[BIOSYNTHESIS OF THYROID HORMONES. I. THE PATHWAY IN THE CONVERSION TYROSINE INTO THYROID HORMONES].
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Carbon Isotopes↗
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Desmethylimipramine, a potent inhibitor of synaptosomal norepinephrine uptake, has diverse effects on thyroid hormone processing in rat brain. I. Effects on in vivo uptake of 125I-labeled thyroid hormones in rat brain.
Several lines of evidence point to an interaction between amine uptake inhibitors (tricyclic antidepressants) and thyroid hormones. To examine this issue under conditions which would minimize secondary effects of drug treatment, desmethylimipramine (DMI), a highly specific norepinephrine uptake inhibitor, was given acutely as a single i.p. dose one hour before i.v. [125I]triiodothyronine (T3*) or [125I]thyroxine (T4*). Tissues were analysed after rat decapitation at 3, 5, 10, and 20 min intervals thereafter. DMI had a small but significant inhibitory effect on the brain uptake of both T3* (7.4%) and T4* (19%) over their respective 20-min time courses as indicated by two-way ANOVA. To examine the drug response further and to determine the effect of thyroid status on the response, hypothyroid (HYPO) and T4-induced hyperthyroid (HYPER) rats, were given i.v. T3* and, 5 min later, i.p. DMI or saline. They were killed 3 h later and tissue analysed. Because DMI effects on T4* uptake could not be evaluated over a 3 h period without blocking T4* to T3* conversion, sodium ipodate (60 mg/kg) was given in 2 doses before i.v. T4*. Under these conditions, DMI significantly reduced brain concentrations of the administered T3* and T4* in HYPO (15% and 19%) and in HYPER rats (13% and 25%). These results suggest that, as it does in the case of norepinephrine, DMI blocks the uptake site for T3 and T4 in rat brain. No information is available regarding the relationship, if any, between the thyroid hormone and norepinephrine uptake sites.
Animals↗
Aberrant dynamics of histone deacetylation at the thyrotropin-releasing hormone gene in resistance to thyroid hormone.
Histone acetylation status influences transcriptional activity, and the mechanism of negative gene regulation by thyroid hormone remains unclear, although its impairment by a mutant thyroid hormone receptor (TR) is critical for resistance to thyroid hormone (RTH). We found a novel RTH mutant, F455S, that exhibited impaired repression of the TRH gene and had a strong dominant-negative effect on the gene. F455S strongly interacted with nuclear receptor corepressor (NCoR) and was hard to dissociate from it. To analyze the dynamics of histone acetylation status in vivo, we established cell lines stably expressing the TRH promoter and wild-type or F455S TR. Treatment with a histone deacetylase (HDAC) inhibitor completely abolished the repression of the gene by T3. The histones H3 and H4 at the TRH promoter were acetylated, and addition of T3 caused recruitment of HDACs 2 and 3 within 15 min, resulting in a transient deacetylation of the histone tails. TR and NCoR were located on the promoter, and T3 caused NCoR dissociation and steroid receptor coactivator-1 recruitment. In the presence of F455S, the histones were hyperacetylated, and HDAC recruitment and histone deacetylation were significantly impaired. This is the first report demonstrating the direct involvement of aberrant dynamics of chromatin modification in RTH.
Acetylation↗
Both thyroid hormone and 9-cis retinoic acid receptors are required to efficiently mediate the effects of thyroid hormone on embryonic development and specific gene regulation in Xenopus laevis.
Tissue culture transfection and in vitro biochemical studies have suggested that heterodimers of thyroid hormone receptors (TRs) and 9-cis retinoic acid receptors (RXRs) are the likely in vivo complexes that mediate the biological effects of thyroid hormone, 3,5,3'-triiodothyronine (T3). However, direct in vivo evidence for such a hypothesis has been lacking. We have previously reported a close correlation between the coordinated expression of TR and RXR genes and tissue-dependent temporal regulation of organ transformations during Xenopus laevis metamorphosis. By introducing TRs and RXRs either individually or together into developing Xenopus embryos, we demonstrate here that RXRs are critical for the developmental function of TRs. Precocious expression of TRs and RXRs together but not individually leads to drastic, distinct embryonic abnormalities, depending upon the presence or absence of T3, and these developmental effects require the same receptor domains as those required for transcriptional regulation by TR-RXR heterodimers. More importantly, the overexpressed TR-RXR heterodimers faithfully regulate endogenous T3 response genes that are normally regulated by T3 only during metamorphosis. That is, they repress the genes in the absence of T3 and activate them in the presence of the hormone. On the other hand, the receptors have no effect on a retinoic acid (RA) response gene. Thus, RA- and T3 receptor-mediated teratogenic effects in Xenopus embryos occur through distinct molecular pathways, even though the resulting phenotypes have similarities.
