Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of immunoglobulin preparations from hyperthyroid Graves' disease patients on primary cultures of thyroid cells have been studied at the mRNA level. Autoantibodies to the thyrotropin (TSH) receptor from these patients, which had been initially characterized by their ability to stimulate adenylate cyclase and inhibit the binding of radiolabelled TSH to thyroid membrane preparations, were studied for their effects on thyroglobulin and thyroid peroxidase mRNA levels. Incubation of thyroid cells with TSH receptor autoantibodies from different Graves' disease patients for 48 h led to time- and dose-dependent increases in the levels of thyroid peroxidase and thyroglobulin mRNA in primary cultures of thyrocytes. The incomplete correlation between G protein-linked adenylate cyclase activation and thyroid mRNA elevation indicates the possibility of the involvement of alternative second messenger pathways in the regulation of thyroid cell function and differentiation.
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PMID:Autoantibody stimulation of the human thyrotropin receptor: regulation of adenylate cyclase activity, thyroglobulin and thyroid peroxidase mRNA levels in primary cultures of Graves' thyroid tissue. 191 36

Iodide inhibits cyclic AMP accumulation in the thyroid by a process which is prevented by inhibition of iodide uptake and of thyroid peroxidase. By a similar process, it also exerts other independent effects such as the enhancement of iodinated protein release. Iodide inhibited the stimulation of adenylate cyclase by prostaglandin E1, cholera toxin and forskolin. The action of iodide was not relieved by phosphodiesterase inhibitors and was not additive with the effect of norepinephrine or adenosine. Iodide did not decrease the cellular level of ATP. The data are compatible with an inhibition of adenylate cyclase beyond the level of the receptor, presumably at the level of the catalytic unit or its interaction with the positive transducing unit NS. The effect of iodide required TSH for its expression but not for its installation. It was decreased under all conditions in which iodide organification was decreased: decreased iodide or increased methimazole concentration, absence of calcium in the medium, etc. However, the relation between iodide binding to proteins and effect was not linear. The effect was not relieved by washing in the absence of iodide and in the presence of perchlorate, but it was partly reversible in the presence of methimazole propylthiouracyl or thiourea. It was not relieved by cooling to 20 degrees C and cytochalasin b, which block stimulated thyroglobulin hydrolysis and iodothyronine release, nor by actinomycin D, cycloheximide, puromycin, mepacrine or indomethacin. The data suggest that iodide binds to a saturable cell component by a reaction which is reversible only in the presence of thiol-containing drugs.
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PMID:Further characterization of the iodide inhibitory effect on the cyclic AMP system in dog thyroid slices. 240 38

The expression of the microsomal (M) antigen on the surface and in the cytoplasm of a strain of rat thyroid cells (FRTL-5) is under the regulation of TSH. In the present report the mechanism by which TSH induces such expression was investigated with the use of human microsomal antibody-positive serum and an indirect immunofluorescence technique. Studies were also performed to ascertain whether the M antigen of FRTL-5 cells could be identified with thyroid peroxidase (TPO), as suggested by recent data obtained in human thyroid tissue. Preabsorption experiments showed that, like solubilized human thyroid microsomes, purified human TPO completely abolished the binding of microsomal antibody to FRTL-5 cells. No inhibition was obtained by preabsorption with control human tissues (placenta, liver, and spleen) or human thyroglobulin, indicating that the antigen recognized by microsomal antibody in FRTL-5 cells was TPO. After 72 h of TSH withdrawal from the culture medium the M/TPO antigen disappeared from the surface and the cytoplasm of FRTL-5 cells. Readdition of TSH (250 microU/ml) to the culture medium of cells lacking the M/TPO antigen elicited its reappearance within 24-48 h. This effect of TSH was prevented by 10 microM cycloheximide or 0.5-5 micrograms/ml actinomycin D. Two well known stimulators of the adenylate cyclase-cAMP system, cholera toxin and forskolin, mimicked TSH in inducing the reappearance of the M/TPO antigen. A similar effect was observed with use of the phosphodiesterase inhibitor isobutylmethylxanthine. Reappearance of M/TPO antigen was also produced by the cAMP analog 8-bromo-cAMP. The tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate, which stimulates thyroid cell growth through a cAMP-independent pathway, was ineffective in inducing the M/TPO antigen in FRTL-5 cells. The present data indicate that 1) thyroid peroxidase accounts for most, if not all, of the microsomal antigen of FRTL-5 cells; and 2) TSH modulates the expression of the M/TPO antigen in FRTL-5 cells by a mechanism that involves cAMP production and requires mRNA formation and subsequent protein synthesis.
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PMID:Studies on the mechanism responsible for thyrotropin-induced expression of microsomal/peroxidase antigen in FRTL-5 cells. 245

