Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iodide uptake, which is necessary for thyroid hormone synthesis, can be inhibited by aging, withdrawal of TSH, or increased tumor necrosis factor (TNF) and transforming growth factor (TGF)-beta1 levels resulting from the nonthyroid illness syndrome. TNF induces receptor-mediated activation of sphingomyelinase, which converts sphingomyelin to ceramide, a mediator of TNF actions. Thyroid follicular cells transport iodide from blood into the follicular lumen against an iodide gradient by means of coupled transport of Na+ ions and I- ions via the Na+/I- symporter (NIS). An inward Na+ gradient is maintained by Na+/K+-ATPase. The recent cloning and sequencing of the rat NIS complementary DNA has made possible studies on the mechanism by which TSH, aging, and cytokines regulate I- uptake by thyroid cells. Young (<20 passages) and aged (>40 passages) FRTL-5 cells grown with or without TSH were treated with various concentrations of TNF, TGF-beta1, sphingomyelinase, or ceramide. NIS messenger RNA (mRNA) levels in aged cells were only 2% of those in young cells. Withdrawal of TSH from young cells reduced NIS mRNA levels by more than 90%. TNF reduced NIS mRNA levels in young cells grown with TSH at t1/2 = 0.62 days, a cycloheximide inhibitable effect. Similar treatments with TGF-beta1, sphingomyelinase, or ceramide reduced NIS mRNA by 70-90%. Ceramide reduced 125I(-)-uptake by 50%. The addition of TNF increased both the sphingomyelin and ceramide levels 3- to 5-fold in young and old cells. We conclude that 1) the decline in iodide uptake due to aging, a fall in serum TSH or an increase in TNF or TGF-beta1 is mediated primarily by a reduction in thyroid NIS expression; and 2) that receptor-mediated activation of sphingomyelinase is an important, protein synthesis-dependent, intracellular pathway for inhibition of NIS expression by TNF.
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PMID:Tumor necrosis factor, ceramide, transforming growth factor-beta1, and aging reduce Na+/I- symporter messenger ribonucleic acid levels in FRTL-5 cells. 944 44

The recently cloned sodium-iodide symporter (NIS) represents a key molecule for thyroid function by efficiently accumulating iodide from the circulation into the thyrocyte against an electrochemical gradient. This uptake requires energy, is coupled to the action of Na+/K+-ATPase, and stimulated by TSH, the main hormone regulating thyroid-specific functions. NIS mutations are found in congenital hypothyroidism, and potential defects in the NIS gene, its expression, or function of the NIS protein are currently under investigation in various thyroid diseases. Increased NIS expression has been found in autonomous adenoma and Graves' disease, decreased levels of NIS protein and/or mRNA were observed in Hashimoto's disease, cold nodules, most thyroid cancers and cell lines derived therefrom. Autoantibodies directed against NIS have been identified in autoimmune thyroid disease and blocking antibodies isolated from sera of patients with Hashimoto's disease inhibit NIS function in NIS-transfected CHO cells. NIS mRNA expression can be up-regulated by retinoic acid in human thyroid carcinoma cell lines whereas retinoic acid treatment decreases NIS expression and function in differentiated rat thyroid FRTL-5 cells. Apart from thyrocytes, NIS is also expressed in other tissues known to transiently accumulate radioiodide, albeit at much lower levels, requiring RT-PCR for detection of the transcript. Diagnostic and therapeutic implications of the recent cloning of the human NIS gene such as development of NIS-directed drugs, ligands, antibodies, vaccines, gene therapeutic approaches combining NIS targeting and expression together with the long-established, efficient and safe method of radioiodide therapy are discussed both for application to thyroid related diseases and carcinoma, and non-thyroid benign and malignant diseases. Apart from these therapeutic and diagnostic perspectives the availability of the NIS gene will also open new opportunities to develop sensitive and homologous diagnostic test systems to identify factors involved in autoimmune thyroid disease, evolution of goitre, adenoma and thyroid cancer as well as NIS-directed new drugs. Advanced and sophisticated molecular diagnostic approaches (RT-PCR from fine needle aspirations, screening for mutations, analysis of gene defects) are already developed for NIS and will complement or overcome some established procedures in thyroid diagnostics.
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PMID:Implications of the molecular characterization of the sodium-iodide symporter (NIS). 986 44

