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

---

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

Thyroid hormone formation requires the coincident presence of peroxidase, H2O2, iodide, and acceptor protein at one anatomic locus in the cell. The peroxidase enzyme appears to be a protoporphyrin lX containing heme protein, with binding sites for both iodide and tyrosine. It is probable that both iodide and tyrosine are oxidized to free radical forms which unite to form iodotyrosine. The peroxidase is also involved through an uncertain mechanism in iodotyrosine coupling and probably in oxidation of sulfhydryl bonds in thyroglobulin. H2O2 may be supplied by microsomal NADPH-cytochrome c reductase or NADH-cytochrome b5 reductase. Other possible intracellular H2OI generating systems include monoamine oxidase and xanthine oxidase. The usual acceptor for iodide is thyroglobulin, which is currently believed to be iodinated within apical secretory vesicles at the cell border just prior to liberation into the colloid, or possibly after liberation into the colloid. Other soluble an insoluble proteins are also iodinated within the gland. The peroxidase is present in numerous cellular structures, but iodination activity occurs primarily, if not only, at the apical cell border. The controls of iodination are imperfectly known. Thyrotrophin modulation of iodide uptake, H2O2 generation, thyroglobulin synthesis, and peroxidase enzyme level obviously are the main regulations. Many of these actions are thought to involve mediation of adenyl cyclase and subsequent activation of intracellular phosphokinases. Antithyroid drugs of the thiocarbamide group are competitive inhibitors of iodination under some circumstances, but if much iodide is present, they react with the oxidized iodine intermediate and are irreversibly inactivated themselves. Clinical problems involving defective peroxidase function are among the most frequent hereditary defects of thyroid hormone formation. Recognized abnormalities include deficient peroxidase, abnormality in binding of the peroxidase apoprotein to its prosthetic group, and other less well-identified abnormalities in peroxidase structure and function. Peroxidase is typically elevated in thyroid tissue from patients with hyperthyroidism sometimes deficient in cold thyroid nodules, and frequently diminished in tissue from patients with Hashimoto's thyroiditis.
...
PMID:Biosynthesis of thyroid hormone: basic and clinical aspects. 6 47

Thyroid cells in culture constitute a suitable system for the study of thyroid gland function and its regulation. The natural thyroid stimulator (TSH) induces the in vitro reorganization of thyroid cells into three-dimensional follicles morphologically and metabolically similar to gland follicles. In contrast, nonstimulated cells develop as a monolayer and in a concerted manner rapidly lose the enzymes involved in iodine metabolosm and the aptitude to bind TSH to specific receptor sites. The morphogenetic action of TSH and its ability to maintain the specific metabolic properties of thyroid cells in culture are mediated by cyclic AMP via new RNA and new protein synthesis. Therefore comparison of the properties of a given cell type in morphologically and metabolically different status should provide a valuable tool for studying the TSH mechanism of action. Using 125-I-labeled TSH of high purity, high specific radioactivity, and preserved biologic potency, TSH interaction with intact cells and their derived plasma membranes was studied. At both the cellular and the sub-cellular level a very good agreement was found for the values of the rate and equilibrium constants of labeled TSH binding. A single type of high-affinity low-capacity site was revealed. In contrast, in both systems dissociation of bound labeled TSH was not of single-order kinetics and showed two kinetic components with half-lives of 3 and 30 min. An excellent correlation between half-stimulation of adenylate cyclase and iodide transport mechanism activation, and the dissociation constant of TSH binding, was found, indicating that the in vitro system studied was relevant to physiologic regulation.
...
PMID:Thyrotropin-receptor interaction and cyclic AMP-mediated effects in thyroid cells. 16 62

The adenylate cyclase activity and the binding of 125I-labeled thyroid-stimulating hormone (TSH) of normal and tumor rat thyroid plasma membranes were compared. No significant difference in the basal and fluoride-sensitive adenylate cyclase activity between normal and tumor plasma membranes was observed. Thyroid plasma membranes responded to TSH, whereas the enzyme from the tumor plasma membranes was TSH insensitive. Thyroid plasma membranes boud 125I-TSH. Tumor plasma membranes bound 125I-TSH poorly. At the highest concentration of unlabeled TSH used, 80% of the 125I-TSH that was bound to thyroid plasma membranes was displaced, whereas only 10% of the 125I-TSH bound to tumor plasma membranes was displaced. Therefore, it seems likely that the failure of this tumor to respond to TSH is due to an alteration in the functional unit of membrane adenylate cyclase at the level of the receptor subunit.
...
PMID:Diminished binding of thyroid-stimulating hormone in a transplantable rat thyroid tumor as a possible cause of hormone unresponsiveness. 17 Oct 62