Humoral and cellular immune responses are both involved in autoimmune disorders of the thyroid gland. In the last five years, new substantial data have been obtained on the nature and the expression of thyroid cell surface autoantigens and on the demonstration of the functional heterogeneity of autoantibodies to the thyroid stimulating hormone (TSH) receptor. In the present report, attention will be mainly focused on recent studies carried out in our laboratory. The main autoantigens so far identified include the 'microsomal' antigen, thyroglobulin and the TSH receptor. For many years the 'microsomal' antigen (M) was considered a poorly characterized constituent of the cytoplasm of the thyroid cell. In the last five years, several lines of evidence were provided indicating that M is also well represented on the surface of the follicular cell and is identical to thyroid peroxidase (TPO). The use of anti-TPO monoclonal antibodies, presently available, have confirmed this antigenic identity. Microsomal (anti-TPO) antibodies are very useful markers of autoimmune thyroid disorders and are generally present in Hashimoto's thyroiditis, idiopathic myxedema and Graves' disease. TSH receptor antibodies (TRAb) are present in the sera of patients with Graves' disease. TRAb are able to stimulate thyroid adenylate cyclase and also to mimic TSH in its thyroid growth stimulation. Thus, these antibodies may have a pathogenetic role in goiter formation and in thyroid hyperfunction in Graves' disease. TRAb were also shown to inhibit both TSH binding to its receptor and TSH-stimulated adenylate cyclase activity. Recently TRAb, which inhibited TSH-stimulated adenylate cyclase activity, were found in idiopathic myxedema patients and may be responsible for impairment of thyroid function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thyroid autoantigens and their relevance in the pathogenesis of thyroid autoimmunity. 249 24

In this review new data are reported indicating that the thyroid microsomal-microvillar antigen can be identified with thyroid peroxidase (TPO). This concept derives from binding studies of monoclonal and polyclonal microsomal antibodies to TPO purified by affinity chromatography or obtained by recombinant DNA technology. Furthermore, immunofluorescence studies performed on cultured thyroid cells have shown the presence of a TPO-related antigen on the surface of the cells. The expression of the TPO antigen is modulated by TSH through the cAMP pathway. The functional activities of TSH receptor autoantibodies have also been characterized. From these studies the following conclusions can be drawn: (i) TSH receptor antibodies possess multiple biological activities, interfering or mimicking TSH actions; (ii) a good correlation is observed between stimulation of adenylate cyclase and of iodide uptake by Graves' IgG. In these IgG preparations, adenylate cyclase- and growth-stimulating activities cannot be separated; (iii) antibodies blocking the TSH-dependent AC are present in patients with autoimmune hypothyroidism; (iv) a mixture of stimulating and blocking antibodies may coexist in the same patient, whose clinical status may result from the sum of the biological activities of these antibodies. Finally, new data are reported on the identification and characterization of T cell clones infiltrating the thyroid tissue of subjects with thyroid autoimmune disorders. The majority of these clones were CD8+ cytolytic T cells with natural killer activity. These latter data may be of importance in the mechanisms of thyroid damage observed in Hashimoto's glands.
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PMID:Recent advances in the understanding of humoral and cellular mechanisms implicated in thyroid autoimmune disorders. 264 70

In the present report the mechanisms responsible for the expression of the thyroid microsomal autoantigen (M-Ag) were studied in primary cultures of human thyroid cells prepared from Graves' or non-toxic goitres. The indirect immunofluorescence (IFL) technique using human sera positive for anti-microsomal antibody (anti-MAb) was employed to detect M-Ag. Studies were performed to ascertain whether M-Ag recognized by anti-MAb could be identified with thyroid peroxidase (TPO). Preabsorption experiments showed that, similarly to solubilized thyroid microsomes, purified human TPO abolished the binding of anti-MAb to thyrocytes, while no inhibition was obtained with control human tissues. The identity of M-Ag and TPO was also demonstrated using a double layer IFL technique which allowed a simultaneous staining of the antigen(s) recognized by anti-MAb and by a monoclonal anti-TPO antibody. After 5-15 days of TSH withdrawal from the culture medium the M/TPO-Ag disappeared from the surface and the cytoplasm of human thyroid cells. Readdition of TSH (0.1-100 mU/ml) to cells lacking M/TPO-Ag elicited its reappearance within 48-72 h. This effect of TSH was prevented by 10 microM cycloheximide but not by methimazole (0.1-2 mM). Two stimulators of the adenylate cyclase-cAMP system, cholera toxin and forskolin, and 8-bromo-cAMP mimicked TSH in inducing M/TPO-Ag. Thyroid stimulating antibody (TSAb) of Graves' disease also reproduced the effect of TSH on M/TPO-Ag reexpression in human thyroid cells. By contrast, epidermal growth factor, oestradiol or NaI were ineffective in inducing M/TPO-Ag. The present data indicate that: (i) the expression of M/TPO-AG in human thyroid cells is dependent on TSH stimulation, through pathways which involve cAMP production and protein synthesis, (ii) TSAb reproduces this effect of TSH; (iii) oestradiol and NaI have no direct influence on the expression of M/TPO-Ag.
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PMID:The expression of the microsomal/peroxidase autoantigen in human thyroid cells is thyrotrophin-dependent. 266 Oct 62

