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PubMed2005

Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators.

Thyroid hormone (3,5,3'-triiodo-L-thyronine, T3) is an endocrine hormone that exerts homeostatic regulation of basal metabolic rate, heart rate and contractility, fat deposition, and other phenomena (1, 2). T3 binds to the thyroid hormone receptors (TRs) and controls their regulation of transcription of target genes. The binding of TRs to thyroid hormone induces a conformational change in TRs that regulates the composition of the transcriptional regulatory complex. Recruitment of the correct coregulators (CoR) is important for successful gene regulation. In principle, inhibition of the TR-CoR interaction can have a direct influence on gene transcription in the presence of thyroid hormones. Herein we report a high throughput screen for small molecules capable of inhibiting TR coactivator interactions. One class of inhibitors identified in this screen was aromatic beta-aminoketones, which exhibited IC50 values of approximately 2 microm. These compounds can undergo a deamination, generating unsaturated ketones capable of reacting with nucleophilic amino acids. Several experiments confirm the hypothesis that these inhibitors are covalently bound to TR. Optimization of these compounds produced leads that inhibited the TR-CoR interaction in vitro with potency of approximately 0.6 microm and thyroid signaling in cellular systems. These are the first small molecules irreversibly inhibiting the coactivator binding of a nuclear receptor and suppressing its transcriptional activity.

Binding, Competitive↗
PubMed1993

Thyroid hormone receptor can modulate retinoic acid-mediated axis formation in frog embryogenesis.

Thyroid hormone receptor acts as a hormone-dependent transcriptional transactivator and as a transcriptional repressor in the absence of thyroid hormone. Specifically, thyroid hormone receptor can repress retinoic acid-induced gene expression through interactions with retinoic acid receptor. (Retinoic acid is a potent teratogen in the frog Xenopus laevis, acting at early embryonic stages to interfere with the formation of anterior structures. Endogenous retinoic acid is thought to act in normal anterior-posterior axis formation.) We have previously shown that thyroid hormone receptor RNA (alpha isotype) is expressed and polysome-associated during Xenopus embryogenesis preceding thyroid gland maturation and endogenous thyroid hormone production (D. E. Banker, J. Bigler, and R. N. Eisenman, Mol. Cell. Biol. 11:5079-5089, 1991). To determine whether thyroid hormone receptor might influence the effects of retinoic acid in early frog development, we have examined the results of ectopic thyroid hormone receptor expression on retinoic acid teratogenesis. We demonstrate that microinjections of full-length thyroid hormone receptor RNA protect injected embryos from retinoic acid teratogenesis. DNA binding is apparently essential to this protective function, as truncated thyroid hormone receptors, lacking DNA-binding domains but including hormone-binding and dimerization domains, do not protect from retinoic acid. We have shown that microinjections of these dominant-interfering thyroid hormone receptors, as well as anti-thyroid hormone receptor antibodies, increase retinoic acid teratogenesis in injected embryos, presumably by inactivating endogenous thyroid hormone receptor. This finding suggests that endogenous thyroid hormone receptors may act to limit retinoic acid sensitivity. On the other hand, after thyroid hormone treatment, ectopic thyroid hormone receptor mediates teratogenesis that is indistinguishable from the dorsoanterior deficiencies produced in retinoic acid teratogenesis. The previously characterized retinoic acid-responsive gene, Xhox.lab2, can be induced by thyroid hormone in embryos ectopically expressing thyroid hormone receptor and is less responsive to retinoic acid in such embryos. The fact that both thyroid hormone and retinoic acid can affect overlapping gene expression pathways to produce abnormal embryonic axes and can regulate the same early-expressed gene suggests a model in which thyroid hormone receptor blocks retinoic acid receptor-mediated teratogenesis by directly repressing retinoic acid-responsive genes.

Animals↗
PubMed2001

Molecular cloning and characterization of thyroid hormone receptors in teleost fish.

Thyroid hormones are pleiotropic factors important for many developmental and physiological functions in vertebrates. Their effects are mediated by two specific receptors (TRalpha and TRbeta) which are members of the nuclear hormone receptor superfamily. To clarify the function of these receptors, our laboratory has started a comparative study of their role in teleost fish. This type of approach has been hampered by the isolation of specific clones for each fish species studied. In this report, we describe an efficient reverse transcription/PCR procedure that allows the isolation of large fragments corresponding to TRalpha and TRbeta of a wide range of teleost fish. Phylogenetic analysis of these receptors revealed a placement consistent with their origin, sequences from teleost fish being clearly monophyletic for both TRalpha and TRbeta. Interestingly, this approach allowed us to isolate (from tilapia and salmon) several new TRalpha or TRbeta isoforms resulting from alternative splicing. These isoforms correspond to expressed transcripts and thus may have an important physiological function. In addition, we isolated a cDNA encoding TRbeta in the Atlantic salmon (Salmo salar) encoding a functional thyroid hormone receptor which binds specific thyroid hormone response elements and regulates transcription in response to thyroid hormones.

