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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to compare the effects of hypothyroidism and hyperthyroidism on sarcoplasmic reticulum (SR) Ca(2+)-pump activity, together with assessment of the functional role of SR in providing activator Ca2+ under these altered thyroid states. In response to a shift from hypothyroid to hyperthyroid state, a 10 fold and 2 fold increase in SR Ca(2+)-pump activity in atria and ventricles, respectively, were observed. This was associated with the 8-9 fold increases in atrial contractility (+dT/dt) and relaxation (-dT/dt), but only with a 3-4 fold increase in their ventricular counterparts. Also, the recirculation fraction of activator Ca2+ (RFA) increased to a far greater extent in atria (4 fold) than in papillary muscles, and the relative increment in inhibition of developed tension by ryanodine became 3 times larger in atria than in papillary muscles. A positive force-frequency relationship (FFR) was observed in hypothyroid atria, whereas the hyperthyroid atria, hypothyroid and hyperthyroid papillary muscles showed a negative FFR. These results suggest the greater role of transsarcolemmal (SL) Ca2+ and smaller role of SR Ca2+ in activating contraction in hypothyroid atria compared to other preparations. Thyroid hormones decrease the contribution of SL and increase that of SR in providing activator Ca2+ to the greater extent in atria than in ventricles. This effect of thyroid hormones is based on larger stimulation of SR Ca(2+)-pump in atria compared to ventricles.
Mol Cell Biochem 1997 Nov
PMID:Thyroid hormones differentially affect sarcoplasmic reticulum function in rat atria and ventricles. 940 53

Thyroid hormone is required for basal and estrogen-induced expression of anterior pituitary galanin. Steady-state anterior pituitary galanin mRNA levels decreased 6-fold in hypothyroid rats after 3 weeks of treatment. Similarly, hypothyroidism resulted in a 2.6-fold decrease in estrogen induction of galanin gene expression. The effect of thyroid hormone on anterior pituitary galanin gene expression appears to be exerted, at least in part, at the pituitary itself. Transient expression assays in GH3 cells suggest the involvement of transcriptional mechanisms in the regulation of galanin gene expression by thyroid hormone. A region between -41 and -132 bp upstream of the transcriptional start site confers thyroid hormone responsiveness to the galanin gene. Gel-mobility shift assays show specific binding of 'SPI-like' proteins in GH3 nuclear extracts to this region of the galanin gene. This binding was greatly enhanced by thyroid hormone.
Brain Res Mol Brain Res 1997 Nov
PMID:Regulation of anterior pituitary galanin gene expression by thyroid hormone. 942 2

1. Regulation of pulsatile secretion of growth hormone (GH) relies on hypothalamic neuronal loops, major transmitters involved in their operation are growth hormone releasing hormone (GHRH) synthetized mostly in arcuate nucleus (ARC) neurons, and somatostatin (SRIH), synthetized both in hypothalamus periventricular (PVe) and ARC neurons. 2. Neurons synthetizing both peptides can inhibit each other in a reciprocal manner. Other neuropeptides synthetized in ARC neurons, such as galanin, or in ARC interneurons, such as neuropeptide Y (NPY), are able to modulate synthesis and release of GHRH and SRIH into the hypothalamohypophyseal portal system. 3. In addition, the hitherto uncharacterized endogenous ligand of the recently cloned growth hormone releasing peptide receptor, expressed mostly in the ARC, triggers GH release, presumably by actions on ARC interneurons. 4. Thyroid, gonadal, and adrenal steroid hormones also affect the GHRH-SRIH balance; a differential distribution of sex steroid receptors in the ARC and the PVe is likely to account for the different pattern of GH secretion in male and female animals. 5. Growth hormone itself is able to inhibit the amplitude of GH secretory episodes and to increase their frequency, by entering the brain (presumably by receptor-mediated internalization at the level of the choroid plexus) and acting subsequently on ARC neurons. 6. At the pituitary level, major neurotransmitters regulating GH cells act on receptors of the VIP/PACAP/GHRH family and of the somatostatin family, in particular, sst2 and sst3. Those are coupled to accumulation of cAMP as a second messenger. 7. In addition, patch-clamp experiments and measurement of intracellular Ca2+ indicate that GH cells present characteristic, GHRH-dependent, but self-maintained Ca2+ spikes and [Ca2+]i transients, which reflect adaptive mechanisms to constraints of episodic release. 8. Recent data on transcription factors affecting GH gene expression and somatotrope differentiation are also summarized. 9. Regulation and differentiation of somatotropes also depend upon paracrine processes within the pituitary itself and involve growth factors and several neuropeptides, for instance, vasoactive intestinal peptide, angiotensin 2, endothelin, and activin. 10. Finally, characteristic changes occur in the GH secretory pattern under discrete, pathological conditions, such as abnormal growth and dwarfism, diabetes, and acromegaly, as well as during inflammatory processes.
Cell Mol Neurobiol 1998 Feb
PMID:Hypothalamic and hypophyseal regulation of growth hormone secretion. 952 32