Animals↗
Generalized thyroid hormone resistance: identification of an arginine to cystine mutation in codon 315 of the c-erb A beta thyroid hormone receptor.
The present report studies a large kindred (WR) with generalized thyroid hormone resistance that has varying degrees of neuropsychological dysfunction, hyperactivity, poor attention span, decreased IQ and/or abnormalities in spatial perception. In this kindred, there has been found tight linkage of the syndrome with the c-erb A beta gene. The present study was performed to identify the presence of a possible gene mutation as a cause for this syndrome. DNA from peripheral leukocytes was isolated from 15 unaffected and 8 affected individuals from the kindred. Primers encompassing exons 9 (nucleotides 1171-1429) and 10 (nucleotides 1430-1698) were synthesized and used in PCR reactions to amplify these exons. Direct sequencing revealed a consistent substitution in each affected subject, but in none of the unaffected individuals, of a C to T change in one allele from nucleotide 1243, resulting in an arg to cys change in codon 315. The mutant and wild-type human beta 1 receptors were prepared and their translated proteins were analyzed for T3 binding. The WR T3 receptor from affected patients had reduced T3 binding affinity, with values approximately 2.5 x 10(10) M-1 compared to about 5 x 10(10) M-1 in normals. In summary, we have: i) identified a consistent and reproducible mutation of a C to T change in nucleotide 1243 in each of the affected but in none of the unaffected individuals of a large well characterized kindred with generalized thyroid hormone resistance; and ii) noted that the WR allele causes an approximate 50% decrease in the T3 binding affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
Arginine↗
Thyroid hormone suppresses hepatic sterol 12alpha-hydroxylase (CYP8B1) activity and messenger ribonucleic acid in rat liver: failure to define known thyroid hormone response elements in the gene.
Sterol 12alpha-hydroxylase (CYP 8B1) is a microsomal cytochrome P450 enzyme involved in bile acid synthesis that is of critical importance for the composition of bile acids formed in the liver. Thyroidectomy of rats caused a more than twofold increase of CYP8B1 and an almost fourfold increase of the corresponding mRNA levels compared to sham-operated rats. Treatment of intact rats with thyroxine caused a 60% reduction of enzyme activity and a 50% reduction of mRNA levels compared to rats injected with saline only. To investigate whether the promoter of the gene contains thyroid hormone response elements, the complete structure of the rat gene was defined. In similarity with the corresponding gene in mouse, rabbit and man, the rat gene was found to lack introns. It had an open reading frame containing 1500 bp corresponding to a protein of 499 amino acid residues. Although thyroid hormone decreased CYP8B1 activity and mRNA in vivo, no hitherto described thyroid hormone response elements were identified 1883 bases upstream of the transcription start site. It is concluded that rat CYP8B1 is regulated by thyroid hormone at the mRNA level. The results are discussed in relation to the structure of the gene coding for the enzyme.
Amino Acid Sequence↗
Comparison of the mechanisms of nongenomic actions of thyroid hormone and steroid hormones.
Steroids and thyroid hormone are thought primarily to act via binding to hormone-specific nuclear receptor superfamily members. The nuclear ligand-receptor complexes then initiate transcriptional activity. Actions of steroids and iodothyronines that are nongenomic or extranuclear in mechanism have been recognized recently and new insights into such mechanisms are available. Despite their distinct structures and biologic effects, the two families of hormones have similarities in the mechanisms of their nongenomic actions. That is, both steroids and thyroid hormone appear to interact with specific cell surface G protein-coupled receptors and to activate signal transducing kinases such as those involved in the mitogen-activated protein kinase (MAPK) pathway. Much is known about the ability of certain steroids such as estrogen and mineralocorticoids to increase [Ca2+]i acutely and stimulation of the MAPK cascade by L-T4 appears to depend upon a hormone-induced increase in [Ca2+]i via phosphoinositide pathway activation. At least in the case of iodothyronines, hormone activation of the MAPK pathway modulates the cellular activities of certain cytokines and growth factors. One of the two cell surface estrogen receptors (ERs) may be an expression of the same transcript as that for nuclear ER, whereas the mineralocorticoid and progesterone-binding proteins in the plasma membrane appear to be products of genes different from those of nuclear receptors. Iodothyronine structure-activity relationships at the plasma membrane binding site for thyroid hormone suggest that the cell surface receptor for T4 that also binds 3,5,3'-triiodo-L-T3 is different from the nuclear T3 receptor (TR). There are interfaces of nongenomic and genomic mechanisms for both steroids and thyroid hormone. For example, by nongenomic mechanisms, estrogen and thyroid hormone can promote serine phosphorylation, respectively, of nuclear ER and TR. Transcriptional activity of the nuclear receptor proteins can be altered by such phosphorylation.
