofactors, for activation of hormone responsive genes.

Animals↗
PubMed1975

Free diiodotyrosine effects on protein iodination and thyroid hormone synthesis catalyzed by thyroid peroxidase.

Free diiosotyrosine exerts two opposite effects on the reactions catalyzed by thyroid peroxidase, thyroglobulin iodination and thyroid hormone formation. 1. Inhibition of thyroglobulin iodination catalyzed by thyroid peroxidase was observed when free diiodotyrosine concentration was higher than 5 muM. This inhibition was competitive, suggesting that free diiodotyrosine interacts with the substrate site(s) of thyroid peroxidase. Free diiodotyrosine also competively inhibited iodide peroxidation to I2. 2. Free diiodotyrosine, when incubated with thyroid peroxidase in the absence of iodide was recovered unmodified; in the presence of iodide an exchange reaction was observed between the iodine atoms present in the diiodotyrosine molecule and iodide present in the medium. Using 14C-labelled diiodotyrosine, 14C-labelled non-iodinated products were also observed, showing that deiodination occurred as a minor degradation pathway. However, no monoiodo[14C]tyrosine or E114C]tyrosine were observed. Exchange reaction between free diiototyrosine and iodide is therefore direct and does not imply deiodination-iodination intermediary steps. Thyroglobulin inhibits diiodotyrosine-iodide exchange and vice versa, again suggesting competition for both reactions. These results support, by a different experimental approach, the two-site model for peroxidase previously described by us in this journal. 3. Free diiodotyrosine when present at a very low concentration, 0.05 muM, exerts a stimulatory effect on throid hormones synthesis. The relationship between diiodotyrosine concentration and thyroid hormone synthesis give an S-shaped curve, suggesting that free diiodotyrosine acts as a regulatory ligand for thyroid peroxidase. Evidence is also presented that free diiodotyrosine is not incorporated into thyroid hormones. Therefore, thyroid peroxidase catalyzes only intra-molecular coupling between iodotyrosine hormonogenic residues. 4. Finally, although no direct proof exists that these free diiodotyrosine effects upon thyroglobulin iodination and thyroid hormone synthesis are physiologically significant, such a possibility deserves further investigation.

Animals↗
PubMed1996

Structural features of thyroid hormone response elements that increase susceptibility to inhibition by an RTH mutant thyroid hormone receptor.

The chicken lysozyme silencer F2 (F2) thyroid hormone response element (TRE) contains an unusual everted palindromic arrangement, has a high affinity for thyroid hormone receptor (TR) homodimers, and is especially sensitive to dominant negative inhibition by, the T3 resistance (RTH) mutant TR beta P453H. We used various TREs and TR mutations to determine the mechanisms for this sensitivity. Changing the F2 orientation from an everted palindrome to a direct repeat with a 4-bp gap (DR+4) (F2-DR) decreased the sensitivity to inhibition at high T3 concentrations, while a loss of this sensitivity occurred with a palindromic arrangement of these same half-sites. F2 contains the dinucleotide TG 5' to each consensus half-site conforming to the optimal TR-binding octamer, YRRGGTCA. A T to A change in position 1 of both F2 half-sites markedly reduced T3-induction, yet only slightly reduced TR homodimer or TR-retinoid X receptor (RXR) heterodimer binding. The TR beta ninth heptad mutation, L428R, prevents TR heterodimerization with RXR and eliminates the inhibitory effect of the P453H mutant TR on the F2-DR, but not the F2 element. Structural features of a TRE that favor strong TR binding of both TR homodimers and TR-RXR heterodimers containing the mutant TR, such as the everted palindromic conformation or the optimal TR-binding consensus octamer, enhance the sensitivity of a TRE to inhibition by the mutant TR. Thus, both half-site orientation and sequence contribute to the sensitivity of a given TRE to dominant negative inhibition by a mutant TR.

Amino Acid Sequence↗
PubMed1996

Periodically hyperthyroid phenotype in thyroid hormone resistance is associated with mutation D322N in the thyroid hormone receptor beta gene: transcriptional properties of the mutant and the role of retinoid X receptor.

We report a point mutation in the ligand-binding domain of the TR beta 1 gene in an affected patient and his daughter. The phenotype was borderline hyperthyroid with periodic aggravation of symptoms. In the cognate variant TR beta (TR beta-CN) amino acid codon 322 was exchanged from aspartic acid to asparagine. TR beta-CN revealed strongly decreased T3-binding activity. At low T3 levels TR beta-CN transactivated a palindromic thyroid hormone response element (TRE-PAL) only to a limited extend, whereas full activity was retained at a high T3 concentration. At low T3 levels, TR beta-CN exerted a dominant negative effect on wild-type TR beta, whereas this effect was diminished in the presence of high T3 concentrations. TR beta-CN could not be activated by retinoid X receptor (RXR) beta in the presence of T3, whereas addition of 9cis-retinoic acid (9c-RA) resulted in the transactivation of TRE-PAL through RXR beta independently of the presence of TR beta-CN. In conclusion, the time dependent variable THR phenotype of patient CN might be influenced by the differential expression of RXRs and the T3 and 9c-RA hormonal status.

