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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A patient with type I pseudohypoparathyroidism was found to have mild hypothyroidism. The patient had an elevated basal TSH level and an exaggerated TSH response to TRH. There was no goiter despite increased TSH levels, and the 131I thyroidal uptake was low before and after exogenous TSH administration. These studies suggested that the patient might have partial resistance to TSH. The binding of radioiodinated TSH to thyroid membranes obtained by biopsy was next studied. The displacement of iodinated TSH by unlabeled TSH was found to be identical to that in normal control membranes. The adenylate cyclase stimulation by a supramaximal dose of TSH, however, was blunted (120.1 +/- 11.5 vs. 387.2 +/- 40.3 pmol cAMP/min/mg protein), while basal and NaF-stimulated activities were quite similar to the activities in normal membranes. These findings suggested a lack of signal transmission between the TSH receptor and the catalytic unit. Incubation of control membranes with TSH and GTP resulted in a synergistic effect on the adenylate cyclase activity. This was not found with the patient's membranes and suggested that the coupling failure was due to a defective guanine nucleotide regulatory protein. We conclude that in this case of type I pseudohypoparathyroidism, the associated mild primary hypothyroidism was due to a partial TSH refractoriness caused by a coupling defect between the TSH receptor and adenylate cyclase. This observation suggests that a common pathogenetic mechanism might underly type I pseudohypoparathyroidism and its associated hypothyroidism.
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PMID:Coupling defect of thyrotropin receptor and adenylate cyclase in a pseudohypoparathyroid patient. 627 85

The localization of adenylate cyclase and 5'-nucleotidase activities in the follicular cells of adenomatous goiter and normal thyroid was studied by light and electron microscopy. Simultaneous biochemical measurement for both activities was carried out to confirm the histochemical findings. Adenylyl-imidodiphosphate (AMP-PNP) was used as an effective substrate for adenylate cyclase. The specificity of the adenylate cyclase reaction was also examined by adding oxalacetic acid or PCMB as an adenylate cyclase inhibitor, and by adding sodium fluoride or TSH as an adenylate cyclase stimulator to the reaction mixture. In the case of tissue from adenomatous goiter, a large amount of the reaction product of the adenylate cyclase activity was found uniformly in the apical and lateral plasma membrane and not in the basal plasma membrane. In the cases of normal thyroid, a small amount of the reaction product of adenylate cyclase activity was demonstrated, and only in the lateral plasma membrane of the follicular cells. On the otherhand, the histochemical localization of 5'-nucleotidase activity was the same in adenomatous goiter and normal thyroid. The reaction product of 5'-nucleotidase activity was found predominantly in the apical plasma membrane of the follicular cells. The biochemical findings indicated that the activity of adenylate cyclase per gram tissue was approximately 2 times higher in the case of adenomatous goiter than that in the case of normal thyroid, while the 5'-nucleotidase activity in adenomatous goiter was in slightly higher level than in normal thyroid. Thus the histochemically demonstrable amount of adenylate cyclase and 5'-nucleotidase reflected the activity levels measured biochemically. The lack of demonstrable adenylate cyclase activity in the basal plasma membrane suggests the possibility that this structure may not play any important role in TSH reception.
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PMID:Localization of adenylate cyclase and 5'-nucleotidase activities in human thyroid follicular cells. 628 89

The adenylate cyclase and 5'-nucleotidase activity was measured biochemically in the thyroid glands from patients with various thyroid diseases in comparison with normal thyroid. The basal adenylate cyclase activity in normal thyroid was 159.3 p-moles cAMP/min./g tissue. The activity was elevated to 230% of basal with 20 mM NaF and 190% of basal with 100 mU/ml TSH. These values in chronic thyroiditis and Graves' disease were not significantly different from the values of normal thyroid. In adenomatous goiter, adenoma and carcinoma, the basal adenylate cyclase activity was significantly higher than that of normal thyroid. Parallel to the biochemical determination of both enzyme activities, the distribution of histochemically demonstrable adenylate cyclase and 5'-nucleotidase activity was described in the follicular cells with normal and various thyroid diseases. The reaction product of adenylate cyclase and 5'-nucleotidase activity was restricted to the plasma membrane of the follicular cells. However, the distribution and intensity of the adenylate cyclase reaction varied in each thyroid disease, except for the absence of reaction product in the basal plasma membrane. The lack of demonstrable adenylate cyclase activity in the basal plasma membrane suggests the possibility that the basal plasma membrane may not play an important role of TSH-reception.
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PMID:Histochemical and biochemical study on adenylate cyclase and 5'-nucleotidase activity in thyroid glands with normal and various thyroid diseases. 631 19

