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PubMed1997

Isoform variable action among thyroid hormone receptor mutants provides insight into pituitary resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). The mutant TR interferes with the action of normal TR to cause the clinical syndrome. Selective pituitary resistance to thyroid hormone (PRTH) results in inappropriate TSH secretion and peripheral sensitivity to elevated thyroid hormone levels. Association of the PRTH phenotype with in vitro behavior of the mutant TR has proved elusive. Alternative exon utilization results in two TR-beta isoforms, TR-beta 1 and TR-beta 2, which differ only in their amino termini. Although the TR-beta 1 isoform is ubiquitous, the TR-beta 2 isoform is found predominantly in the anterior pituitary and brain. To date, in vitro evaluation of RTH mutations has focused on the TR-beta 1 isoform. Site-directed mutagenesis was used to create several PRTH (R338L, R338W, V349M, R429Q, I431T) and generalized RTH (delta 337T, P453H) mutations in both TR-beta isoforms. The ability of mutant TRs to act as dominant negative inhibitors of wild type TR-beta function on positive and negative thyroid hormone response elements (pTREs and nTREs, respectively) was evaluated in transient transfection assays. PRTH mutants had no significant dominant negative activity as TR-beta 1 isoforms on pTREs found in peripheral tissues or on nTREs found on genes regulating TSH synthesis. PRTH mutants, in contrast, had strong dominant negative activity on these same nTREs as TR-beta 2 isoforms. Cotransfected retinoid X receptor-alpha was required for negative T3 regulation via the TR-beta 1 isoform but was not necessary for negative regulation via the TR-beta 2 isoform in CV-1 cells. The differing need for retinoid X receptor cotransfection demonstrates two distinct negative T3-regulatory pathways, one mediated by the TR-beta 1 and the other mediated by TR-beta 2. The selective effect of PRTH mutations on the TR-beta 2 isoform found in the hypothalamus and pituitary vs. the TR-beta 1 isoform found in peripheral tissues suggests a molecular mechanism for the PRTH disorder.

Alleles↗
PubMed1989

A structural study of the rat proximal and distal nephron: effect of peptide and thyroid hormones.

The effects of the absence of various hormones (antidiuretic hormone, thyroid hormone, parathyroid hormone, and calcitonin) on proximal and distal structures were studied in diabetes insipidus (DI) Brattleboro rats. The cross-sectional area of the first segment of proximal convoluted tubules (S1) was significantly reduced in thyroparathyroidectomized (TPTX) DI rats compared with Long-Evans rats (the strain of origin of DI rats) and untreated DI rats. Administration of triiodothyronine (T3, 10 micrograms/day for 7 days) to TPTX-DI rats restored the proximal tubule structure. In the distal convoluted tubule (DCT) the cross-sectional area of the epithelium and the number of nuclei per cross-sectional area were significantly greater in untreated ADH-deficient DI rats than in the control Long-Evans rats. Daily administration of 1-desamino-8-D-arginine vasopressin (dDAVP, 500 ng/day for 3 wk) significantly reduced the size and the number of DCT cells in DI rats. Cortical micropuncture data indicated that the Na+ concentration in the fluid delivered to the DCT and the absolute amount of Na+ reabsorbed along the DCT were higher in DI than in dDAVP-treated DI rats. It is concluded that functional changes in the PCT, subsequent to chronic TPTX, are accompanied by marked alteration of the cell anatomy of this nephron segment, and that the processes that modify the Na load delivered to the DCT and the Na transport in the DCT are accompanied by structural modifications of this segment.

Animals↗
PubMed1993

Thyroid hormones in human follicular fluid and thyroid hormone receptors in human granulosa cells.