Na+ K+ ATPase located at the basolateral pole of thyroid epithelial cells, contributes to thyroid hormone synthesis by generating the driving force for the uptake of the substrate, iodide. We have investigated whether the expression of the alpha- and beta-subunits and activity of Na+ K+ ATPase were subjected to variations in response, (a) to TSH, that controls the expression of differentiation in thyroid cells and (b) to thyroid hormones as potential autocrine factors. Studies were carried out on pig thyroid cells cultured (a) without TSH to obtain thyroid cell monolayers (TCM) in basal state or (b) with TSH in the form of cell monolayers (TCM-T) or as reconstituted thyroid follicles (RTF). Iodide uptake activity, thyroperoxidase protein and thyroglobulin mRNA taken as parameters of thyroid cell differentiation were 6 to 25-fold higher in RTF and TCM-T than in TCM. Western blot analyses of Na+ K+ ATPase subunits revealed that the alpha-subunit (105 kDa) content of TCM-T and RTF was similar but 8-fold higher than that of TCM. In contrast, the beta-subunit (50 kDa) content of TCM-T and RTF was only about twice that of TCM. Similar relative variations were observed at the mRNA level for both alpha- and beta-subunits. Na+ K+ ATPase activity was only 40% higher in RTF and TCM-T than in TCM. A 48 h treatment of RTF by either T4 or T3 (1-100 nM) induced a 3-fold increase of the alpha-subunit but did neither alter the beta-subunit nor the Na+ K+ ATPase activity. In conclusion, Na+ K+ ATPase activity and the level of expression of its beta-subunit, known to control the assembly and targetting of alpha-beta oligomers and thus the amount of functional sodium pump at the plasma membrane, are only moderately altered when thyroid cells undergo major changes in their differentiation status. Our data show that the expression of the alpha-subunit of Na+ K+ ATPase by thyroid cells is up-regulated by TSH and thyroid hormones.
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PMID:Expression of alpha- and beta-subunits and activity of Na+K+ ATPase in pig thyroid cells in primary culture: modulation by thyrotropin and thyroid hormones. 1002 67

Thyroid hormones influence the function of many organs and mediate their diverse actions through two types of thyroid hormone receptors, TRalpha and TRbeta. Little is known about effects of ligands that preferentially interact with the two different TR subtypes. In the current study the comparison of the effects of the novel synthetic TRbeta-selective compound GC-1 with T3 at equimolar doses in hypothyroid mice revealed that GC-1 had better triglyceride-lowering and similar cholesterol-lowering effects than T3. T3, but not GC-1, increased heart rate and elevated messenger RNA levels coding for the I(f) channel (HCN2), a cardiac pacemaker that was decreased in hypothyroid mice. T3 had a larger positive inotropic effect than GC-1. T3, but not GC-1, normalized heart and body weights and messenger RNAs of myosin heavy chain alpha and beta and the sarcoplasmic reticulum adenosine triphosphatase (Serca2). Additional dose-response studies in hypercholesteremic rats confirmed the preferential effect of GC-1 on TRbeta-mediated parameters by showing a much higher potency to influence cholesterol and TSH than heart rate. The preferred accumulation of GC-1 in the liver vs. the heart probably also contributes to its marked lipid-lowering effect vs. the absent effect on heart rate. These data indicate that GC-1 could represent a prototype for new drugs for the treatment of high lipid levels or obesity.
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PMID:The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. 1096 73

