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At least 919 records · Page 51Linked to original sources
PubMed1998

Physical linkage of the human growth hormone gene family and the thyroid hormone receptor interacting protein-1 gene on chromosome 17.

A P1 cloned insert of about 85.5 kilobases (kb) was isolated, containing four members of the human growth hormone/chorionic somatomammotropin (GH/CS) gene family and the thyroid hormone receptor interacting protein (TRIP-1) gene. The presence of the CS-like, CS-A, GH-variant and, most downstream, CS-B gene was confirmed by DNA blotting and sequence analysis. The TRIP-1 gene was detected 40 kb downstream of the CS-B gene and in the reverse transcriptional orientation to all the GH/CS genes. The TRIP-1 gene is highly homologous to the SUG-1 gene in yeast and is evolutionarily conserved among several species. Based on the common location of the GH and TRIP-1 (or homologue) genes on the same chromosome in the human, pig and rat genomes, we suggest that these loci are physically linked. Previously, it was reported that a muscle-specific sodium channel (SCN4A) gene is located immediately upstream of the pituitary growth hormone (GH-N) gene, and is linked to the GH gene locus in both humans and rats. This suggests a further linkage between the SCN4A, GH and TRIP-1 loci. Also, deoxyribonuclease hypersensitive sites have been reported in and around these loci and were associated with an important locus control region for the GH/CS genes. Unlike the GH/CS genes, we show, using reverse transcriptase-polymerase chain reaction that the TRIP-1 gene is expressed ubiquitously and, through RNA blotting, as a 1.4-kb transcript. This implies an open and active chromatin structure. The possible effect of this structure on the adjacent human GH/CS gene locus is discussed.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1982

Modulation of estrogen-induced peroxidase activity in the rat uterus by thyroid hormones.

The effect of thyroid hormones, iodide, propylthiouracil and other thyroid-active agents on estrogen receptor concentration and on the induction of peroxidase in the immature rat uterus by estradiol (E2) was examined T3 (0.5 mg/Kg) given daily for 6 days produced a large decrease in E2-induced uterine peroxidase but lowered only slightly the concentration of cytosolic or nuclear receptors in this organ. T4 also decreased the effect of E2 on uterine peroxidase induction and the inhibitory action of T3 was observed in thyroidectomized rats. The administration of iodide (10 mM) in the drinking water for 6 days caused a 2-fold increase in estrogen-induced peroxidase in both normal and thyroidectomized immature animals without influencing the estrogen receptor concentration in the uterus. The effect of other thyroid-active agents on serum T3 and T4 levels was also determined. Treatment for 6 days with propylthiouracil (6 mM) increased the concentration of estrogen receptors in the uterus and decreased serum T3 and T4 levels without any effect on uterine peroxidase activity while bromide and perchlorate did not influence these parameters. Possible mechanisms for the inhibitory effects of thyroid hormones on uterine peroxidase induction by E2 are discussed.

Animals↗
PubMed2004

A novel splice variant involving the 5' untranslated region of thyroid hormone receptor beta1 (TRbeta1).

The thyroid hormone receptor beta (TRbeta) gene generates two different proteins by use of a different promoter (beta1 and beta2). We now report a novel short TRbeta1 RNA splice variant in humans lacking 35 nucleotides at the 3' end of the non-coding exon 1 due to an alternative 5' splice donor site. This short variant was first identified in sequences of cDNA obtained from cultured human fibroblasts. Both variants were found in human fibroblasts, brain, pituitary, adrenal gland, placenta, muscle, thyroid and lymphocytes. These TRbeta1 variants possess splice donor sites with a sequence score slightly favoring the TRbeta1 long variant. Variant-specific real-time polymerase chain reaction (PCR) showed that their relative proportions were equal except in pituitary and muscle, in which the long form was 3- and 5-fold in excess. T3 treatment of fibroblasts grown in thyroid hormone depleted medium did not affect the absolute or relative expression of the two variants. Furthermore, the expression level in fibroblasts from patients with resistance to thyroid hormone with or without TRbeta gene mutations was not different to that in fibroblasts from normal controls.

5' Untranslated Regions↗
PubMed1993

Distinct dimerization domains provide antagonist pathways for thyroid hormone receptor action.