OBJECTIVE: To demonstrate the presence of thyroid hormone in human follicular fluid (FF) and the binding of antithyroid hormone antibodies in human granulosa cells (GCs). DESIGN: Follicular fluids and GCs collected from women undergoing oocyte retrieval after superovulation. SETTING: In Vitro Fertilization-America/Allegheny General Hospital and Reproductive Sciences Research Laboratories, the Department of Obstetrics and Gynecology, The Medical College of Pennsylvania/Allegheny Campus. MAIN OUTCOME MEASURES: Follicular fluid levels of triiodothyronine (T3) determined by a microparticle enzyme immunoassay and FF levels of thyroxine (T4) determined by a fluorescence polarization immunoassay. Three anti-thyroid receptor antibodies were used to determine the presence of thyroid receptor. The binding of these antibodies in GCs was assessed by fluorescent microscopy and flow cytometry. RESULTS: Both T3 and T4 were present in the FF of eight patients studied. A large majority of the samples of individual fluids fell within the normal range for serum. There was a positive correlation between serum T4 values and FF T4 values. The three antithyroid receptor antibodies showed positive nuclear staining of GCs by fluorescent microscopy. The antibody to all thyroid hormone receptors yielded 35% positive cells by flow cytometry, and the site specific antibody for either the alpha-1 or beta-1 receptors yielded 78% and 44% positive cells, respectively. CONCLUSION: These data demonstrated, for the first time, the presence of T3 and T4 in human FF and the presence of T3 binding sites in human GCs and suggest a role for thyroid hormone in the regulation of human GCs.

Adult↗
PubMed1995

A novel point mutation (R243Q) in exon 7 of the c-erbA beta thyroid hormone receptor gene in a family with resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) is characterized by variable tissue hyporesponsiveness to thyroid hormones. Recently, a large number of different point mutations have been identified in the c-erbA beta thyroid hormone receptor (TR beta) in subjects with RTH. We describe a Japanese family with RTH with a novel point mutation in exon 7 of the TR beta gene. A single nucleotide substitution, guanine for adenine, was identified at the second position of codon 243 located in the hinge domain between the ligand binding and DNA binding domains in one of the two alleles of the proband and his mother, resulting in the substitution of the normal arginine (CGG) with a glutamine (CAG). Except for one family, point mutations so far described in RTH are clustered at exons 8-10 of the TR beta gene. This report presents a novel mutation in the characteristic portion in exon 7 of the TR beta.

Amino Acid Sequence↗
PubMed2004

A novel 1297-1304delGCCTGCCA mutation in the exon 10 of the thyroid hormone receptor beta gene causes resistance to thyroid hormone.

INTRODUCTION: Resistance to the thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to hormonal action caused by mutations located in the ligand-binding domain and adjacent hinge region of the thyroid hormone receptor beta (TRbeta) gene. PATIENT: The patient in this study, a 42-year-old Caucasian male, came to medical attention because he experienced atrial fibrillation. Clinical evaluation showed a small and diffuse goiter and biochemical tests revealed markedly elevated concentrations of total T4, total T3, and free T4, normal thyroid-stimulating hormone (TSH) values and slightly increased I131 thyroid uptake at 24 hours. The thyroperoxidase, thyroglobulin, and TSH receptor antibodies were positive. He was treated with cabergoline plus methimazole. This treatment was stopped because of the inconsistent response, monotherapy with tri-iodothyroacetic acid (TRIAC) was then prescribed after molecular diagnosis confirmed RTH syndrome. METHODS: The exons 9 and 10 of the TRbeta gene, including splicing signals and the flanking intronic regions of each intron, were amplified with PCR. DNA sequences from each amplified fragment were performed with the Taq polymerase-based chain terminator method and using the specific TRbeta forward and reverse primers. RESULTS: Direct sequence analysis of the exons 9 and 10 of the TRbeta gene revealed an eight basepair deletion, 1297-1304delGCCTGCCA in exon 10. The mutation produces a frameshift at amino acid 433 and introduces a stop codon TGA at position 461, 85 nucleotides downstream from deletion. This alteration was not detected in either the father or mother of the patient, suggesting a de novo mutation that was confirmed by DNA fingerprint analysis. CONCLUSIONS: In the present study we have identified a novel sporadic mutation corresponding to 1297-1304delGCCTGCCA deletion in the activating function 2 (AF-2) region of TRbeta. To our knowledge, this is the first time that the presence of a partial deletion of eight nucleotides in the TRbeta has been reported.