Alternative Splicing↗
PubMed2001

Thyroid hormone stimulates acetyl-coA carboxylase-alpha transcription in hepatocytes by modulating the composition of nuclear receptor complexes bound to a thyroid hormone response element.

Triiodothyronine (T3) stimulates a 7-fold increase in transcription of the acetyl-CoA carboxylase-alpha (ACCalpha) gene in chick embryo hepatocytes. Here, we characterized an ACCalpha T3 response element (ACCalpha-T3RE) with unique functional and protein binding properties. ACCalpha-T3RE activated transcription both in the absence and presence of T3, with a greater activation observed in the presence of T3. In nuclear extracts from hepatocytes incubated in the absence of T3, ACCalpha-T3RE bound protein complexes (complexes 1 and 2) containing the liver X receptor (LXR) and the retinoid X receptor (RXR). In nuclear extracts from hepatocytes incubated in the presence of T3 for 24 h, ACCalpha-T3RE bound a different set of complexes. One complex contained LXR and RXR (complex 3) and another contained the nuclear T3 receptor (TR) and RXR (complex 4). Mutations of ACCalpha-T3RE that inhibited the binding of complexes 1 and 2 decreased transcriptional activation in the absence of T3, and mutations of ACCalpha-T3RE that inhibited the binding of complexes 3 and 4 decreased transcriptional activation in the presence of T3. The stimulation of ACCalpha transcription caused by T3 was closely associated with changes in the binding of complexes 1-4 to ACCalpha-T3RE. These data suggest that T3 regulates ACCalpha transcription by a novel mechanism involving changes in the composition of nuclear receptor complexes bound to ACCalpha-T3RE. We propose that complexes containing LXR/RXR ensure a basal level of ACCalpha expression for the synthesis of structural lipids in cell membranes and that complexes containing LXR/RXR and TR/RXR mediate the stimulation of ACCalpha expression caused by T3.

Acetyl-CoA Carboxylase↗
PubMed1978

Thyroid hormones in the adult rat lung.

Thyroid hormones have been postulated to be involved in lung development and the regulation of the surfactant system. This study was designed to determine the concentration of thyroxine and of triiodothyronine in adult rat lung. Tissue-to-plasma ratios of thyroxine and triiodothyronine were determined in adult rats by the equilibrium distribution of radiolabeled hormones. Extracellular thyroid hormone space was estimated by equilibrium distribution of radiolabeled bovine serum albumin. The mean +/- SE ratio of lung triiodothyronine to plasma triiodothyronine, corrected for extracellular space, as 2.57 +/- 0.40, indicating appreciable concentration of this hormone. In contrast, lung thyroxine ratios indicate that this hormone is virtually excluded from adult lung parenchyma. Such results support the hypothesis that thyroid hormone may have a significant role in the regulation of the surfactant system.

Animals↗
PubMed1992

Thyroid hormone resistance.

Generalized resistance to thyroid hormone (GRTH) encompasses a heterogeneous group of conditions characterized by reduced responses of target tissues to thyroid hormone due to defects at the site of hormone action. In the majority of patients, GRTH is inherited as a dominant trait associated with mutations in the hormone-binding domain of the thyroid hormone receptor. GRTH serves as a prototype of other resistance syndromes for hormones that act via nuclear receptors.

Diagnosis, Differential↗
PubMed1997

The influence of vasopressin or oxytocin on thyroid-stimulating hormone and thyroid hormones' concentrations in blood plasma of euthyroid rats.

The effects of arginine vasopressin (AVP) and oxytocin (OT) upon thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) release were studied in euthyroid rats. Intracerebroventricular (i.c.v.) infusion of AVP in doses of 0.5 ng or 5 ng led to significant increases in plasma levels of TSH as well as FT4 and FT3. The effects of OT injected i.c.v. in similar doses were not consistent (there was no parallel between the changes of respective hormones plasma levels). It may be concluded that vasopressin modulate the pituitary-thyroid system function; AVP is probably a physiological stimulator of TSH and thyroid hormones secretion.

Animals↗
PubMed1975

Thyroid hormone receptors. Binding characteristics and lack of hormonal dependency for nuclear localization.