Transcriptional regulation by thyroid hormone is mediated through its nuclear receptors, which bind to target response elements as homodimers or as heterodimers with proteins such as retinoid X receptors (RXR). Thyroid hormone response elements exhibit remarkable flexibility in that the receptor binding half-sites can be arranged as direct repeats, inverted repeats, or everted repeats. We report that a limited region at the carboxyl-terminal end of the thyroid hormone receptor differentially contributes to the formation of receptor homo- and heterodimers. The functionally inactive thyroid hormone receptor splicing variant alpha 2, which is altered at the juncture of the homo- and heterodimerization domains, cannot form homodimers. However, alpha 2 can form a heterodimer when bound to half-sites arranged as a direct repeat spaced by 4 base pairs (DR4), but not with other arrangements of response element half-sites. The alpha 2-RXR heterodimer strongly inhibits wild type receptor function mediated by the DR4 element, suggesting that the alpha 2 isoform modulates thyroid hormone action by binding as an antagonist to a subset of response elements.

Amino Acid Sequence↗
PubMed1993

Nonbiased identification of DNA sequences that bind thyroid hormone receptor alpha 1 with high affinity.

Thyroid hormone receptors are transcription factors that bind to specific DNA sequences and regulate gene expression in a ligand-dependent manner. Although thyroid hormone receptors are known to bind to the hexamer 5'-AGGTCA, it is not known if this represents the optimal binding site. Therefore, a nonbiased strategy was used to identify DNA sequences which bind thyroid hormone receptor alpha 1 with high affinity. Such DNA sequences were isolated from a pool of random sequences using a strategy combining an electrophoretic mobility shift assay with the polymerase chain reaction. It was found that thyroid hormone receptor alpha 1 binds with highest affinity to the octamer 5'-TAAGGTCA. Mutation of the two 5'-nucleotides decreased the affinity of thyroid hormone receptor alpha 1 for this DNA sequence approximately 5-fold, and the importance of those nucleotides in receptor binding was confirmed by DNA footprinting. A single copy of the octamer sequence (but not the hexamer AGGTCA) could impart T3 responsiveness to a heterologous promoter in a transient transfection assay. The results indicate that the optimal binding site for thyroid hormone receptor alpha 1 is 2 base pairs larger than previously thought, and that a single binding site can function as a response element. In addition, we speculate that the optimal binding sites for thyroid hormone, vitamin D, and retinoic acid receptors may not be identical, as had previously been thought.

Animals↗
PubMed1979

Hormones and the lung. II. Immunohistochemical localization of thyroid hormone binding in type II pulmonary epithelial cells clonally-derived from adult rat lung.

The type II pulmonary epithelial cell is the recognized state of surfactant synthesis and storage. Results of recent studies indicate that the thyroid hormones, triiodothyronine (T3) and thyroxine (T4), may be important regulators of surfactant production and/or release. Direct and indirect immunofluorescence techniques were used in an attempt to demonstrate binding of T3 and T4 in monolayer cultures of isolated type II cells. These cultured epithelial cells are clonally-derived from adult rat lung, retain a diploid karyotype through 35 population doublings in vitro, contain granular inclusions (lamellar bodies) in the perinuclear cytoplasm, and synthesize phosphatidylcholine via the CDP-choline pathway. In isolated type II cells, either of two fluorescent patterns was observed: (a) nuclear fluorescence accompanied by a reticular perinuclear network; or (b) diffuse cytoplasmic accumulations with concentrations around perinculear cytoplasmic inclusions. Ultrastructurally these inclusions had the typical appearance of lamellar bodies. Histochemical studies demonstrated that these inclusions contained surfactant-associated nonspecific esterases and stained with Nile blized markers for pulmonary surfactant indicate that these inclusions are indeed lamellar bodies, the putative sites of surfactant synthesis and/or storage. These findings suggest that the type II pulmonary epithelial cell contains specific binding sites for thyroid hormones, and support the hypothesis that thyroid hormones are regulators of surfactant metabolism.

Animals↗
PubMed1997

Kinetic parameters of Thymidine kinase and DNA synthesis during liver regeneration: role of thyroid hormones.