Adult↗
PubMed1999

Human trabecular meshwork cells as a thyroid hormone target tissue: presence of functional thyroid hormone receptors.

PURPOSE: To determine whether human trabecular meshwork cells (HTM) are a potential target tissue for thyroid hormone (3,3',5-triiodothyronine, T3). METHODS: Cultured HTM were assayed for the presence of thyroid hormone receptors (TRs) and retinoid X receptors (RXRs) by reverse-transcriptase polymerase chain reaction (RT-PCR) to detected TR and RXR mRNA, and by immunohistochemistry to detect nuclear TR and RXR proteins. Functionality of the TR was determined by analysis of 125I-T3 binding affinity and capacity in HTM nuclear extracts. Effects of T3 on modulation of hyaluronic acid (HA) levels in HTM were measured as a function of dose and duration of T3 administration. RESULTS: Analysis of RT-PCR and immunohistochemistry demonstrated that cultured HTM expressed TRalpha1, TRalpha2, and TRbeta1 but not TRbeta2; and RXRalpha but not RXRbeta and RXRgamma isoforms. Saturation binding and analysis of 125I-T3 to HTM nuclear extracts revealed Kd of 57 pM. The number of T3 binding sites extrapolated from a Scatchard plot was 7.3 x 10(10)/microg of HTM nuclear protein extract. T3 supplementation reduced the concentration of HA in the cell medium by 32-43% compared to cells grown in the absence of T3. CONCLUSIONS: Cultured HTM express three TR isoforms and one RXR isoform, bind T3 with an affinity similar to that of TR in responsive cells, and modulate their HA production in response to T3. These findings indicate that the human trabecular meshwork tissue has the capacity to respond to thyroid hormones.

Adult↗
PubMed2006

Expression of thyroid hormone receptor isoforms down-regulated by thyroid hormone in human medulloblastoma cells.

The role of thyroid hormone (T3) in the regulation of growth and development of the central nervous system including the cerebellum has been well established. However, the effects of thyroid hormone on malignant tumors derived from the cerebellum remain poorly understood. Our analysis mainly focused on expression levels of TR isoforms and the effects of thyroid hormone in human medulloblastoma HTB-185 cells. Northern blot analysis revealed TRalpha2 mRNA but not TRalpha1, beta1 or beta2 mRNA in the cell. The TRalpha1 and TRbeta1 mRNAs were detected only by RT-PCR method and TRbeta2 was not expressed. Incubation of T3 for 24 h decreased TRalpha1, TRalpha2 and TRbeta1 mRNA. Addition of actinomycin D caused an acute increase in the basal TR mRNA levels and the rate of decrease of all kinds of TR isoform mRNA was accelerated in the T3-treated groups compared to controls, indicating that the stability of TR mRNA was affected by T3. Incubation with cycloheximide also blocked a decrease in TR mRNA levels in the T3-treated HTB-185 cells suggesting that down-regulation of TR mRNA required the synthesis of new protein. Our data provide novel evidence for the expression of TRs down-regulated by T3 in HTB-185 cells, suggesting that TR expression is post-transcriptionally regulated by T3 at the level of RNA stability.

Brain Neoplasms↗
PubMed1995

A structural role for hormone in the thyroid hormone receptor.

The crystal structure of the rat alpha 1 thyroid hormone receptor ligand-binding domain bound with a thyroid hormone agonist reveals that ligand is completely buried within the domain as part of the hydrophobic core. In addition, the carboxy-terminal activation domain forms an amphipathic helix, with its hydrophobic face constituting part of the hormone binding cavity. These observations suggest a structural role for ligand, in establishing the active conformation of the receptor, that is likely to underlie hormonal regulation of gene expression for the nuclear receptors.

Allosteric Regulation↗
PubMed1993

Urinary cortisol metabolites in the assessment of peripheral thyroid hormone action: application for diagnosis of resistance to thyroid hormone.