The effect of the phorbol esther phorbol myristate acetate (PMA) on iodide uptake was studied in primary cultures of calf thyroid cells. PMA caused a dose- and time-dependent inhibition of thyrotropin (TSH), forskolin, and db-cAMP stimulation, indicating an effect distal to both TSH receptor and cAMP generation. No action was found on iodide efflux, indicating a selective inhibition of iodide uptake. This inhibition was observed even after 5 minutes of incubation, thus excluding a possible genomic action. Bisindolmaleimide (BS), a specific inhibitor of the protein kinase C (PKC) pathway, reverted the effect of PMA. A similar degree of inhibition of the Na+/K+ adenosine triphosphatase (ATPase) and iodide uptake by PMA was found, thus suggesting a link between both parameters. These results indicate that the PKC pathway inhibits thyroid iodide uptake by an action distal to cAMP generation and probably because of a decrease in Na+/K+-ATPase activity.
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PMID:The protein kinase C pathway inhibits iodide uptake by calf thyroid cells via sodium potassium-adenosine triphosphatase. 1157 49

Thyroid hormone exerts its biological effect by binding to a TR. Both liganded and unliganded TRs regulate the transcription of T(3)-responsive genes. Cofactors with activating or repressing function modulate the transcriptional regulation by TRs. We showed that steroid receptor coactivator 1 (SRC-1)-deficient mice (SRC-1(-/-)) exhibit partial resistance to thyroid hormone at the level of the pituitary thyrotrophs. To determine whether SRC-1 deficiency affects globally T(3)-dependent transcriptional regulation, we studied the effects of thyroid hormone deprivation and replacement on the expression of several genes in different tissues of SRC-1(-/-) and wild-type mice (SRC-1(+/+)). Thyroid hormone deficiency was induced by a low iodine diet (LoI) supplemented with propylthiouracil (PTU) for 2 wk. L-T(3) was injected ip for the last 4 d in one group (PTU+T(3) group), and another group (PTU group) received only vehicle. Levels of mRNAs for T(3)-responsive genes were determined by Northern blotting: GH and TSH beta in pituitary; type 1 iodothyronine 5'-deiodinase, spot 14 (S14), and malic enzyme in liver; and sarcoplasmic reticulum calcium adenosine triphosphatase 2 and myosin heavy chain alpha and beta in heart. Serum parameters, TSH, total cholesterol, creatine kinase, and alkaline phosphatase (AP), were also measured. Hypothyroidism produced a comparable increase in TSH beta mRNA in both genotypes, but its suppression by L-T(3) was attenuated in SRC-1(-/-) mice. In contrast, hypothyroidism failed to reduce S14 mRNA levels in SRC-1(-/-) mice. As a consequence, the response to L-T(3) was not observed in these mice. SRC-1 deficiency had no effect on the expression of the rest of the T(3)-responsive genes examined. Of the four serum parameters, the T(3)-mediated decrease in TSH and changes in AP were attenuated in SRC-1(-/-) mice. We conclude that SRC-1 deficiency altered the expression of only some of the T(3)-responsive genes. SRC-1 appears to be involved not only in transcriptional activation by liganded TRs, but also in the suppression by liganded or unliganded TRs. Some of the effects of SRC-1 may be TR isoform specific.
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PMID:Steroid receptor coactivator-1 deficiency causes variable alterations in the modulation of T(3)-regulated transcription of genes in vivo. 1189 91

Vitamin E administration prevented DEHP induced deleterious effects like (i) degenerative changes in the brain and thyroid, (ii) decrease in the activity of neuronal membrane Na+ - K+ ATPase, (iii) decrease in the concentration of insulin, cortisol and TSH, and (iv) the increase in T3 and T4 in female Albino rats. The results suggest use of vitamin E to prevent harmful effects of repeated transfusion of DEHP containing blood as in thalassemia patient. The possibility of using vitamin E to prevent the harmful effects of repeated transfusion of DEHP containing blood, as in thalassemia patients, is discussed.
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PMID:Vitamin E prevents deleterious effects of di (2-ethyl hexyl) phthalate, a plasticizer used in PVC blood storage bags. 1546 79