The role of thyroid hormones in DNA synthesis and in the activity of Thymidine kinase (TK), a key regulatory enzyme of DNA synthesis was studied in proliferating hepatocytes in vivo. Liver regeneration after partial hepatectomy was used as a model for controlled cell division in rats having different thyroid status - euthyroid, hypothyroid and 3,3',5'-triiodo-L-thyronine (T3)-treated hypothyroid. Partial hepatectomy caused a significant elevation of DNA synthesis (p<0.01) in all the three groups compared to their sham-operated counterparts. Hypothyroid hepatectomised animals showed significantly lower (p<0.01) level of DNA synthesis than euthyroid hepatectomised animals. A single subcutaneous dose of T3 to hypothyroid sham-operated animals resulted in a significant increase (p<0.01) of DNA synthesis in the intact liver. This was comparable to the level of DNA synthesis occurring in regenerating liver of euthyroid animals. In hypothyroid hepatectomised animals, T3 showed an additive effect on DNA synthesis and this group exhibited maximum level of DNA synthesis (p<0.01). Studies of the kinetic parameters of TK show that the Michelis-Menten constant, (K(m)) of TK for thymidine was altered by the thyroid status. K(m) increased significantly (p<0.01) in untreated hypothyroid animals when compared to the euthyroid rats. T3 treatment of hypothyroid animals reversed this effect and this group showed the lowest value for K(m) (p<0.01). Thus our results indicate that thyroid hormones can influence DNA synthesis during liver regeneration and they may regulate the activity of enzymes such as Thymidine kinase which are important for DNA synthesis and hence cell division.

Animals↗
PubMed1981

Peripheral resistance to thyroid hormone in an infant.

Peripheral resistance to thyroid hormone, a syndrome characterized by elevated serum total and free thyroid hormone levels and abnormal TSH suppression without manifestations of hyperthyroidism, was studied in a clinically euthyroid 6-month-old infant. Initial serum concentrations of T4, T3, and TSH were 22.1 micrograms/dl, 334 ng/dl, and 7.6 microunits/ml, respectively; infusion of synthetic TRH increased the serum TSH to 47.4 microunits/ml, an exaggerated response. Pituitary insensitivity to T3 was investigated by measuring these parameters in response to consecutive 7-day courses of increasing doses of T3. Four times the calculated replacement dose of T3 (40 micrograms/day) was required to normalize the serum T4 and the serum TSH response to TRH. After administration of 80 micrograms/day T3, the serum TSH response to TRH was virtually abolished, but no clinical signs of thyroid hormone excess were observed. High doses of T4 blunted the serum TSH response to TRH in a manner similar to T3. Prednisone also decreased the TSH response to TRH but had no effect on serum thyroid hormone concentrations. In an attempt to determine the mechanism of thyroid hormone resistance, specific nuclear T3 binding was compared in cultured skin fibroblasts from the patient and a normal infant. Normal fibroblast nuclei had a single binding site with a Ka of 3.1 X 10(9) M-1. In contrast, the Scatchard plot of the patient's T3 binding was curvilinear, compatible with a high affinity site that had a Ka (4.2 X 10(9) M-1) similar to that of the normal fibroblasts and a second low affinity site (Ka = 2.7 X 10(8) M-1). Supraphysiological concentrations of T3 elicited a dose-related increase in fibroblast glucose consumption, which was similar in cells from both the patient and from a normal infant. In conclusion, pituitary and peripheral resistance to thyroid hormone has been demonstrated in this infant, but despite the abnormality of nuclear T3 binding, the cellular mechanisms remain unclear.

Adolescent↗
PubMed1985

[Induction of cytosolic proteins controlling mitochondrial protein synthesis by thyroid hormone].

The effect of thyroid hormone on the generation of modulators of mitochondrial protein synthesis was investigated. The modulators were present in the 150,000 X g supernatant (S-150) prepared from Wistar rat liver and kidney. A stimulator was found in the liver, and an inhibitory modulator was present in kidney tissue. Generation of these modulators was stimulated by T4 administration to the animals. Both the stimulatory and inhibitory modulators were inactivated by pretreatment with trypsin or boiling. The molecular weight of these modulators was estimated by gel filtration study and for both the stimulatory and inhibitory modulator proteins was approximately 10,000 daltons. The results suggested that thyroid hormone regulates mitochondrial protein synthesis through the stimulation of synthesis of mitochondrial protein synthesis modulators, and that the tissue specific modulators (stimulatory in liver and inhibitory in kidney) can be produced by the hormone.