The enzyme thyroid peroxidase (TPO) plays a central role in thyroid hormone synthesis and is the target for the autoimmune attack in lymphocytic thyroiditis. We have examined the activation of the TPO gene in cultured human thyrocytes using slot-blot hybridization with a synthetic 40 mer oligonucleotide probe derived from the nucleotide sequence of the human TPO gene. The oligonucleotide probe was shown by Northern blotting to hybridize specifically to an approximately 3 kb RNA species from thyroid tissue of patients with Graves' disease, but not to RNA preparations from human or bovine retinal tissue, providing compelling evidence for the specificity of the probe for TPO mRNA. Addition of TSH (10 mU/ml) to primary thyroid cultures for 4 h led to increased TPO mRNA levels which were maximal after 48 h and significantly higher than basal even after 7 days of co-culture. Activation of TPO mRNA by TSH showed dose dependency over a wide range (0.01-100 mU/ml), with a maximal effect at 10 mU TSH/ml in cells cultured for a period of 72 h. Comparison of TPO mRNA levels with the accumulation of thyroglobulin mRNA levels following stimulation by TSH indicated that the induction of the gene encoding thyroglobulin precedes transcription of the TPO gene. The adenylate cyclase activator forskolin (1-100 microM) mimicked TSH in increasing TPO mRNA levels whilst, in contrast, the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA; 0.01-1 microM) led to levels of TPO mRNA that were lower than basal. Thus TSH induces a specific dose-dependent activation of TPO mRNA which is mimicked by agents which increase cyclic AMP. In contrast, TPA-induced activation of protein kinase C inhibits this response.
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PMID:Activation of the thyroid peroxidase gene in human thyroid cells: effect of thyrotrophin, forskolin and phorbol ester. 274 42

Within the last decades multiple iodolipid-classes have been identified in thyroid tissue. For a long time they have been supposed to be involved in thyroid autoregulation, but for the time being no specific compounds could be isolated. A new approach was stimulated by the finding that thyroid cells were able to iodinate polyunsaturated fatty acids to form iodolactones and by the identification of alpha-iodohexadecanal (alpha-IHDA) as the major compound of an iodolipid fraction. alpha-IHDA exerts multiple inhibitory effects on adenylate cyclase, NADPH-oxidase and thyroid peroxidase. Therefore, it is speculated as a mediator of the Wolff-Chaikoff-effekt and to be involved in the autoregulation of specific thyroid functions mediated by the cyclic adenosine-3',5'-monophosphate (cAMP)-pathway. Meanwhile 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid delta-lactone (delta-iodolactone) has been identified in human thyroid tissue and it could be demonstrated that this iodoeicosanoid specifically inhibits signal transduction pathways induced by local growth factors such as epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Therefore, delta-iodol-actones seem to act as mediators of iodine, especially in the autoregulation of cAMP-independent thyroid cell proliferation. We will summarize these important new findings and discuss the role of these iodolipids on thyroid cell growth regulation.
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PMID:Iodolactones and iodoaldehydes--mediators of iodine in thyroid autoregulation. 898 Oct

Thyroperoxidase-catalyzed iodination of thyroglobulin and subsequent oxidative coupling of iodinated tyrosyl residues to protein-bound iodothyronines are the key reactions in thyroid hormone biosynthesis. Under sufficient iodine supply, both synthesis steps are rate-limited by the availability of hydrogen peroxide (H(2)O(2)), which is required as final electron acceptor. The primary enzyme feeding H(2)O(2) to thyroid peroxidase is a heterodimeric NADPH oxidase complex of dual oxidase 2 (DUOX2) and DUOX maturation factor 2 (DUOXA2) at the apical plasma membrane. While the thyrotropin receptor mediates most biological effects through the Gs/adenyl cyclase/cAMP pathway, the Gq/phospholipase C-beta cascade induces H(2)O(2) generation via synergistic effects of increased intracellular calcium and protein kinase C activation on DUOX2/DUOXA2. Defects in thyroidal H(2)O(2) generation have been identified in a subset of patients with congenital hypothyroidism. These include loss-of-function mutations in DUOX2 and DUOXA2. Thyrotropin receptor mutations with preferential loss of Gq-coupling may indirectly affect H(2)O(2) production. Expressivity of the defects can be highly variable owning to the presence of genetic modifiers (e.g., the paralogs DUOX1 and DUOXA1), and environmental factors particularly nutritional iodide intake.
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PMID:Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism. 2012 87