Expression of sodium/iodide symporter (NIS) by thyroid epithelial cells is primarily regulated by TSH, which acts at the level of NIS gene transcription. Knowledge of the mechanisms governing NIS expression mainly comes from studies of rat thyroid-derived cell lines forming cell monolayers. In this study we investigated the impact of the three-dimensional organization of thyroid cells into follicles on the regulation of NIS expression. We used porcine thyrocytes in primary culture that, depending on cell density and the moment TSH is added, either predominantly form a cell monolayer (CM) or reconstitute thyroid follicles (RTF). NIS expression analyzed at transcript and protein levels was remarkably high in RTF compared with CM. Cells forming RTF were NIS positive, whereas in CM, NIS was only detected in the limited number of cells forming follicle-like structures. When thyrocytes were cultured at increasing cell density to obtain a gradual shift from CM to RTF, the progressive increase in the proportion of cells enrolled in RTF was accompanied by a parallel increase in NIS expression. Other TSH-regulated genes, thyroperoxidase, Na(+),K(+)-adenosine triphosphatase alpha-subunit, and thyroglobulin, were expressed at similar levels whatever the organization of thyrocytes in culture. The transcription factor, Pax-8, was equally expressed in NIS-negative CM and NIS-positive RTF. We show that TSH highly activates NIS expression only when thyrocytes have undergone histiotypic morphogenesis. This finding suggests that TSH activation of NIS gene transcription might involve, in addition to Pax-8, a regulatory factor(s) whose synthesis and/or activity are triggered by cell-cell interaction(s) occurring in the course of folliculogenesis.
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PMID:Three-dimensional organization of thyroid cells into follicle structures is a pivotal factor in the control of sodium/iodide symporter expression. 1633 5

Acrylamide (ACR) is an industrial neurotoxic chemical that has been recently found in carbohydrate-rich foods cooked at high temperatures. ACR was designated as a probable human carcinogen by IARC (1994) and USEPA (1988). Panax ginseng extract has efficacies such as anticancer, antihypertension, antidiabetes and antinociception. The objective of the current study is to evaluate the protective effects of Panax ginseng extract against ACR-induced toxicity in rats. Sixty adult Sprague Dawley female rats were divided into six groups included a control group, a group treated orally with ACR (50 mg kg(-1) body weight; b.w.) for 11 days, a group treated orally with Panax ginseng extract (20 mg kg(-1) b.w.) for 11 days and groups treated orally with Panax ginseng for 11 days before, during or after 11 days of ACR treatment. The results indicated that treatment with ACR alone resulted in a significant increase in lipid peroxidation level and LDH activity in brain homogenate as well as in serum CK activity, whereas it caused a significant decrease in SOD activity and a small but statistically insignificant decrease in Na(+)K(+)-ATPase activity in brain homogenate. Serum serotonin, corticosterone, T3, T4, TSH, estradiol, progesterone and plasma adrenaline were significantly decreased in ACR-treated rats. Treatment with Panax ginseng before, during or after ACR treatment reduced or partially antagonized the effects induced by ACR towards the normal values of controls. It could be concluded that Panax ginseng extract exhibited a protective action against ACR toxicity and it is worth noting that treatment with Panax ginseng extract before or at the same time as ACR treatment was more effective than when administered after ACR treatment.
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PMID:Protective role of Panax ginseng extract standardized with ginsenoside Rg3 against acrylamide-induced neurotoxicity in rats. 1638 59

Sodium iodide symporter (NIS) is a transmembrane glucoprotein located in the basolateral membrane of the follicular thyroid cells, as well as in other normal and abnormal tissues such as the lactating mammary gland, well differentiated thyroid carcinoma and breast adenocarcinoma. It uses the electrochemical gradient generated by the Na-K ATPase to import an iodide molecule to the intracellular space along with two sodium molecules. The importance of NIS to diagnostic and research activities of Nuclear Medicine such as the radioiodine uptake, serum levels of TSH, TPO and TBG and thyroid diseases, especially cancer are described. NIS gene cloning in 1996 opened new prospective in diagnosis and treatment of thyroid and other diseases.
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PMID:[Sodium-iodine symporter in thyroid, normal and cancer tissues and its relation to nuclear medicine and to gene cloning treatment]. 1967 82


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