Recent evidence suggests that epidermal growth factor (EGF) may play an important role in the regulation of thyroid growth and function. We have examined the interaction of murine EGF (mEGF) with human and porcine thyroid membranes and compared this with the binding of bovine TSH (bTSH) using 125I-labelled hormones as tracers. The characteristics of the binding of mEGF were found to be similar for human and porcine thyroid membranes. Epidermal growth factor bound with high affinity (affinity constant = 1.4 X 10(9) l/mol); the density of binding sites was low compared with the TSH receptor. At 37 degrees C, the binding of 125I-labelled EGF was maximal at 1 h and was saturable in the presence of unlabelled EGF; half-maximal inhibition was at 1 ng EGF/tube (0.5 nmol/l) using 0.5 mg membrane protein/tube. Unlabelled bTSH had no effect on the binding of labelled EGF. Similarly, unlabelled EGF did not affect the binding of labelled TSH; hence it was concluded that mEGF and bTSH bound to independent sites. Epidermal growth factor had no effect on adenylate cyclase activity in membranes prepared from human non-toxic goitre; increasing concentrations of EGF did not affect basal, TSH-stimulated or fluoride-stimulated enzyme activity.
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PMID:Interaction of epidermal growth factor with receptors on human and porcine thyroid membranes. 633 Feb 67

The thyrotropin receptor (TSHR) has been used as an example to illustrate how disease may be the consequence of: 1. Modifications or inappropriate production of the natural ligand. 2. Production of abnormal agonists or antagonists such as autoantibodies. 3. Modifications in receptor structure resulting in constitutive activation or the absence of activation following ligand binding. 4. Changes in the cellular machinery which transduces the signal from the receptor to the cytoplasmic or nuclear endpoint target. This chapter concentrates on mechanisms (2) and (3). Since the cloning of the TSHR it has been shown that approximately 50% of cases of toxic adenoma can be explained by somatic point mutations in the nucleotide sequence of the receptor gene which causes single amino acid substitutions. The resulting modified TSHR structure constitutively activates adenylate cyclase (via Gs), intracellular cAMP levels are increased and, since cAMP controls both growth and function of the human thyrocyte clonal expansion of the mutated cell ensues. Similarly, activating mutations of the TSH receptor gene in the germline are responsible for hereditary hyperthyroidism with goitre, which is transmitted in the autosomal dominant mode. Changes in receptor primary structure, i.e. a modified autoantigen, do not seem to be responsible for the escape from tolerance which must precede production of thyroid stimulating antibodies (TSAB) which cause hyperthyroid Graves' disease and thyroid blocking antibodies (TBAB) which are responsible for some cases of hypothyroid idiopathic myxoedema. The eukaryotic expression of wild-type, experimentally mutated and chimeric TSHR has enabled some progress in delineating the residues involved in binding TSH, TSAB and TBAB. All three ligands bind numerous discontinuous residues in the extracellular domain of the receptor. The difference between the bioactivity of TSAB and TBAB cannot be explained completely by different binding sites on the receptor. Subtle differences in, for example, glycosylation and sialation of the immunoglobulins may be implicated, since bioactivity of TSH itself seems to depend on these. Attempts to define T cell epitopes have not identified a major immunogenic region. Indeed heterogeneity seems to be a hallmark of TSHR autoantibodies (TRAB). The possibility that thyroid-associated ophthalmopathy and pretibial myxoedema may be receptor antibody diseases is discussed. Further progress awaits large-scale production of TSHR able to bind TSH to facilitate X-ray crystallographic studies, the development of specific T cell clones and the cloning of TSAB autoantibodies.
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PMID:The thyrotropin receptor as a model to illustrate receptor and receptor antibody diseases. 772