Thyroid hormone receptors can act through response elements (TREs) having a wide variation of sequence. We screened for transcription factors that bind the rat (r) glycoprotein hormone alpha-subunit TRE (alpha-sub), and isolated a cDNA, termed zinc finger homeodomain enhancer-binding protein (Zfhep), which encodes two separate zinc finger domains (ZD1 and ZD2), and a region similar to homeodomains. DNA-binding assays show that ZD1 or ZD2 can bind the alpha-subunit, rat growth hormone, or thyrotropin beta (TSHbeta) gene TREs, but do not bind DR4 or palindromic (pal) TREs. Methylation interference footprinting demonstrates that Zfhep binds the alpha-sub overlapping the TR-binding site. Similarly, the ZD1 protein footprints over TR-binding halfsites of the rat growth hormone (rGH) and TSHbeta TREs. Hence, Zfhep binding is dependent on sequences within and outside the AGGTCA TR-binding halfsite. Interactions of non-receptor transcription factors (such as Zfhep) with certain TREs are important to modify gene-specific regulation by thyroid hormones.
Mol Cell Endocrinol 1998 Apr 30
PMID:A zinc finger homeodomain transcription factor binds specific thyroid hormone response elements. 970 71

Hypothyroidism was induced in a group of male Fischer 344 rats by administration of 0.05% propylthiouracil (PTU) in the drinking water for 12 weeks. Control rats were not treated. Plasma levels of thyroid hormones indicated that PTU treatment had produced severe thyroid hormone deficiency. In PTU-treated rats compared to control rats, levels of total T3 and total T4 were reduced 54.5% and 53.7%; while levels of free T3 and free T4 were reduced 87.1% and 96.5%. Functional hypothyroidism was demonstrated by: (i) a 49.1% decrease in hepatic plasma membrane alpha1-adrenergic receptor binding, and (ii) a 11.2-fold increase in hepatic gamma-glutamyltranspeptidase activity; relative to the expression of these parameters in control rats. Membranes were isolated from hippocampi of control, PTU-induced hypothyroid and thyroxine-replaced rats and specific adrenergic receptor binding determined by radioligand binding techniques. Hypothyroidism resulted in a shift in the balance of alpha1 and beta2 adrenergic receptor binding by evoking: an increase in alpha1-adrenergic receptor binding to 1.57-fold of control levels; and, a decrease in beta2-adrenergic receptor binding to 64% of control levels. Thyroid hormone replacement carried out in PTU-treated hypothyroid rats at 30 microg/kg s.c. per day for the last 3 days of the 12 week PTU-treatment protocol, which reversed physical and functional hypothyroidism, reversed the observed changes in hippocampal adrenergic receptor binding, indicating them to be thyroid hormone, and not PTU, -dependent. This receptor shift evoked by hypothyroidism may, in part, explain the protective effect of hypothyroidism on ischemia-induced hippocampal damage by favoring inhibitory input and limiting excitotoxic input by catecholamines.
Mol Cell Biochem 1998 Aug
PMID:Hypothyroidism-evoked shifts in hippocampal adrenergic receptors: implications to ischemia-induced hippocampal damage. 974 22