Adult↗
PubMed1990

Immunocytochemical localization of thyroid hormone nuclear receptors in cultured acetylcholinesterase-positive neurons: a correlation between the presence of thyroid hormone nuclear receptors and L-tri-iodothyronine morphological effects.

A monoclonal antibody against the rat liver L-tri-iodothyronine nuclear receptor and acetylcholinesterase cytochemistry were used for the localization of thyroid hormone nuclear receptors in acetylcholinesterase-positive cell nuclei in fetal rat cerebral hemisphere neuronal cultures. After 3 days in vitro, the ratio of acetylcholinesterase-positive cells that were immunoreactive for the thyroid hormone nuclear receptor to those not stained for this receptor (74-26%, respectively) remains unchanged despite an increase in the number of acetylcholinesterase-positive cells with time (from day 3 to day 21) in culture. Furthermore, the addition of 3 X 10(-8) L-tri-iodothyronine in culture did not modify this ratio or have an effect on the number of acetylcholinesterase-positive cells, but significantly increased the neurite density in those acetylcholinesterase-positive cells that were immunoreactive for the thyroid hormone receptor. Conversely, no difference in the neurite densities of those acetylcholinesterase-positive cells not stained for this receptor was observed when cultured in the presence or absence of thyroid hormone. In other experiments with the same fetal brain cultures, treatment of cultures for 8 days with L-tri-iodothyronine, beginning on culture day 20, demonstrated the presence of a critical period which occurs in vitro around day 20, since the stimulatory effect of L-tri-iodothyronine on immunoreactive acetylcholinesterase-positive cell neurite density is lost after 20 days in vitro. These results demonstrate, for the first time, the presence of L-tri-iodothyronine nuclear receptors in fetal rat acetylcholinesterase-positive neurons and the existence of a cellular heterogeneity in the distribution of the thyroid hormone receptor. The presence of these receptors in fetal brain acetylcholinesterase-positive neurons suggests that some effects of L-tri-iodothyronine on the maturation of a subpopulation of acetylcholinesterase-positive neurons may result from a direct effect of this hormone through an interaction with its specific nuclear receptors.

Acetylcholinesterase↗
PubMed1984

Potentiation of surfactant release in fetal lung by thyroid hormone action.

Thyroid hormone has been shown to accelerate fetal lung development, but the mechanisms by which this hormone acts are yet unknown. Since this hormone may act indirectly by potentiating the action of endogenous catecholamines, we studied this mechanism by measuring beta-adrenergic receptors in fetal lung. Fetal rabbits at 27 days of gestation were treated with triiodothyronine (T3), 100 micrograms/100 g, in the presence and absence of propranolol, 200 micrograms/100 g, or actinomycin D, 20 micrograms/100 g. Fetuses were killed by decapitation either after 4 or 24 h of T3 treatment. The beta-adrenergic antagonist l-[3H]dihydroalprenolol was used to directly estimate the number and affinity of beta-adrenergic receptor in lung membranes. T3 increased the number of beta-adrenergic receptors in fetal lung, but the affinity of binding did not change. The enhancement of binding capacity after 4 h of T3 treatment was not inhibited by actinomycin D. However, 24-h T3-mediated stimulation was partially blocked by actinomycin D. In addition, T3 stimulated the catecholamine content, adenylate cyclase activity, and adenosine 3',5'-cyclic monophosphate content of lung. T3 increased the lecithin-to-sphingomyelin ratio, phosphatidylglycerol, and disaturated phosphatidylcholine content of the pulmonary lavage fluid. These parameters were completely inhibited by propranolol after 4 h and partially inhibited by actinomycin D after 24 h. Thus thyroid hormone enhances lung maturation by increasing the number of beta-adrenergic receptors in fetal lung.

Animals↗
PubMed1988

Developmental changes in rat brain 5'-deiodinase and thyroid hormones during the fetal period: the effects of fetal hypothyroidism and maternal thyroid hormones.