Urinary cortisol metabolites are altered both quantitatively and qualitatively in thyroid dysfunction. This study was conducted to elucidate the usefulness of urinary cortisol metabolites in the assessment of peripheral thyroid hormone action, particularly in the patients with inappropriate thyrotropin secretion. Twenty-four hour urinary 17-hydroxycorticosteroid (17-OHCS) level and gas chromatographical steroid profile were studied in 25 hyperthyroid, 18 hypothyroid, and 24 euthyroid control subjects. Five patients with generalized thyroid hormone resistance and two patients with thyrotropin secreting pituitary tumor were also studied. The ratio of urinary tetrahydrocortisone to tetrahydrocortisol (THE/THF) was significantly elevated in hyperthyroidism (4.58 +/- 1.49) and depressed in hypothyroidism (1.31 +/- 0.55) compared to control (1.93 +/- 0.35). There were good correlations between THE/THF and serum thyroid hormone levels, especially in hypothyroidism. THE/THF can be a good biochemical indicator for deficiency of peripheral thyroid hormone action. Two patients with thyrotropin-secreting tumor showed high THE/THF, which reflected thyroid hormone excess. In contrast, THE/THF in the patients with generalized thyroid hormone resistance was low as compared to high serum thyroid hormone levels. Similar findings were demonstrated with 17-OHCS but discrimination of thyroid hormone resistance was insufficient. Thus, the ratio of the urinary concentrations of cortisol metabolites, THE/THF, appears to be a good marker for peripheral thyroid hormone resistance.

17-Hydroxycorticosteroids↗
PubMed1989

Mutations of the rat growth hormone promoter which increase and decrease response to thyroid hormone define a consensus thyroid hormone response element.

We have previously identified sequences required for thyroid hormone (T3) induction of the rat GH (rGH) promoter, which lie in a region from -188 to -164 upstream of the mRNA start site. Within this region, Domains A, -189 to -184 and B, -179 to -174, are imperfect direct repeats, and domain C, -172 to -167, is a divergent inverted copy that matches the A domain at 4/6 positions. A series of synthetic mutant versions of this sequence were inserted upstream of a truncated rGH promoter, or as a replacement for wild-type sequences in a synthetic 237 base pair rGH promoter or upstream of the heterologous thymidine kinase promoter. Mutations changing the B domain to a perfect copy of the A domain significantly increased T3 induction (21.3-fold) relative to the wild type (3.6-fold). A single point mutation making the C domain a better match to the A domain also increased T3 induction to 16.2-fold. Combining this up-mutation with any of three down-mutations in the A, B, or C domains strongly decreased response, showing that all three domains contribute to the amplified T3 response. Binding affinity of the various mutant oligonucleotides was assessed using in vitro translated receptor and affinity paralleled the functional responses for most binding site mutations. Requirements for in vitro binding were, however, less rigorous than those for functional T3 induction. Based on these results, we propose a consensus T3 receptor binding half-site, AGGT(C/A)A, at least two copies of which are required for a T3 response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Thyroid hormone for preventing of neurodevelopmental impairment in preterm infants.