This paper discusses the mechanisms of two basic effects of thyroid hormones on atrial responses to beta-adrenergic agonists, i.e. increased inotropic sensitivity and decreased maximal contractile responsiveness. The increased sensitivity of atria to beta-adrenergic agonists under thyroid hormones appears to be related to increases in beta-adrenoceptor density and Gs/Gi protein ratio, leading to activation of Gs-mediated pathway, but suppression of Gi-mediated pathway of adenylate cyclase regulation. Therefore, the i/c concentrations of cAMP and corresponding inotropic responses achieve their maximums at lower doses of beta-adrenergic agonist. Thyroid hormones also decrease the expression of phospholamban, but increase the expression of sarcoplasmic reticulum Ca2+-pump. As a result, the basal activity of sarcoplasmic reticulum Ca2+-pump increases, but its beta-adrenergic activation through phosphorylation of phospholamban decreases. It is suggested that these changes are causal for decreased maximal inotropic and lusitropic responses of atria to beta-adrenergic agonists.
Mol Cell Biochem 1998 Jul
PMID:Mechanisms of thyroid hormone control over sensitivity and maximal contractile responsiveness to beta-adrenergic agonists in atria. 974 36

Thyroid hormone plays an important role in brain development, in part by regulating myelination. Previous studies have shown that the myelin basic protein (MBP) promoter is activated by thyroid hormone (T3) via a T3-response element (T3RE) at position -186. Surprisingly, although MBP levels are initially decreased in hypothyroid neonates, they approach later control levels, in most brain regions, despite persistent hypothyroidism. We have studied the T3-independent transcriptional regulation of this gene, using transient transfection assays. We found that, in the absence of T3, the RXR ligand, 9-cis-retinoic acid (9cRA) was able to stimulate transcription of the MBP promoter in a dose-dependent manner. This activation was unaffected by the mutation or deletion of the T3RE and required DNA sequences located between positions -162/+60. Accordingly, this MBP promoter fragment bound RXR in vitro. The 9cRA-dependent activation of the MBP promoter required the presence of both, the DNA binding and the ligand-dependent transactivation domain (AF-2) in RXR. Furthermore, as T3, 9cRA was able to stimulate MBP expression in the CG-4 cell line after differentiation to oligodendrocytes and increased the number of cells expressing the MBP protein in primary rat optic nerve glial cell cultures.
Brain Res Mol Brain Res 1999 Jan 22
PMID:Stimulation of the myelin basic protein gene expression by 9-cis-retinoic acid and thyroid hormone: activation in the context of its native promoter. 988 31