Thyroid hormones have diverse effects on growth and metabolism. Specific "receptor" proteins which bind triiodothyronine and other biologically active analogs and which may be involved in thyroid hormone action have been recently found in nuclei of responsive tissues. This report presents studies of these receptors in rat liver nuclei. Confirming previous reports, a Scatchard analysis of the binding data suggests the reaction, triiodothyronine + specific receptor in equilibrium with triiodothyronine-receptor complex, with an apparent equilibrium dissociation constant (Kd) at 22 degrees of about 190 pM and a capacity of about 1 pmol of triiodothyronine-binding sites per mg of DNA. The kinetics of the binding were also examined. Triiodothyronine-receptor complex formation is second order and dissociation is first order. The apparent association (k+1) and dissociation (k minus 1) rate constants at 22 degrees are, respectively, 4.7 times 10-7 m-minus 1 min-minus 1 and 7.6 times 10-minus 3 min-minus 1. The apparent Kd, estimated from the ratio of the rate constants (k minus 1:k+1), was about 150 pM, similar to that determined from the equilibrium data. These data support the expression written above for the interaction of thyroid hormone with its receptor. Additional kinetic experiments indicate that some of the triiodothyronine binding by cell-free nuclei is to sites previously occupied by hormone in the intact animal, providing further evidence that the intact cell and cell-free reactions are the same. It was previously found that nuclear-bound triiodothyronine is localized in chromatin. We found that isolated chromatin retains specific binding activity similar to that of isolated nuclei. Thus, binding may not require cytoplasmic, nucleoplasmic, or nuclear membrane factors. These findings may imply that chromatin localization of the receptor does not depend on the hormone. This idea is supported by an earlier finding that binding activity is present in nuclei from thyroidectomized animals. However, many stimuli such as steroid hormones, bacterial inducers, and cyclic adenosine 3':5'-monophosphate in bacteria influence regulatory proteins at the gene level by promoting the protein's addition to or removal from chromatin. Thus, we studied the effect of thyroid hormone on the nuclear content of receptors under assay conditions of receptor stability and reversible binding. Receptor levels in hypothyroid animals are identical with those in euthyroid animals. These data suggest that the hormone does not influence the nuclear localization of receptors. Thus, the basis for thyroid hormone action may be to regulate the activity of receptors resident in chromatin rather than to promote receptor addition to or removal from chromatin.

Animals↗
PubMed1987

Increased thyroidal T4/T3 ratio in nodular and paranodular tissues of nontoxic goiter following suppressive treatment with thyroid hormones.

The effect of suppressive treatment with thyroid hormones on thyroidal iodothyronines and T4/T3 ratio in nodular and paranodular tissues was investigated in 12 patients with nontoxic goiter. Results were compared to those from 11 nontreated patients. Continuous thyroid hormone administration produced a significant increase in thyroidal T4 and T4/T3 ratio in nodular tissues while T3 remained unchanged. In paranodular tissues a significant rise of T4/T3 ratio, an insignificant increase in T4 and a decrease in T3 were observed following the administration of thyroid hormones. The results are very similar to those obtained in paranodular tissue of autonomously functioning thyroid nodule, and are probably the consequence of suppressed TSH secretion, as TSH predominantly stimulates the synthesis of T3 and/or thyroidal T4 monodeiodination.

Goiter, Nodular↗
PubMedDate not supplied

Excessive thyroid hormone replacement therapy.

BACKGROUND: Excessive thyroid hormone replacement carries the potential for serious long-term metabolic complications (e.g., accelerated osteoporosis). The increased bioavailability of commercially available products, along with improved laboratory assays for measuring thyrotropin (TSH), has led to an increased chance of actual or detected iatrogenic hyperthyroxinemia. The purpose of this study was to determine the frequency of excessive prescribing and to examine the impact of changes in potency of replacement thyroid hormone formulations and sensitivity of thyroid function tests on its incidence. METHODS: A retrospective chart review was done of patients requiring thyroid hormone replacement therapy treated at a university-based, family medicine residency training program. The following information was extracted from each chart: specific thyroid medication (including dose and date of onset of therapy) and thyroid laboratory tests results (including serum thyroxine [T4] and TSH). This information from two different time periods (1975 to 1981 and 1982 to 1989) was compared using one-way analysis of variance. RESULTS: Serum T4 levels were not significantly different between the two time periods, 1975 to 1981 and 1982 to 1989 (8.06 +/- 2.93 micrograms/dl versus 9.0 +/- 03.69 micrograms/dl; NS), despite significant changes in TS serum levels (23.6 +/- 38.9 mIU/mL versus 7.44 +/- 18.7 mIU/ml; P = 0.009) and levothyroxine dosage (184 +/- 59.6 micrograms/d versus 145 +/- 64.1 micrograms/d; P = 0.002). Significantly more patients had low (supersuppressed) TSH levels between 1982 and 1990 than between 1975 and 1981 (33 percent versus 10 percent; P = 0.02.) CONCLUSIONS: Excessive thyroid hormone replacement with iatrogenic hyperthyroxinemia is a common occurrence. Clinicians need to be aware of this problem and implement measures (e.g., periodic monitoring of TSH) to minimize the occurrence of overdosing and the potential for long-term complications.