A role of thyroid autoimmunity in the pathogenesis of myxedematous endemic cretinism was suggested by reports indicating the presence of thyroid growth-blocking antibodies in the sera of these patients. To check this hypothesis, we searched for TSH receptor antibodies with thyroid growth-blocking or adenylate cyclase (AC)-inhibiting (TSH-blocking) activity in immunoglobulin G (IgG) from 18 euthyroid and 21 hypothyroid endemic cretins living in Italy and Peru. Among hypothyroid cretins, 12 had no palpable goiter. Stages I-III goiters were present in 12 of 18 euthyroid cretins. Controls included 25 euthyroid nongoitrous subjects living in the same endemic regions as cretins, and 10 normal subjects from an iodine-sufficient area. IgG from 4 selected patients with autoimmune atrophic thyroiditis and from 2 neonates with sporadic transient congenital hypothyroidism due to maternal TSH-blocking antibodies were included in the study. The blocking effect of the IgG was assessed in FRTL-5 cells by measuring TSH-stimulated [3H]thymidine incorporation, DNA accumulation, and AC activation. A radioreceptor assay was used to detect TSH-binding inhibiting antibodies (TBIAb). No IgG from hypothyroid endemic cretins without goiter contained TBIAb or inhibited TSH-stimulated cell growth or AC activation. The effect of IgG from hypothyroid nongoitrous cretins did not differ from that produced by IgG from hypothyroid cretins with goiter, euthyroid cretins with or without goiter, or normal controls. In contrast to these results, IgG from patients with autoimmune atrophic thyroiditis and from neonates with sporadic transient congenital hypothyroidism contained TBIAb that inhibited both TSH-stimulated cell growth and AC activation. In conclusion, our results indicate that, similar to other types of endemic cretinism, hypothyroid endemic cretins without goiter do not have TSH receptor antibodies able to inhibit TSH-stimulated thyroid cell growth or function. These observations argue against a role of humoral thyroid autoimmunity in the development of myxedematous endemic cretinism.
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PMID:Humoral thyroid autoimmunity is not involved in the pathogenesis of myxedematous endemic cretinism. 774 93

To study the growth control of human thyroid cells in different stages of differentiation, we established two human thyroid cell lines of adenomatous goiter and papillary carcinoma. A 59-year-old female patient with adenomatous goiter was operated in September 1991, and a 27-year-old female patient with papillary carcinoma in May 1990. The thyroid cell lines were established by successive passage without cellular or genetic manipulations such as fusing other cell lines or oncogenic viral infection. These cell lines, human adenomatous goiter cells (hAG) and human papillary thyroid carcinoma cells (hPTC), exhibited a flattened polygonal shape and proliferated as a monolayer in cell culture. The doubling time of the hAG cells was 60 h in Ham's F12 medium supplemented with 10% fetal bovine serum, and that of the hPTC cells, 18 h in the same medium. Both cell lines expressed mRNA for TSH receptor and secreted cAMP into the medium during incubation with thyrotropin (TSH) at concentrations as low as 0.01 mU/mL. The effects of activators of protein kinase A (PKA), protein kinase C (PKC), tyrosine kinase (TK), and estradiol (E2) on proliferation of the hAG cells and the hPTC cells were assessed by measuring cellular DNA content in 24-well plates with diaminobenzoic acid. TSH stimulated proliferation of the hAG cells, but it inhibited proliferation of the hPTC cells. Since TSH activates two signaling pathways, the adenyl cyclase-PKA system and phospholipase C-PKC system, we tested effects of dibutylyl cAMP (dBC) and phorbol myristate 13-acetate (PMA), separately. dBC stimulated proliferation of the hAG cells, but it inhibited that of the hPTC cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Different growth control of the two human thyroid cell lines of adenomatous goiter and papillary carcinoma. 778 32

TSH initiates its action by binding to specific membrane receptors' thyroid cells and induces activation of the adenylate cyclase-cAMP cascade. The factors involved in the regulation of TSH receptors are poorly known, except for the TSH dose-dependent regulatory effect. The fact that the thyroid gland of Graves' patients has a normal density of TSH receptors with suppressed TSH and high T4 and T3 levels suggests a modulatory role of thyroid hormones on TSH receptors. To evaluate this hypothesis, the density of TSH receptors and the activity of adenylate cyclase were determined in the thyroid membranes from hyperthyroid and hypothyroid adult male rats; they were rendered hyperthyroid either with bovine TSH, TRH, or T3 for 7 days and hypothyroid by propylthiouracil treatment or by hypophysectomy. NaCl was given to the control group. Plasma T4, T3, and TSH were also quantified. Bovine TSH and TRH treatments induced mild hyperthyroidism with a small goiter and a 50% reduction in the density of TSH receptors due to hyperstimulation of the gland by either exogenous or endogenous high TSH levels. Severe hyperthyroidism caused by T3 treatment resulted in low T4, high T3, and suppressed TSH thyrocyte stimulation; it was associated with a significant increase in the number of TSH receptors (29.6 +/- 2.3 vs. control 17.9 +/- 1.7 mU TSH/mg protein). These last results suggest a putative positive effect of T3 on TSH receptors. To confirm this effect, hypothyroid rats were investigated. Severe primary hypothyroidism due to propylthiouracil treatment was associated with a large goiter, high plasma TSH levels (11.8 +/- 1.2 vs. control 1.5 +/- 0.1 mU TSH/ml), low plasma T4 and T3, and a 70% reduction in TSH receptors, confirming the down-regulatory effect of high TSH on the thyroid cell. However, in hypophysectomized rats, a 45% reduction in the density of TSH receptors was also observed in the absence of TSH. Injections of either TSH or T3 to these hypophysectomized rats restored a normal number of TSH-binding sites, and simultaneous TSH and T3 treatments resulted in a mildly additive effect in the number of TSH receptors, which was slightly greater than that of the controls. No important changes were found in the adenylate cyclase activity in the thyroid membrane preparations from hyperthyroid and hypothyroid rats despite variations in the density of TSH receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Severe but not mild alterations of thyroid function modulate the density of thyroid-stimulating hormone receptors in the rat thyroid gland. 789 80