Thyroid hormone-induced ventricular hypertrophy is characterized by the absence of fibrosis. Previously, we demonstrated that thyroid hormone inhibits collagen type I gene expression in the myocardium and in cardiac fibroblasts. We also demonstrated that thyroid hormones act as inhibitor of pro alpha1(l) collagen promoter activity. In this study we determined the sequences on pro alpha1(l) collagen gene and transcription factors in cardiac fibroblasts involved in the inhibitory effect of 3,3',5-triiodothyronine (T3). Transient transfection of cells with chloramphenicol acetyl transferase (CAT)-linked deletion mutants of pro alpha1(l) collagen promoter demonstrated that the inhibitory effect of T3 is transmitted via proximal sequences(-225/+115). Gel shift analysis using [32P]-labeled -225/+115 gene fragment and nuclear proteins of cardiac fibroblasts showed T3-induced DNA binding by two proteins. Analysis of non-overlapping restriction sub-fragments by gel shift along with supershift analysis with antibodies to types alpha and beta thyroid hormone receptors identified the lower molecular weight DNA-binding protein as beta receptor and confirmed that the T3-induced protein-DNA binding sites are located at -15/+115. Selective base mutation (C in place of G at +93 and G in place of C at +97) in the activator protein-1 (AP-1) core binding motif(+92/+97) abolished the higher molecular weight T3-induced DNA-protein complex obtained with [32P]-labeled wild type sequences (-225/+115). Additional gel shift analyses using an oligonucleotide containing the AP-1 core binding motif, as an unlabeled competitor and as [32P]-labeled probe, confirmed the T3-induced protein binding to an AP-1 site. Transient transfection with CAT-linked -225/+115 sequences in which the AP-1 site was mutated abolished the T3-induced inhibition of CAT activity. Together, these findings identify sequences necessary for T3-induced inhibition of collagen type I promoter to which thyroid hormone receptor type beta and protein(s) with affinity for AP-1 element bind. They also demonstrate that the AP-1 response element located on these sequences is necessary for T3-induced inhibition of pro alpha1(l) collagen promoter activity. These data identify molecular mechanisms involved in thyroid hormone-induced inhibition of collagen expression in the heart.
J Mol Cell Cardiol 1998 Nov
PMID:An activator protein-1 (AP-1) response element on pro alpha1(l) collagen gene is necessary for thyroid hormone-induced inhibition of promoter activity in cardiac fibroblasts. 992 84

The immunological mechanisms leading to Graves' disease are not yet fully understood. The athymic nude mouse has immunological properties which allow in vivo studies concerning autoimmune thyroid diseases with special regard to the interaction of TSH, TSH receptor antibodies, cytokines, antithyroid drugs, TSH receptor antagonists and human lymphocytes. In our own studies thyroid tissues of patients with Graves' disease, toxic adenomas and non-toxic nodular goiter were xenotransplanted to athymic nude mice. Histology, morphology and function of the transplants were examined 2 days to 2 weeks after injection of bovine TSH, interferon-gamma, Graves' sera with or without addition of a TSH-receptor antagonist and lymphocytes of patients with Graves' disease. Thyroid transplants can be stimulated by TSH, interferon-gamma, Graves' sera and immunoglobulin G. Additional treatment with asialoagalacto-hCG inhibits stimulation of the immunoglobulin. Furthermore, preliminary results show, that engrafted peripheral and especially intrathyroidal lymphocytes from patients with Graves' disease specifically migrate into human thyroid transplants ("homing") and are able to induce functional and histological changes in these tissues. In summary, the xenotransplantation model is well suited for studies concerning pathogenesis, diagnosis and therapy of autoimmune thyroid diseases.
J Mol Med (Berl) 1999 Jan
PMID:Graves' disease: xenotransplantation model (athymic nude mice). 993 Sep 60

Background: Thyroid tumors have mutations of the ras oncogenes, although the prognostic and diagnostic significance of this remains unclear. Usually, thyroid follicular adenoma, follicular carcinoma, and papillary carcinoma are easy to differentiate histologically. Occasionally, follicular carcinoma may be difficult to separate from the follicular variant of papillary carcinoma, and a molecular test to help differentiate the two would be critical, as their behavior and clinical management differ. In earlier reports, K- ras mutations have been suggested as such a marker. Methods and Results: To study genetic differences between thyroid tumors, the authors examined 79 cases (58 papillary carcinomas, 12 follicular carcinomas, and 9 adenomas) for the presence of a K-ras mutation in codon 12 by polymerase chain reaction and restriction endonuclease digestion. Only six papillary carcinomas (12%) showed a K-ras mutation; no mutations were detectable in the other thyroid tumors. Conclusion: K-ras mutation analysis does not help differentiate thyroid tumor types.
Mol Diagn 1998 Sep
PMID:Can Different Thyroid Tumor Types Be Distinguished by Polymerase Chain Reaction-Based K-ras Mutation Detection? 1008 71


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