Adult↗
PubMed1980

Thyroid hormone in autistic children.

Thyroid hormone plays an important role in the pre- and postnatal development and function of the central nervous system. Disturbances in thyroid hormone regulation have been hypothesized in childhood autism. We evaluated blood indices of thyroid function, including serum thyroxine, triiodothyronine, and thyroid-stimulating hormone, in a large population of autistic children. No differences were found between autistic and normal children.

Adolescent↗
PubMed1996

Functional characterization of a mutant thyroid hormone receptor in Xenopus laevis.

Thyroid hormone plays a causative role during frog metamorphosis, and its effect is mediated by thyroid hormone receptors (TRs). To investigate the function of Xenopus TRs, we have recently developed a thyroid hormone dependent in vivo transcription system by introducing TRs and RXRs (9-cis-retinoic acid receptors) into Xenopus oocytes. Interestingly, using this system, we have found that the TRalphaB cloned previously is defective in transcriptional activation compared with TRalphaA. In vitro DNA binding experiments show that TRalphaB.RXR heterodimers have drastically reduced affinity for a thyroid hormone response element. Site-directed mutagenesis shows that two of the seven amino acid residues that differ between TRalphaA and TRalphaB are responsible for the defect in TRalphaB function. These two residues affect the DNA binding by both TR.RXR heterodimers and TR homodimers. In contrast, heterodimer formation with RXRs is not affected as demonstrated by coimmunoprecipitation and dominant-transcriptional inhibition experiments. By cDNA and genomic DNA sequence analysis, we have demonstrated that the residues, which affect TRalphaB function when mutated, are identical between the wild type TRalphaB and TRalphaA. Thus, our experiments have discovered the first amphibian TR mutant. The DNA binding and transcription activation functions of the mutant are discussed in relation to the recently published TR crystal structure.

Amino Acid Sequence↗
PubMed1993

Autoimmune hypothyroidism in a patient with generalized resistance to thyroid hormone.

Generalized resistance to thyroid hormone is a rare condition; affected individuals have elevated serum levels of free thyroxine and free triiodothyronine with inappropriately normal or slightly elevated levels of thyrotropin, yet are generally clinically euthyroid. However, responsiveness to thyroid hormone varies from tissue to tissue, and some patients may benefit from treatment with exogenous hormone. We have described the case of a patient with this disorder who initially had a mildly elevated serum thyrotropin level and was clinically euthyroid but in whom symptomatic autoimmune hypothyroidism subsequently developed. The serum free thyroxine level, although diminished from its previously elevated value, remained within the normal range. The patient required substantial doses of levothyroxine to return basal and stimulated TSH to their prior levels. Criteria for the treatment of adults with this disorder have not been firmly established. This case suggests that one indication for thyroid hormone supplementation may be the presence of high-titer serum antithyroid antibodies in patients who initially have mildly elevated thyrotropin values; they could be at increased risk for progression to overt hypothyroidism.

Aged↗
PubMed2002

Effects of chronic mild stress on lymphocyte proliferative response. Participation of serum thyroid hormones and corticosterone.

There is increasing evidence that stress produces changes in various immune processes. Some of these changes may be due to neurochemical and hormonal alterations including thyroid hormones levels. This work was carried out to study the impact of chronic mild stress (CMS) exposure on proliferative responses and its correlation with serum thyroid hormone levels. In addition, the influence of serum corticosterone levels on these responses was also studied. For this purpose, mice were submitted from1 to 6 weeks to a CMS model. After undergoing the stress schedule for 4 weeks, an alteration in the proliferative response was observed. Lymphocytes from exposed animals showed a decrease in T-cell response to concanavalin-A (Con A) and phytohemagglutinin (PHA) and an increase in B-cell proliferation to lipopolysaccharides (LPS). In parallel, a reduction in T3 and T4 serum levels was observed. On the contrary, serum corticosterone levels increased in animals exposed to CMS for 1 or 2 weeks and then return to normal values. Lowering serum thyroid hormone levels by propylthiouracil (PTU) treatment negatively modulates T-cell response without affecting B-cell response. On the other hand, the substitutive T4 treatment in stressed animals improved significantly the proliferative T-cell response. Non-significative changes in CD4/CD8 ratio were observed neither in stressed, PTU- or T4-treated animals. Taken together, our results suggest an impact of chronic stress on thyroid function that in turn alters T-cell response. These findings may help to elucidate the physiological mechanisms through which stress plays a roll in the etiology of many diseases.