Animals↗
PubMed1999

Tissue-specific differential repression of gene expression by a dominant negative mutant of thyroid hormone beta1 receptor.

Resistance to thyroid hormone (RTH) is a genetic disease caused by the mutations of the thyroid hormone beta receptor (TRbeta) gene, producing receptors with a dominant negative action. The present study addressed the question as to whether tissue-specific factors modulate the dominant negative function in different tissues. We prepared stably transfected pituitary GH3 (GH3-PV) and liver SK-Hep-1 (SK-Hep-1-PV) cell lines with a potent dominant negative mutant, PV. The growth hormone (GH) and the malic enzyme genes (ME) in GH3 and SK-Hep-1, respectively, are directly regulated by the thyroid hormone, 3,3,'5-triiodo-L-thyronine (T3). The ratio of the expressed PV/endogenous TRbeta1 proteins was approximately 20 and 5 for GH3-PV and SK-Hep-1-PV cells, respectively. However, the T3-activated expression of the GH gene in GH3-PV and ME gene in SK-Hep-1-PV was repressed by approximately 30% and 90%, respectively, indicating the lack of correlation of PV/TRpbeta1 protein ratio with the dominant negative potency of mutant PV. Furthermore, the synergistic effect of the pituitary-specific factor 1 on the TR-mediated GH promoter activity was not repressed by mutant PV. Taken together, these results suggest that the dominant negative effect of mutant TR is variable in the tissues studied.

Animals↗
PubMed1998

Thyroid hormone treatment aiming at reduced, but not suppressed, serum thyroid-stimulating hormone levels in nontoxic goitre: effects on bone metabolism amongst premenopausal women.

OBJECTIVES: To study the effects of six months' treatment with either T4 or T3, aiming at reduced but not totally suppressed serum TSH levels, as measured by a third generation TSH assay, on biochemical bone turnover parameters as well as bone mass in patients with nontoxic goitre. DESIGN: Prospective randomized study with a matched control group, not blinded. SETTING: Two University Hospital Clinics in Copenhagen. SUBJECTS AND INTERVENTION: Twenty-four consecutive premenopausal women with moderate sized nontoxic goitre. Fourteen patients randomized to T4 or T3 treatment for six months with monthly titration of the dose, aiming at TSH values between 0.005 and 0.2 mUL(-1). Ten controls. MAIN OUTCOME MEASURES: Serum parathyroid hormone (PTH), serum procollagen I C-terminal propeptide (PICP), serum alkaline phosphatase, serum osteocalcin, u-pyridinoline, u-deoxypyridinoline, u-hydroxyproline. Bone mass (BMD) at the lumbar spine and at both femoral necks. RESULTS: Serum TSH was generally kept within the desired interval. There was no difference in any marker of bone metabolism between the effects of T4 and T3. Consequently, these groups were combined in order to evaluate the effect of thyroid hormones on the bone and mineral metabolism. Thyroid hormone treatment resulted in increased levels of serum ionized calcium (Ca) (P=0.02), serum alkaline phosphatase (P=0.007), serum-PICP (P=0.003), serum osteocalcin (P=0.02) and urinary excretion of deoxypridinoline (P=0.03) compared to untreated controls. Bone mass did not change. CONCLUSION: Six months treatment with either T4 or T3 of premenopausal women with nontoxic goitre, aiming at reduced but not totally suppressed TSH values, resulted in biochemical signs of increased bone turnover, whereas bone mass remained unaltered. No differences were found between the effects of T4 or T3 treatment.

Adult↗
PubMed1984

Relation of structural polarity to responses of cyclic 3', 5'-adenosine monophosphate accumulation and thyroid hormone release in cultured human thyroid follicles.