Studies of TSH release and production were performed in short term monolayer cultures of transplantable, thyroid hormone responsive, thyrotropin (TSH) producing mouse pituitary tumors. These tumors contained large amounts of TSH, small amounts of growth hormone (GH) and no detectable luteinizing hormone (LH), indicating that the predominant hormone product of tumor cells was TSH. The TSH content per tumor cell was similar to that of the normal pituitary where thyrotrophs represent a small fraction of the total cells, suggesting that the TSH content per tumor cell was less than that of the normal thyrotroph. There was a time dependent release and production of TSH by tumor cells in monolayer culture. Thyrotropin releasing hormone (TRH) increased the release into the media and the production of TSH in a dose dependent manner. Maximum effects were noted at 0.2 ng/ml. Thyroid hormones and somatostatin inhibited both basal and TRH induced effects on both TSH release and production. TSH release as induced by TRH was calcium dependent. TSH release was stimulated by ouabain (10(-3)M) and potassium (57 mM), agents known to promote cellular calcium uptake in a calcium dependent manner. These studies indicate that tumor derived cells function in monolayer culture in a similar fashion to normal thyrotrophs. Studies were conducted to test the hypothesis that TRH action is mediated by adenosine 3',5' monophosphate (cAMP). Dibutyryl cAMP (6 mM) and theophylline (10 mM) increased TSH release suggesting that cAMP is involved in TSH release. However, TRH had no detectable effect on tumor cell adenylate cyclase activity or levels of cAMP. In contrast, PGE1 (1-10 mug/ml) stimulated adenylate cyclase activity and elevated cellular levels of cAMP without increasing TSH release. Thus, we are unable to confirm the postulate that cAMP is the intracellular mediator of TRH action.
...
PMID:Regulation of thyrotropin (TSH) release and production in monolayer cultures of transplantable TSH-producing mouse tumors. 17 85

Thyroid cells from euthyroid patients with Graves' disease were cultured in a chemically defined medium. The cells preserved the ability to respond to TSH with 8-fold increase in cyclic AMP concentration. This cyclic AMP response to TSH was diminished by prior exposure of cells to TSH. The decrease in cyclic AMP response to TSH induced to TSH was reversible, was not associated with a similar decrease to cyclic AMP response to PGE1, and could not be attributed to increased phosphodiesterase activity or to decreased adenyl cyclase activity. The partial resistence to TSH stimulation of thyroid cells previously exposed to TSH may be due to changes in the TSH receptor, possibly caused by TSH itself.
...
PMID:Cyclic AMP level of human thyroid cells in monolayer culture. TSH induced refractoriness to TSH action. 18 6

Thyroid cells, obtained from both normal human tissue and benign nodular goiter, were cultured and maintained in vitro in 4-18 passages. Cultures with confluent cells accumulated cyclic AMP (10-150 times the basal amount) upon addition of bovine thyrotropin (100 milliunits/ml), indicating that the cells in culture maintained a thyrotropin-sensitive adenylate cyclase system. Addition of high doses of thyrotropin also induced a characteristic and reversible change in the morphology of the cells. The effect of thyrotropin on cell growth was studied in short- and long-term experiments. Thyrotropin reduced [(3)H]thymidine incorporation in a dose-dependent fashion in all cultures of thyroid cells. The maximal inhibition over a 24-hr period was about 50%. The thyroid cells were notably sensitive, and the half-maximal effect occurred at about 100 milliunits of thyrotropin per ml. In contrast, the hormone had no effect on [(3)H]-thymidine incorporation into human glial cells. Low doses of thyrotropin also had no effect on human fibroblasts and, at high doses, a stimulation of [(3)H]thymidine incorporation was seen. Thyroid cell cultures grown in the presence of 10 milliunits of thyrotropin per ml for 7-14 days had a slower growth rate and 24-36% lower cell numbers at saturation density than control dishes, indicating that the hormone also had a long-term effect on cell proliferation. The data agree with in vitro studies by others of the effects of corticotropin and lutropin on target cells and suggest that in vivo the primary action of pituitary trophic hormones on endocrine tissues is not stimulation of growth.
...
PMID:Thyrotropin is not a growth factor for human thyroid cells in culture. 22 11

Thyroid stimulating hormone (TSH) and other substances increase adenylate cyclase (AC) activity and growth of normal and neoplastic thyroid tissue. Factors that inhibit cAMP may provide targeted therapy to tumors dependent on cAMP for growth. Somatostatin has been reported to inhibit the growth of gastrinomas and carcinoid tumors. We therefore studied the effects of somatostatin on basal, TSH, pertussis toxin, and forskolin stimulated adenylate cyclase activity in normal and neoplastic thyroid tissue from 19 patients. Adenylate cyclase (AC) activity was determined by the conversion of alpha 32P-ATP to 32P-cAMP in pmoles/mg protein/30 minutes in an 8000 x g particulate fraction rich in thyroid plasma membranes. TSH (300 mU/ml) and forskolin (100 mM) (a diterpine that directly stimulates the catalytic unit of AC) increased AC activity in normal and neoplastic thyroid tissue. The AC stimulation was greater in the neoplasms (p less than 0.01). Somatostatin (5 x 10(-6)M) decreased basal and TSH stimulated AC activity below basal levels in both normal and neoplastic thyroid tissue (including papillary, follicular, and medullary carcinomas). The inhibition of AC by somatostatin was greater in neoplastic tissue (p less than 0.025). Pertussis toxin (which blocks the inhibitory guanyl nucleotide regulatory protein) was able to partially reverse the effect of somatostatin. Somatostatin partially inhibited forskolin stimulated AC activity. Somatostatin inhibits basal and TSH stimulated AC activity in both normal and neoplastic human thyroid tissue, with a greater effect on neoplasms. These studies establish that somatostatin blocks a major regulator of thyroid growth and provides the rationale for the use of somatostatin analogs in the treatment of thyroid cancers.
...
PMID:Effect of somatostatin on adenylate cyclase activity in normal and neoplastic thyroid tissue. 135 26