Animals↗
PubMed1980

Thyroid hormone resistance.

General resistance to the action of thyroid hormones is characterized by increased levels of thyroid hormones and normal thyroid hormone binding proteins but clinical euthyroidism. There is a wide clinical spectrum ranging from patients with congenital goitre and signs of subclinical hypothyroidism to subjects with no physical abnormality. In the most affected patients special physical features have been described. Serum thyrotrophin (TSH) and the response to thyrotrophin releasing hormone (TRH) is mostly normal but may fluctuate being at times elevated and even markedly increased values may be encountered. Studies on lymphocytes and fibroblasts indicate that a decreased affinity of thyroid hormones for nuclear receptors, a decreased binding capacity of the receptors or some post-receptor mechanism may be responsible for these changes. Hitherto, six families, comprising 24 patients and seven single cases, have been described. The pedigrees are compatible with dominant inheritance. Selective refractoriness of the pituitary thyrotrophs to thyroid hormones has been described in five patients with hyperthyroidism. Excessive secretion of TSH is the cause of hyperthyroidism. In four of the cases reported TRH caused an exaggerated TSH response and TSH was partially suppressible by additional exogenous thyroid hormone. The response of TSH and the behaviour of the alpha- and beta-subunits of TSH distinguish this syndrome from TSH-induced hyperthyroidism due to pituitary tumours. The underlying mechanisms are unknown.

Female↗
PubMed1991

An essential role of domain D in the hormone-binding activity of human beta 1 thyroid hormone nuclear receptor.

By analogy with steroid receptors, human placental thyroid hormone nuclear receptor (hTR beta 1) could be divided into four functional domains: A/B (Met1-Leu101), C (Cys102-Ala170), D (Thr171-Lys237), and E (Arg238-Asp456). The E domain was thought to bind thyroid hormone. To evaluate whether domain E alone is sufficient to bind T3 or requires the presence of other domains for functional T3-binding activity, a series of deletion mutants was constructed. The mutants were expressed in Escherichia coli, and the expressed proteins were purified. Analysis of the T3-binding affinity and analog specificity of the purified truncated hTR beta 1 indicated that domain E alone did not have T3-binding activity. Extension of the amino-terminal sequence of domain E to include part of domain D yielded a mutant (Lys201-Asp456) with a Ka for T3 of 0.5 +/- 0.2 x 10(9) M-1. Further extension to include the entire domain D (Met169-Asp456) yielded a mutant with T3-binding activity with a Ka of 0.8 +/- 0.1 x 10(9) M-1. Further extension of the amino-terminal sequence to include domain C increased the affinity for T3 by nearly 2-fold (Ka = 1.5 +/- 0.4 x 10(9) M-1). The Ka for the wild-type hTR beta 1 is 1.5 +/- 0.2 x 10(9) M-1. Furthermore, mutant (Met169-Asp456) binds to 3',5',3-triiodo-L-thyropropionic acid, D-T3, L-T4, and L-T3 with 307%, 37%, 7%, and 0.1%, respectively, of the activity of L-T3. This order of analog affinity is similar to that of the wild-type hTR beta 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1989

[The effect of thyroid hormone on the growth of thyroid cancer].

Thyroid cancer is well known to be hormone sensitive as well as breast cancer, prostatic cancer, and endometrial cancer of the uterus. Various experimental results suggest that the growth regulation for thyroid cancer, as well as the normal thyroid gland, appears to depend upon the TSH (Thyroid stimulating hormone) receptor on cell membranes. Differentiated thyroid carcinoma cells possess TSH receptor, although anaplastic carcinoma cells do not; therefore suppression therapy of TSH with thyroid hormone is considered to be effective against differentiated thyroid carcinoma. It has been recognized that some recurrent differentiated thyroid cancers cause regression in size in response to treatment with thyroid hormone. But the administration of the thyroid hormone after the operation for the differentiated thyroid carcinoma does not necessarily enhance the survival rate. To analyze the difference in survival rate is very difficult because of the excellent survival rate of thyroid cancer patients after the operation. It is hoped that further clinical study and laboratory investigation about suppression in adjuvant therapy for differentiated thyroid cancer will give us a conclusive answer.

Adolescent↗