The relationship of structural polarity to functional activities was examined in cultured human thyroid follicles, which were isolated from the thyroid gland of patients with Graves' disease by collagenase treatment. Structural polarity was examined morphologically by electron microscopy, while the functional response to bovine TSH was examined by measuring intracellular cAMP accumulation and T3 release. In freshly isolated thyroid follicles, structural polarity was normal and TSH induced significant cAMP accumulation but no significant release of T3. After culture for 5 days the structural polarity of thyroid follicles became inverted in the absence of thyroid stimulators, but normal polarity was retained in the presence of TSH or dibutyryl cAMP [Bu)2 cAMP). The response to TSH of cAMP accumulation increased markedly after culture in either the presence or absence of TSH, suggesting that cAMP accumulation in response to TSH is not related to structural polarity. In contrast, thyroid follicles cultured without thyroid stimulators showed no significant T3 release in response to TSH, whereas those cultured with TSH or (Bu)2 cAMP showed significant T3 release in response to TSH. These data indicate that in cultured human thyroid follicles, the responses to TSH of cAMP accumulation and T3 release are not always correlated. Among many other explanations, the results were at least compatible with the idea that normal structural polarity is necessary for thyroid hormone release in response to TSH.

Bucladesine↗
PubMed2002

Oxytocin decreases plasma levels of thyroid-stimulating hormone and thyroid hormones in rats.

Oxytocin (OXT) administered to rats induces several long-lasting physiological and metabolic effects. The aim of the present study was to investigate the effects of oxytocin treatment on plasma levels of thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3). For this purpose, oxytocin or NaCl was administered intracerebroventricularly (i.c.v.) (0.3 micro g) or subcutaneously (s.c.) (1 mg/kg) once a day for 5 days to male rats. Five or ten days after the last injection, rats were decapitated, blood was collected and hormone levels were analyzed by fluoroimmunoassay. The oxytocin treatment i.c.v. decreased plasma levels of TSH (p<0.05), fT3 (p<0.01) and fT4 (p<0.05) when measured at day 5 after oxytocin treatment, whereas the effect was abolished when measured at day 10. Oxytocin treatment s.c. did not affect plasma levels of TSH, fT3 or fT4. Thus, the effect seems to have been mediated within the central nervous system, and TSH and the thyroid hormones may be involved in some of the metabolic effects in response to oxytocin.

Animals↗
PubMed1993

Regulation of renal cytochrome P450s by thyroid hormone in diabetic rats.

Effects of thyroid hormone treatment on renal P450 expression in the diabetic rats were investigated. Diabetes produced by streptozotocin induced CYP4A2 and P450 K-2 (similar form with CYP2C23) but not P450 K-4 (similar form with CYP4A8) and induced lauric acid hydroxylation activity. The serum thyroid hormone level was decreased with diabetes. Treatment of diabetic rats with thyroid hormone (T3) as well as with insulin reversed the increase in the levels of CYP4A2 and P450 K-2. Thyroidectomy also induced CYP4A2 and P450 K-2 in the rat kidney. The increase was reversed by treatment of thyroidectomized rats with T3. These findings suggest that expression of CYP4A2 and P450 K-2 in rat kidney is suppressively regulated by thyroid hormone and the decrease in thyroid hormone level in the diabetic state affects the levels of CYP4A2 and P450 K-2.

Animals↗
PubMed2000

Thyroid hormones and their effects: a new perspective.

The thyroid hormones are very hydrophobic and those that exhibit biological activity are 3',5',3,5-L-tetraiodothyronine (T4), 3',5,3-L-triiodothyronine (T3), 3',5',3-L-triiodothyronine (rT3) and 3,5',-L-diiothyronine (3,5-T2). At physiological pH, dissociation of the phenolic -OH group of these iodothyronines is an important determinant of their physical chemistry that impacts on their biological effects. When non-ionized these iodothyronines are strongly amphipathic. It is proposed that iodothyronines are normal constituents of biological membranes in vertebrates. In plasma of adult vertebrates, unbound T4 and T3 are regulated in the picomolar range whilst protein-bound T4 and T3 are maintained in the nanomolar range. The function of thyroid-hormone-binding plasma proteins is to ensure an even distrubtion throughout the body. Various iodothyronines are produced by three types of membrane-bound cellular deiodinase enzyme systems in vertebrates. The distribution of deiodinases varies between tissues and each has a distinct developmental profile. Thyroid hormones. (1) the nuclear receptor mode is especially important in the thyroid hormone axis that controls plasma and cellular levels of these hormones. (2) These hormones are strongly associated with membranes in tissues and normally rigidify these membranes. (3) They also affect the acyl composition of membrane bilayers and it is suggested that this is due to the cells responding to thyroid-hormone-induced membrane rigidificataion. Both their immediate effects on the physical state of membranes and the consequent changes in membrane composition result in several other thyroid hormone effects. Effects on metabolism may be due primarily to membrane acyl changes. There are other actions of thyroid hormones involving membrane receptors and influences on cellular interactions with the extracellulara matrix. The effects of thyroid hormones are reviewed and appear to b combinations of these various modes of action. During development, vertebrates show a surge in T4 and other thyroid hormones, as well as distinctive profiles in the appearance of the deiodinase enzymes and nuclear receptors. Evidence from the use of analogues supports multiple modes of action. Re-examination of data from th early 1960s supports a membrane action. Findings from receptor 'knockout' mice supports an important role for receptors in the development of the thyroid axis. These iodothyronines may be better thought of as 'vitamone'-like molecules than traditional hormonal messengers.