BACKGROUND: Observational studies have shown an association between transiently low thyroid hormone levels in preterm infants in the first weeks of life (transient hypothyroxemia) and an abnormal neurodevelopmental outcome. Thyroid hormone therapy might prevent this morbidity. OBJECTIVES: To assess whether thyroid hormone therapy in preterm infants without congenital hypothyroidism results in clinically important changes in neonatal and long term outcomes in terms of both benefits and harms. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register, MEDLINE, previous reviews including cross references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching in the English language. SELECTION CRITERIA: All trials using random or quasi-random patient allocation, in which thyroid hormone therapy (either treatment or prophylaxis) was compared to a control in premature infants. DATA COLLECTION AND ANALYSIS: Primary clinical outcomes included measures of neurodevelopmental outcome and mortality. Assessment of trial quality, data extraction and synthesis of data, using relative risk (RR) and weighted mean difference (WMD), were performed using standard methods of the Cochrane Collaboration and its Neonatal Review Group. MAIN RESULTS: Eight studies were identified that compared thyroid hormone treatment to control. Four randomized or quasi-randomized studies met inclusion criteria (Chowdhry 1984, Amato 1989, van Wassenaer 1997 and Vanhole 1997). All studies enrolled preterm infants < 32 weeks gestation, but used different timing, dose and duration of treatment with thyroid hormones. Three studies used thyroxine, whereas Amato 1989 used triiodothyronine. Only two studies with neurodevelopmental follow-up were of good methodology (van Wassenaer 1997 and Vanhole 1997). All studies were of small size with the largest, van Wassenaer 1997, enrolling 200 infants. A lack of comparability of data (neurodevelopmental test or timing of follow-up) prevented meta-analytic pooling of the studies for neurodevelopmental outcomes. There was no significant difference in mortality to discharge (typical relative risk 0.74, 95% CI 0.44, 1.26) in infants who received thyroid hormone treatment compared to controls. In individual studies, no significant differences were found in neurodevelopmental outcomes including risk of abnormal neurological outcome, and Bayley Mental or Psychomotor Development Indices. No data were available for the incidences of cerebral palsy or sensorineural impairment. Fraction of inspired oxygen was lower in infants receiving triiodothyronine in one small quasi-randomized study (Amato 1989), but not in infants receiving thyroxine in a randomized study (Vanhole 1997). No other differences were found to suggest a reduced severity of respiratory distress syndrome in infants receiving early thyroid hormone therapy. REVIEWER'S CONCLUSIONS: This review does not support the use of thyroid hormones in preterm infants to reduce neonatal mortality, improve neurodevelopmental outcome or to reduce the severity of respiratory distress syndrome. The a posteriori subgroup analyses of data from one study (van Wassenaer 1997) which showed benefits in infants 24-25 weeks gestation should be treated with caution. The small number of infants included in trials incorporated in this review limits the power of the meta-analysis to detect clinically important differences in neonatal outcomes. Future trials should be of sufficient size to detect clinically important differences in neurodevelopmental outcomes. They should consider enrolling those infants most likely to benefit from thyroid hormone treatment such as infants born at less than 27 weeks gestation and use thyroid hormones as treatment instead of prophylaxis.

Developmental Disabilities↗
PubMed1996

A mouse model of resistance to thyroid hormone produced by somatic gene transfer of a mutant thyroid hormone receptor.

Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome characterized by hyposensitivity to thyroid hormone caused by mutations in the thyroid hormone receptor-beta (TR beta) gene. Replication-defective recombinant adenoviruses were constructed that express the human wild-type (WT) TR beta, a human mutant TR beta identified in a family with RTH, and luciferase under the control of thyroid hormone (Luc). The efficient introduction and expression of these recombinant genes into adult mouse liver were confirmed by immunocytochemistry. Hypothyroid mice were infected with Luc alone and in combination with the WT TR beta or mutant TR beta. Half of the mice from each group were then treated with T3. Compared with mice infected with Luc alone, T3 treatment of mutant TR beta infected mice showed no changes in liver luciferase, weight, or 5'-deiodinase and spot 14 messenger RNA, and the decrease in the serum cholesterol concentration was blunted as in patients with RTH. The effects of T3 in mice infected with WT TR beta were comparable to those in mice infected with Luc alone. However, overexpression of the WT TR beta tended to further increase serum cholesterol in the hypothyroid state and decrease it in response to T3, suggesting that the unliganded TR has a constitutive effect in vivo and that higher TR levels can aggravate the manifestations of hypothyroidism and enhance the action of thyroid hormone. Transient somatic transfer of mutant TR genes provides a model for the study of RTH. It allows evaluation of the effect of genetic factors interacting with mutant TRs that modify the phenotype of RTH, without animal back-crossing.

Animals↗
PubMed1985

Effect of long-term amiodarone therapy on thyroid hormone levels and thyroid function.