Prior studies in our laboratory have shown that thyroid neoplasms produce increased amounts of cyclic adenosine monophosphate (cAMP). Thyroid-stimulating hormone receptors act through the stimulatory G protein (Gs) to activate adenylate cyclase, the enzyme responsible for cAMP production. The purpose of this study is to measure the activity and amount of Gs in human normal and neoplastic thyroid tissue to see whether alterations in Gs are responsible for the increased cAMP production seen in thyroid neoplasms. Four tumors with a high TSH-stimulated cyclase activity of 497.6 +/- 71.9 pmol/mg/30 min versus 35.9 +/- 13.5 pmol/mg/30 min for normal tissue from the same patients were studied. In reconstitution studies measuring Gs activity, neoplastic thyroid tissue produced 637 +/- 106 pmol cAMP/mg S49/mg thyroid membrane min versus 363 +/- 133 pmol cAMP/mg 549/mg thyroid membrane/min produced by normal thyroid tissue. Qualitative assessments of the amount of Gs present with cholera toxin-mediated adenosine diphosphate ribosylation showed increased Gs in thyroid tumors. Western blotting with antibodies directed against Gs showed a 3.3 +/- 0.6-fold increase in the amount of Gs in these thyroid tumors. These experiments identify an increase in the amount of an otherwise normal Gs as the biochemical defect responsible for the increased cAMP production in this group of tumors.
...
PMID:Increased stimulatory G protein in neoplastic human thyroid tissues. 166 Jun 29

The value of the criteria used to anticipate the outcome of treatment of Graves' hyperthyroid patients with methimazole (MMI) remains controversial. We have reported that high MMI doses combined with T3 administration was correlated with higher remission rates. In this study, we used the lowest MMI dose able to control the hyperthyroidism, keeping the free T4 index (FT4I) values below the normal range throughout treatment, and compared the results with patients treated with a high MMI regimen. Both groups received T3. We also evaluated the usefulness of goiter size, serum thyroid-stimulating antibody (TSAb: adenylate cyclase stimulation in human thyroid membrane), thyroglobulin (Tg) levels, and the T3 suppressibility of 24 h RAIU as prognostic markers for the outcome of Graves' disease therapy. Twenty-four Graves' hyperthyroid patients were treated with high MMI dose (mean +/- SD 60 +/- 19, range 40-120 mg daily), and 25 patients received low MMI dose (17 +/- 4.3, 5-20 mg daily). T3, 75 micrograms daily, was given to both groups of patients for 15 +/- 4 (13-22) months of treatment. After cessation of drug therapy, 31 patients (63%) remained euthyroid for 18 +/- 3 (13-49) months of follow-up, 15 (62.5%) and 16 (64%) patients in the high and low dose groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Thyroid 1991
PMID:Serum thyroid-stimulating antibody, thyroglobulin levels, and thyroid suppressibility measurement as predictors of the outcome of combined methimazole and triiodothyronine therapy in Graves' disease. 168 55

Substantial evidence suggests a link between infections with Yersinia enterocolitica (YE) and Graves' disease. We have now examined the sera of 72 patients recovering from YE infection for immunoglobulins that interacted with the TSH receptor in human thyroid membranes. Compared with controls, in concentrations between 1 and 4 mg/mL, patient IgG produced a significant, concentration-dependent inhibition of TSH binding (p less than 0.001) and stimulation of adenylate cyclase activity (p less than 0.005-0.05). Whereas IgG from normal individuals caused no stimulation of adenylate cyclase, IgG from controls caused some concentration-dependent displacement of TSH, as previously reported. However, IgG from convalescents of YE infections was significantly more potent than normal IgG in reducing the binding of TSH to the membrane. Thus, at each examined concentration, YE patients' IgG displaced more TSH than IgG from normal controls. For each milligram per milliliter increment of IgG in the assay, patients' IgG caused a 10.2% inhibition of TSH binding (r -0.90, p less than 0.001), significantly greater than that seen with normal IgG (p less than 0.02). The present studies provide the first demonstration that IgG of patients recovering from YE infections react with the human TSH receptor. The antibodies presumably are produced against the TSH-binding protein present in YE. However, in view of lack of evidence for thyroid dysfunction in the sera of patients recovering from yersiniosis and the presence of TSH-binding proteins in other bacteria, we postulate that infection with YE is neither necessary nor sufficient to cause thyroid autoimmune disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Thyroid 1991
PMID:Immunoglobulins of patients recovering from Yersinia enterocolitica infections exhibit Graves' disease-like activity in human thyroid membranes. 168 56


1 2 3 4 5 6 7 8 Next >>

---