We have studied the ontogenesis of 5'-deiodinase (5'D) activity in rat brain during fetal life, its capacity to respond to maternal or fetal hypothyroidism, and its regulation by maternal thyroid hormones. Type II 5'D (5' D-II) activity increases 4-fold during the period studied (17 to 22 days of gestation), mainly between days 19 and 21. Fetal brain T4 concentrations increase in parallel with fetal plasma T4, whereas fetal brain T3 concentrations increase 18 times (days 17-21), six times more than would have been expected from the small increase in fetal plasma T3 levels. Maternal thyroidectomy did not affect 5'D-II activity or thyroid hormone concentrations in fetal brain (except brain T4 at 18 days of gestation). Fetal hypothyroidism, induced by giving a goitrogen (methimazole) to the mothers, depleted all fetal tissues studied, including the fetal thyroid, from thyroid hormones. By 19 days of gestation, the fetal brain was able to respond to hypothyroidism with a 3- to 5-fold increase in 5'D-II activity. Earlier onset of treatment with methimazole led to 2- to 3-fold increases in 5'D already at 17 and 18 days of gestation, showing that when fetal thyroid secretion starts the fetal brain 5'D-II is able to respond to hypothyroidism. Replacement of methimazole-treated mothers with physiological doses of T4, given by constant infusion, increased T4 and T3 concentrations in fetal brain, and inhibited fetal, as well as maternal, brain 5'D-II activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Nuclear factors specifically favor thyroid hormone binding to c-ErbA alpha 1 protein (thyroid hormone receptor alpha) over-expressed in E. coli.

A recombinant rat thyroid hormone receptor alpha (TR alpha or c-ErbA alpha 1) was produced in E. coli as a non-mutated, nonfusioned protein and obtained as an efficient DNA and T3 binding protein that could be easily handled in a buffer-soluble state (rec-TR alpha). It was found that nuclear extracts (NE) added to rec-TR alpha markedly amplified not only DNA binding, which has been well documented, but also T3 binding (increased binding site concentration), which has not yet been reported. This T3 binding amplifying effect on rec-TR alpha occurs at low NE protein concentrations that produce no or minimal endogenous TR with respect to rec-TR, while similar concentrations of other proteins (e.g. ovalbumin or cytosol) only moderately enhanced T3 binding. The T3 binding amplifying nuclear factors, which are partly heat-labile, appeared as necessary auxiliaries in the analyses of partially purified rec-TR alpha. A protective effect of NE against a loss of affinity for T3 under the action of antibodies directed to certain sequences in the TR alpha D domain suggests that nuclear factors help rec-TR alpha to acquire and/or stabilize a conformation that allows the high affinity T3 binding. The nature of this nuclear amplifying factor is still unknown: RXR alpha which, produced in vitro, could amplify binding of the rec-TR alpha to a DNA thyroid response element, was unable to display such a rescue of high affinity binding sites.

Animals↗
PubMed1997

A new point mutation (M313T) in the thyroid hormone receptor beta gene in a patient with resistance to thyroid hormone.

Sequence analysis of the TR beta gene from a patient with the syndrome of resistance to thyroid hormone revealed a novel missense mutation in exon 9, changing thymidine in position 1123 to cytosine. The corresponding amino acid alteration is a substitution of a methionine (ATG) for a threonine (ACG) at codon 313 being the patient heterozygous for the mutation. In contrast, his parents had only the wild-type sequence, suggesting a de novo mutational event.

Child↗
PubMed1995

N-terminal variants of thyroid hormone receptor beta: differential function and potential contribution to syndrome of resistance to thyroid hormone.

The human syndrome of resistance to thyroid hormone (RTH) is associated with dominant mutations in the thyroid hormone receptor beta (TR beta) gene that generate mutant receptors with impaired binding for T3. Although the TR beta gene differentially expresses two N-terminal variant receptors, TR beta 1 and TR beta 2, functional analyses of RTH mutants have focused exclusively on TR beta 1. Since TR beta 2 is expressed in tissues that are malfunctional in RTH, the role of mutations in the context of TR beta 2 was examined. We compared the functional properties of corresponding RTH mutations in the common C-terminal domain of both TR beta 1 and TR beta 2. Wild type TR beta 1 and TR beta 2 bound similarly as homodimers and as heterodimers with retinoid X receptors to T3-responsive elements consisting of a direct repeat with 4-base pair spacing or an everted repeat. Homodimers, but not monomers or heterodimers, of both receptor subtypes were dissociated by the addition of T3. However, TR beta 2 formed at least 10-fold more stable homodimers than TR beta 1 on a palindromic repeat element, indicating that the N termini of TR beta 1 and TR beta 2 differentially influence dimerization on DNA. The RTH-like mutants of both TR beta 1 and TR beta 2 were equally insensitive to T3. They were defective in T3 binding but still bound DNA like their wild type counterparts except that the T3-dependent dissociation of homodimers from DNA was severely reduced. Wild type TR beta 1 and TR beta 2 mediated T3-inducible transactivation in cotransfection assays; this, however, was abolished in both mutants. TR beta 1 mediated more sensitive T3-dependent transcriptional suppression than TR beta 2 through the negative T3 response region of the TSH beta gene. Again, the mutation abolished T3-dependent suppression by both mutants. Furthermore, both mutants inhibited T3-inducible transcriptional activation by different wild type TR alpha and beta variants. These results indicate that both mutants have the potential to contribute to the pathogenesis of RTH and suggest that a reassessment of previous models of RTH is required to take into account the inhibitory activity of both TR beta 2 and TR beta 1 mutants.

3T3 Cells↗