The [3H]thymidine incorporation assay in FRTL-5 cells was used to measure thyroid growth-stimulating antibody in the purified immunoglobulin G (IgG) fraction of patients with endemic nontoxic goiter (grade I-III) living in Italy (n = 34) or Peru (n = 37). IgG of euthyroid nongoitrous subjects living in the same endemic area (n = 25) and from an area of sufficient iodine intake were used as controls. Bovine TSH (10 mU/L) and thyroid-stimulating antibody of Graves' disease produced a significant increase in [3H]thymidine incorporation and DNA content in FRTL-5 cells. IgG from Italian or Peruvian patients with endemic goiter produced a small increase in [3H]thymidine incorporation in FRTL-5 cells (131 +/- 54% and 165 +/- 57%, respectively), which was indistinguishable from that obtained with IgG from normal nongoitrous subjects residing in endemic or nonendemic areas (167 +/- 80% and 161 +/- 36%, respectively). For comparison 18 of 25 (72%) IgG of hyperthyroid patients with Graves' disease produced clear-cut increases in [3H]thymidine incorporation (1142 +/- 1065%) and DNA content (219%) in FRTL-5 cells. IgG from patients with endemic goiter, at variance with Graves' IgG, did not cause an increase in DNA in FRTL-5 cells. All Graves' IgG that stimulated [3H]thymidine incorporation in FRTL-5 cells also stimulated cAMP production in this culture system, whereas no adenylate cyclase stimulation was produced by IgG from patients with endemic goiter. The prevalence of thyroglobulin antibody and thyroperoxidase antibody in endemic goiter patients did not differ from that in control subjects residing in the same iodine-deficient area. Our data show that sera of endemic goiter patients are devoid of thyroid growth-stimulating antibody and thyroid-stimulating antibody activities. These observations argue against a direct role of thyroid autoimmunity in the development of goiter in iodine-deficient areas.
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PMID:Failure to detect thyroid growth-promoting activity in immunoglobulin G of patients with endemic goiter. 790 15

In toxic thyroid adenomas, mutations in the TSH receptor (TSH-R) gene or the gene encoding the alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gs alpha) have been demonstrated to constitutively activate the cAMP cascade, which subsequently stimulates the growth and function of these tumors. However, the widely varying thyroid phenotypes in patients with TSH-R germline mutations, ranging from only slightly enlarged diffuse to multinodular goiters, suggest that additional mechanisms may be effective in the pathogenesis of toxic adenomas. We have investigated the levels of stimulatory and inhibitory G protein alpha-subunits together with basal and TSH-stimulated adenylate cyclase (AC) activity in toxic adenomas with or without activating mutations and in nodular and extranodular tissues of a toxic goiter due to a germline mutation in the TSH-R gene. Augmented expression of Gs alpha protein was detected in all toxic adenomas, independent of the presence of mutations, and in the nodular tissue of the toxic goiter, but not in the nonnodular hyperplastic tissue of the toxic goiter with the mutated TSH-R. Analogously, the expression of the alpha-subunit of the inhibitory G protein (Gi alpha) was also increased in all adenomas and the nodular tissue of the goiter, but, again, not in the hyperplastic goiter tissue. Basal AC activity was high in all tissues with mutations, but was only slightly increased in adenomas without detected mutations. No correlation was detectable between basal or TSH-stimulated AC activity and the levels of Gs alpha and Gi alpha. Our data suggest that mutational activation of the cAMP cascade may not be sufficient to generate toxic nodules and adenomas, but far more complex mechanisms, including alterations of G protein signaling, may be effective in the pathogenesis of these tumors.
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PMID:Constitutive activation of the Gs alpha protein-adenylate cyclase pathway may not be sufficient to generate toxic thyroid adenomas. 862 55


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