Both hyperthyroidism and hypothyroidism have been noted to occur in some patients treated with amiodarone for cardiac arrhythmias. To determine the frequency of the development of thyroidal abnormalities in patients receiving amiodarone, 45 euthyroid patients were prospectively evaluated. Serum samples were obtained for measurement of thyroxine, thyrotropin, triiodothyronine, and triiodothyronine resin uptake prior to initiation of amiodarone treatment and serially over a 12- to 27-month period during which amiodarone was administered. The patients were divided into four subgroups as follows: Group I (n = 22) had elevated thyroxine levels, Group IIA (n = 13) had normal thyroxine levels and normal thyrotropin levels, Group IIB (n = 7) had normal thyroxine levels and elevated thyrotropin levels, and Group III (n = 3) had subnormal thyroxine levels. Demographic factors (such as route of administration, cardiac diagnosis, sex of the patient, or indication for amiodarone therapy) and amiodarone levels had no significant effect on the thyroid hormone parameters. However, Group I patients were statistically older than the patients in the other groups. Linear regression analysis revealed a negative correlation for thyroxine levels and a positive correlation with thyrotropin levels with age for the whole group. The various groups were not statistically affected by duration of therapy, but a positive trend existed for increasing thyroxine levels. Although virtually all patients showed changes in their thyroid hormone levels, chemical hyperthyroidism (elevated thyroxine and triiodothyronine levels without symptoms) developed in only two patients (4 percent), and clinical hyperthyroidism (elevated thyroxine and triiodothyronine levels with symptoms) developed in no patients. Four patients (9 percent) became biochemically and clinically hypothyroid. Thus, amiodarone frequently influences thyroid hormonal parameters, but less commonly causes a change in actual thyroid function. However, hyperthyroidism and hypothyroidism do occur in a significant number of patients.

Age Factors↗
PubMed2004

Transgenic analysis reveals that thyroid hormone receptor is sufficient to mediate the thyroid hormone signal in frog metamorphosis.

Thyroid hormone (T3) has long been known to be important for vertebrate development and adult organ function. Whereas thyroid hormone receptor (TR) knockout and transgenic studies of mice have implicated TR involvement in mammalian development, the underlying molecular bases for the resulting phenotypes remain to be determined in vivo, especially considering that T3 is known to have both genomic, i.e., through TRs, and nongenomic effects on cells. Amphibian metamorphosis is an excellent model for studying the role of TR in vertebrate development because of its total dependence on T3. Here we investigated the role of TR in metamorphosis by developing a dominant positive mutant thyroid hormone receptor (dpTR). In the frog oocyte transcription system, dpTR bound a T3-responsive promoter and activated the promoter independently of T3. Transgenic expression of dpTR under the control of a heat shock-inducible promoter in premetamorphic tadpoles led to precocious metamorphic transformations. Molecular analyses showed that dpTR induced metamorphosis by specifically binding to known T3 target genes, leading to increased local histone acetylation and gene activation, similar to T3-bound TR during natural metamorphosis. Our experiments indicated that the metamorphic role of T3 is through genomic action of the hormone, at least on the developmental parameters tested. They further provide the first example where TR is shown to mediate directly and sufficiently these developmental effects of T3 in individual organs by regulating target gene expression in these organs.

Animals↗
PubMed2005

Thyroid hormone T3 acting through the thyroid hormone alpha receptor is necessary for implementation of erythropoiesis in the neonatal spleen environment in the mouse.

Thyroid hormones (THs) mediate many physiological and developmental functions in vertebrates. All these functions are mediated by binding of the active form of the TH T3 to the specific nuclear receptors TRalpha and TRbeta, which are transcription factors. Using mutant mice lacking TRs or deficient for TH production, we show that T3 influences neonatal erythropoiesis through TRalpha. The effect of T3 and TRalpha is restricted to this developmental window and is specific for the spleen but not for other erythropoietic organs. We show that T3 via TRalpha affects late steps of erythrocytic development, promoting the proliferation of late basophilic erythroblasts. In vitro, this effect is exerted directly on erythrocytic cells. In vivo, the action of T3 is also intrinsic to spleen erythrocytic progenitors, as shown by grafting experiments of splenocytes derived from wildtype and TRalpha knockout (TRalpha(0/0)) mice into wild-type and TRalpha(0/0) irradiated recipients. Our results indicate that defective spleen erythropoiesis in hypothyroid and TRalpha(0/0) mice results from impaired recognition of the spleen environment by the mutant erythrocytic progenitors. The data presented support a model in which T3 signaling through TRalpha is essential for the implementation of the transient spleen erythropoiesis at birth.