Animals↗
Quantitative analysis of DNA binding affinity and dimerization properties of wild-type and mutant thyroid hormone receptor beta1.
Thyroid hormone (triiodothyronine [T3]) actions are mediated through binding of thyroid hormone receptors (TRs) to specific DNA sequences (thyroid hormone response elements [TREs]) as monomers, homodimers, and heterodimers with thyroid hormone receptor auxiliary proteins (TRAPs). We quantitatively characterized dimerization of wild-type (WT) and mutant TRbetas by coimmunoprecipitation, and binding to DNA by electrophoretic gel mobility shift assays (EMSA). Binding affinities of TR retinoid X receptor-alpha (RXRalpha) heterodimers to DNA were determined by competing with excess nonradiolabeled TREs in EMSA. TRs in vitro synthesized in reticulocyte lysates (RL), and human RXRalpha expressed in a Sf9 cell-baculovirus system (BAC), were coincubated with 32P-labeled rat malic enzyme (ME), palindromic (PAL), or chicken lysozyme F2 (F2) TREs. The mutant TRbetas tested were R316H and G345R, which have nondetectable T3 binding and have previously been reported to show weak and potent dominant negative effect, respectively. Scatchard analysis showed no significant differences in Kas between WT and mutant TR-RXRalpha heterodimers binding to DNA. We measured affinity of heterodimerization between TRs and RXRalpha in solution in the absence of DNA, and by coimmunoprecipitation using anti-TRbeta1WT specific antibodies. 35S-labeled RL-RXRalpha was incubated with BAC-WT or TRbeta or R316H in the absence or presence of increasing amounts of nonlabeled BAC-RXRalpha. Displacement curves were obtained by counting radioactivity of precipitated 35S-RXRalpha, that was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and autoradiography. Kds of WT and TRbeta R316H heterodimerizing with RXRalpha were approximately the same. Binding affinity of TR homodimers for F2-TRE was studied because this TRE binds homodimers strongly. Scatchard analysis clearly showed that DNA binding affinity of BAC-WT homodimers did not differ with or without 100 nM T3, but maximal binding capacity (MBC) was reduced three-fold to fourfold in the presence of 100 nM T3. In contrast, BACTRbeta-R316H homodimers showed a fivefold reduction in DNA binding affinity for F2, both in the presence and absence of T3, and approximately the same MBC as WT in the absence of T3. Mutant RL-G345R homodimers showed approximately the same Ka as RL-WT homodimers for binding to F2 and the same MBC in the presence and absence of T3. These results indicate that (1) T3 reduced TRbeta homodimerization in solution but does not effect DNA binding of formed homodimers; (2) T3 does not influence DNA binding affinity of TR/RxR heterodimers; and (3) TRbeta mutant R316H homodimers have reduced DNA binding affinity but homodimerization and heterodimerization in solution does not differ from WT TRbeta.
Animals↗
Resistance to thyroid hormone.
Resistance to thyroid hormone (RTH) is usually dominantly inherited and is characterized by elevated free thyroid hormones in the serum and failure to suppress pituitary thyroid stimulating hormone (TSH) secretion with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features, suggesting predominant pituitary resistance (PRTH). Molecular genetic analyses indicate that both GRTH and PRTH are associated with diverse mutations in the thyroid hormone receptor beta gene, which localize to three regions in the hormone binding domain of the receptor. In addition to being functionally impaired, the mutant receptors are also able to inhibit their wild-type counterparts in a dominant negative manner. Recognized features of RTH include failure to thrive, growth retardation and attention-deficit hyperactivity disorder in childhood, and goitre and thyrotoxic cardiac symptoms in adults. The pathogenesis of variable tissue resistance is not fully understood but may be related to the differing tissue distributions of a and b thyroid hormone receptors and variable dominant negative activity of mutant receptors on different target genes.