Animals↗
PubMed2005

Thyroid hormone withdrawal in patients with differentiated thyroid carcinoma: a one hundred thirty-patient pilot survey on consequences of hypothyroidism and a pharmacoeconomic comparison to recombinant thyrotropin administration.

The study objective was to elucidate clinical, quality-of-life, and pharmacoeconomic effects of hypothyroidism secondary to thyroid hormone withdrawal (withdrawal) in athyroid patients with differentiated thyroid cancer (DTC). We also intended to compare societal costs of withdrawal and recombinant human thyroid-stimulating hormone administration (rhTSH) in this population. We mailed a 13-item pilot survey to patients with DTC who had undergone withdrawal before diagnostic whole-body scan (dxWBS). Using survey results and actual and estimated cost data, we retrospectively constructed a societal cost model comparing withdrawal versus rhTSH and performed a sensitivity analysis by increasing the conservatism of 8 assumptions about withdrawal costs. One hundred thirty (55%) of 236 patients answered the questionnaire. Among respondents, 92% had symptomatic and 85% multisymptomatic hypothyroidism. Almost half sought medical attention for hypothyroid complaints. Approximately one third drove motor vehicles while hypothyroid. Median absence from salaried work was 11 days per withdrawal. In the pharmacoeconomic model, societal costs per dxWBS were approximately 326 euro (25%) greater for withdrawal than for rhTSH. In the sensitivity analysis, societal costs of rhTSH exceeded those of withdrawal by approximately 307 euro (30%). In conclusion, hypothyroidism secondary to withdrawal causes important morbidity, safety risks, and productivity impairment. rhTSH avoids these drawbacks at roughly equivalent societal cost to that of withdrawal.

Adult↗
PubMed1996

Responsiveness of alpha 1 and beta 1 cochlear Na, K-ATPase isoforms to thyroid hormone.

The effects of thyroid hormone on Na, K-ATPase subunit isoforms under euthyroid (EUTH), hypothyroid (HYPO) and hyperthyroid (HYPER) states were investigated via immunocytochemistry and the use of polyclonal antibodies specific to each isoform (alpha 1, alpha 2, alpha 3 and beta 1, beta 2). In HYPO animals, there was a distinct decrease in Na, K-ATPase alpha 1 isoform immunoreactivity in the stria vascularis (SV), spiral ganglion (SG) cells, spiral limbus (SLi) and cochlear nerve (CN) as compared with that in EUTH animals by the 17th day of the experiment. Immunostaining of the alpha 1 isoform increased in HYPER animals as compared with that in HYPO animals, and reached a level comparable to that in EUTH animals after 2 days of triiodothyronine (T3) treatment. Levels of alpha 2, alpha 3 and beta 2 isoforms did not appear to be affected by T3 administration. By the 19th day of a low I2 diet, the immunoreactive intensity of the beta 1 isoform was reduced in cochlear tissues of HYPO animals as compared with that in EUTH animals. The immunoreactivity of the beta 1 isoform increased after treatment with T3 for 4 days and was comparable with levels in EUTH animals. These data indicate that alpha 1 and beta 1 isoforms within specific cochlear regions of the adult rat are responsive to thyroid hormone.

Animals↗