Animals↗
PubMed1989

Functional characterization of the rat growth hormone promoter elements required for induction by thyroid hormone with and without a co-transfected beta type thyroid hormone receptor.

We have extensively characterized the sequences of the rat growth hormone (rGH) promoter required for induction by T3 (thyroid hormone, 3,5,3'-L-triiodothyronine) in a transient transfection system. Oligonucleotides containing portions of the rGH promoter sequence with various deletions and point mutations were placed upstream of the first 137 base pairs of the rGH promoter or the heterologous herpes virus thymidine kinase promoter in chloramphenicol acetyltransferase expression vectors. The rGH137 and thymidine kinase promoters show no or minimal response to T3 in the basal state. The constructs were tested in GH4C1 rat pituitary cells and COS cells (functionally deficient in thyroid hormone receptor) with and without a co-transfected plasmid expressing a beta type c-erbA gene coding for a functional T3 receptor. Oligonucleotides containing the T3 receptor binding site confer hormone-dependent induction in a manner that is independent of either orientation or variation in position on the helix relative to the promoter. Point mutations in the sequence -189 to -173 result in loss of T3 induction, and bases between -173 and -167 were also required for a full T3 response. The minimal length to confer T3 induction to the rGH promoter was 23 base pairs (-190 to -167). Point mutations creating a perfect duplication of 7 base pairs within the receptor binding site conferred 12-fold T3 response to the rGH137 promoter, 3-fold greater than the wild type rGH237 construct. T3 inductibility was also transferred to the thymidine kinase promoter by an oligonucleotide containing the sequence -200 to -157, demonstrating that cell type specific elements located 3' to 157 of the rGH promoter are not required for thyroid hormone responsiveness.

Animals↗
PubMed1991

Regulatory effects of growth hormone, glucocorticoids, and thyroid hormone on the estrogen receptor level in the rat liver.

The multihormonal regulation of the estrogen receptor in the liver of female rats was studied under in vivo conditions. The steroid receptor level was assayed by hormone binding and specific mRNA analyzed by solution hybridization using a 35S-labeled RNA probe complementary to the ligand-binding domain of the estrogen receptor gene. Serum growth hormone levels were measured and correlated to the effects of glucocorticoid and thyroid hormone administration on the estrogen receptor expression. In animals subjected to adrenalectomy plus thyroidectomy, the estrogen receptor concentration was reduced from 59 fmol/mg cytosol protein to 10 fmol/mg protein (i.e., with 87% relative to control animals). Adrenalectomy or thyroidectomy alone caused a decrease with 14% and 66%, respectively. Substitution with 10 micrograms betamethasone and 1 microgram triiodothyronine daily for 9 days completely restored the receptor content to control levels. Substitution with either hormone alone increased, but only partially restored receptor levels. The effect of betamethasone alone was dose dependent from 10 micrograms/d to 100 micrograms/d. This dose dependence was not seen when the animal simultaneously received 1 microgram of triiodothyronine. Superphysiologic doses of triiodothyronine did not raise estrogen receptor levels above those seen in animals treated with physiologic doses. High doses of triiodothyronine (greater than 20 micrograms/d) decreased serum growth hormone levels. The estrogen receptor mRNA levels in livers from hypophysectomized animals were increased after treatment with growth hormone (2.5-fold), thyroid hormone (two-fold), and glucocorticoids (1.5-fold). The results obtained indicate a very complex regulation of liver estrogen receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