Adult↗
Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor alpha.
Thyroid hormone insufficiency leads to impaired neurogenesis, behavioral alterations and cognitive deficits. Thyroid hormone receptors, expressed in brain regions involved in these behaviors, mediate the effects of thyroid hormone deficiency or excess. To determine the contribution of thyroid hormone receptor alpha (TRalpha) in these behaviors, we examined the behavior of euthyroid as well as hypo- and hyperthyroid mice lacking all isoforms of the TRalpha (TRalpha(o/o)). The hypothyroxinemic TRalpha(o/o) mice demonstrated behavioral inhibition, manifested in decreased activity and increased anxiety/fear in the open field test (OFT) and increased immobility in the forced swim test (FST) compared to C57BL/6J mice. TRalpha(o/o) mice also showed learning and recall impairments in the Morris water maze (MWM), which were exaggerated by hypothyroidism in TRalpha(o/o) mice. These impairments were concurrent with increased thigmotaxis, suggesting an increased anxiety-like state of the TRalpha(o/o) mice in the MWM. Expression of genes, known to be involved in processes modulating learning and memory, such as glucocorticoid receptor (GR), growth-associated protein 43 (GAP-43) and neurogranin (RC3), were significantly decreased in the hippocampus of TRalpha(o/o) mice. GR expression was also decreased in the frontal cortex and amygdala of TRalpha(o/o) mice, indicating that expression of GR is regulated, probably developmentally, by one or more isoforms of TRalpha in the mouse brain. Taken together these data demonstrate behavioral alterations in the TRalpha(o/o) mice, indicating the functional role of TRalpha, and a delicate interaction between TRalpha and TRbeta-regulated genes in these behaviors. Thyroid hormone-regulated genes potentially responsible for the learning deficit found in TRalpha(o/o) mice include GR, RC3 and GAP-43.
Analysis of Variance↗
In vivo regulation of hepatic insulin-like growth factor-1 messenger ribonucleic acids with thyroid hormone.
Insulin-like growth factor-1 (IGF-1) is synthesized primarily by the liver in response to growth hormone (GH). Thyroid hormone plays a major role in mediating pituitary GH secretion. In order to clarify the effect of thyroid hormone on IGF-1 gene expression, we measured hepatic IGF-1 mRNA levels in rats with thyroid dysfunction. Female Wistar rats were rendered hypothyroid by surgical thyroidectomy or hyperthyroid by daily injections of thyroxine (12 micrograms/day) for 2 weeks. Northern gel analysis of hepatic poly (A) RNA revealed the multiple sizes of the RNA transcripts ranging from 1.6 to 9.0 kb. After 4 weeks, hepatic IGF-1 mRNA levels were suppressed in hypothyroid rats, to less than 20% of control euthyroid animals. These suppressed mRNA levels were restored to euthyroid levels by thyroid hormone replacement for 2 weeks. Hyperthyroid rats, however, did not contain altered levels of hepatic IGF-1 mRNA as compared to euthyroid rats. The gamma-actin mRNA hybridization signal was not altered in hypothyroid or hyperthyroid rats. These results suggest that thyroid hormone regulates the in vivo expression of hepatic IGF-1 mRNA, probably through the mechanism of GH regulation.
Animals↗
The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements.
We report that the thyroid hormone (T3) receptor binds to DNA recognition sequences that are variations of the palindromic motif 5'-TCAGGTCA.TGACCTGA-3', resulting in transcriptional activation in vivo. This sequence is identical to the vitellogenin A2 estrogen response element except for the absence of 3 bp at the center of dyad symmetry, which we have termed a "gap." The T3 receptor binds to estrogen response elements with high affinity in vitro, as well as to variations of the same sequence containing gaps of 1-6 bp. The T3 receptor not only fails to activate transcription from estrogen response elements in vivo, but inhibits estrogen-dependent transactivation. We propose that the T3 receptor binds to estrogen response elements in a transcriptionally inactive form and competes for estrogen receptor binding, resulting in a net decrease in gene expression. These data reveal that only a subset of T3 receptor DNA-binding elements function as T3 response elements.
Animals↗
A new case of resistance to thyroid hormone caused by a de novo P453T mutation in the thyroid hormone receptor gene in an Israeli child.
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Child↗
Thyroid dysfunction in patients on regular hemodialysis: evaluation of the stable intrathyroidal iodine pool, incidence of goiter and free thyroid hormone concentration.
Thyroid function tests and stable intrathyroidal iodine were evaluated in 17 patients on regular hemodialysis treatment (RHD). Triiodothyronine levels in the hypothyroid range, thyroxine levels in the low normal range, but normal levels of thyroid-stimulating hormone, free thyroxine and free triiodothyronine were found. Normal values of stable intrathyroidal iodine and a normal incidence of goiter for our region were also found. It is concluded that in patients on RHD: (1) free thyroid hormone levels are normal and probably represent the most meaningful way of evaluating thyroid function; (2) in our RHD population goiter is no more prevalent than in normal persons; (3) the iodine storage function of the thyroid is not always altered.
Adult↗
A case of hypersensitivity to thyroid hormones with normally functioning thyroid gland and increased nuclear triiodothyronine receptors.
A 52-year-old male presented himself with tachycardia crises which appeared first during childhood, increased in frequency without goiter or exophthalmos. Cardiac and adrenergic diseases were excluded. The thyroid function was normal regarding T4, free T4 and T3, TBG, radioiodine uptake, TSH and T3 suppressibility; however the TSH response to TRH was decreased. The lymphocyte nuclear T3 receptor was found with an affinity close to that of normal volunteers (Ka: 1.42 x 10(10) M-1 vs 1.95 +/- 0.35 x 10(10) M-1) and a binding capacity markedly increased (9.9 vs 3.7 +/- 0.4 fmol T3/100 micrograms DNA). Pindolol was inefficient on the dysrhythmia which disappeared with carbimazole and relapsed after withdrawal of the antithyroid drug. Under carbimazole, the plasma T4 markedly decreased (27.7 +/- 3.6 nmol/l) but the patient remained euthyroid. The clinical course and the laboratory data suggest that the tachycardia crises are the consequence of a hypersensitivity of the heart to thyroid hormones, associated with an increased number of T3 nuclear receptor sites in lymphocytes.
Carbimazole↗
[Identification of eight new mutations in the c-erbAB gene of patients with resistance to thyroid hormone].
Resistance to thyroid hormone (RTH) is a rare genetic disorder, usually associated with different mutations in the c-erbAB gene that encodes the beta type receptor of thyroid hormone (TRB). It is characterized by elevated serum thyroid hormone and inappropriate TSH secretion. The numerous mutations so far detected are clustered in three hot spot areas in the ligand binding domain of TRB. In the context of a national survey we have detected 16 different mutations in the c-erbAB gene, in 22 families presenting with RTH. Eight of these mutations had not been described previously. Two are located in an area not known to harbor naturally occurring mutations. This observation could lead to define a fourth cluster of mutations in the c-erbAB gene.
Adolescent↗
The effects of P-box substitutions in thyroid hormone receptor on DNA binding specificity.
Three "P-box" amino acids within the DNA recognition alpha-helix of members of the steroid hormone and thyroid hormone families of nuclear receptors are known to determine the identity of two of the six base pairs within the half-sites of cognate DNA elements. We introduced P-box substitutions derived from different members of the thyroid hormone/estrogen receptor (T3R/ER) family into the beta-isoform of human thyroid hormone receptor (hT3R beta) and tested the DNA binding and transactivation activities of these mutants using thyroid hormone response elements (TREs) with half-sites composed of different sequences and arranged in different orientations. Different P-box sequences derived from the T3R/ER family resulted in distinct DNA binding specificities determined by the fourth base pair of the half-site. Thyroid hormone receptor mutants containing EGA, EAA, EGS substitutions for the wild type EGG P-box bound with wild type affinity to consensus AGGTCA half-sites, regardless of orientation. TREs composed of AGGACA half-sites bound hT3R beta s with an EGG or EAA P-box sequence, but not those with EGA or EGS P-box sequence. A reversal of this specificity was observed on a direct repeat TRE with AGGGCA half-sites. Additionally, an ESG P-box substitution in hT3R beta prevented the receptor from binding to a direct repeat as a homodimer, but this mutant could bind as a heterodimer with retinoid X receptor or to the everted repeat TRE from the chicken lysozyme promoter.
Amino Acid Sequence↗
[Hormonal regulation of thyroidal iodide fixation and penetration of the pituitary by thyroid hormones].
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Histological Techniques↗