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)

In crude membranes from human T lymphoblasts Molt 3 cultured under standard conditions, the adenylate cyclase system was stimulated by GTP, its beta gamma-imido analogue (p[NH]ppG,) NaF and forskolin, but not by isoprenaline, prostaglandin E1 and vasoactive intestinal peptide. TPA (tumour-promoting agent phorbol ester) added at low concentration (3.2 nM) to the culture medium induced a marked increase in functional beta 2-adrenoceptors. Competition curves of [125I]cyanopindolol with the antagonist ICI 118.551 and four beta-adrenergic agonists indicated that the emergence of functional beta 2-adrenoceptors corresponded to one class of binding sites, shifting from a high-affinity state for agonists to a low-affinity state in the presence of p[NH]ppG. This expression of beta 2-adrenoceptors after a 4 h lag period depended on newly formed mRNA and protein synthesis as judged by the inhibitory effects of actinomycin D and cycloheximide. Further effects of TPA included alterations of the stimulatory G-protein Gs and/or the catalytic unit of adenylate cyclase.
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PMID:The phorbol ester TPA stimulates the expression of functional beta-adrenoceptors in human T lymphoblasts Molt 3. 255 94

Hepatocyte membranes from both lean and obese Zucker rats exhibited adenylate cyclase activity that could be stimulated by glucagon, forskolin, NaF and elevated concentrations of p[NH]ppG. In membranes from lean animals, functional Gi was detected by the ability of low concentrations of p[NH]ppG to inhibit forskolin-activated adenylate cyclase. This activity was abolished by treatment of hepatocytes with either pertussis toxin or the phorbol ester TPA, prior to making membranes for assay of adenylate cyclase activity. In hepatocyte membranes from obese animals no functional Gi activity was detected. Quantitative immunoblotting, using an antibody able to detect the alpha subunit of Gi, showed that hepatocyte plasma membranes from both lean and obese Zucker rats had similar amounts of Gi-alpha subunit. This was 6.2 pmol/mg plasma membrane for lean and 6.5 pmol/mg plasma membrane for obese animals. Using thiol pre-activated pertussis toxin and [32P]-NAD+, similar degrees of labelling of the 40 kDa alpha subunit of Gi were found using plasma membranes of both lean and obese Zucker rats. We suggest that liver plasma membranes from obese Zucker rats express an inactive Gi alpha subunit. Thus lesions in liver Gi functioning are seen in insulin-resistant obese rats and in alloxan- and streptozotocin-induced diabetic rats which also show resistance as regards the acute actions of insulin. Liver plasma membranes of obese animals also showed an impairment in the coupling of glucagon receptors to Gs-controlled adenylate cyclase, with the Kd values for activation by glucagon being 17.3 and 126 nM for lean and obese animals respectively. Membranes from obese animals also showed a reduced ability for high concentration of p[NH]ppG to activate adenylate cyclase. The use of [32P]-NAD+ and thiol-preactivated cholera toxin to label the 43 kDa and 52 kDa forms of the alpha-subunit of Gs showed that a reduced labelling occurred using liver plasma membranes from obese animals. It is suggested that abnormalities in the levels of expression of primarily the 52 kDa form of alpha-Gs may give rise to the abnormal coupling between glucagon receptors and adenylate cyclase in liver membranes from obese (fa/fa) Zucker rats.
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PMID:Multiple defects occur in the guanine nucleotide regulatory protein system in liver plasma membranes of obese (fa/fa) but not lean (Fa/Fa) Zucker rats: loss of functional Gi and abnormal Gs function. 256 40

Activation of protein kinase C (PKC) by phorbol esters (TPA) results in a modification of the cyclic AMP system leading to either attenuation or amplification of the cyclic AMP signal. In the non-neoplastic T51B rat liver cell line, TPA, when added to intact cells, had no effect on the basal level of cyclic AMP synthesis but caused a 1.5 fold amplification of the stimulation induced by beta-adrenergic agents, cholera toxin and forskolin. The effect appeared to be mediated by PKC since diacylglycerols caused the same amplification as did TPA while inactive phorbol esters were without effect. Phosphorylation of Gs or the catalytic subunit of adenylate cyclase by PKC is likely to be responsible for the enhancement of cyclic AMP synthesis. TPA also caused translocation of PKC; however, the time course of the translocation was longer than the time course of the enhancement of adenylate cyclase activity. Thus, the ability of TPA to amplify cyclic AMP synthesis is probably mediated by activation of PKC that is already present in the membrane.
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PMID:Activation of protein kinase C sensitizes the cyclic AMP signalling system of T51B rat liver cells. 256 51

Treatment of cultured astrocytes from 2-day-old rat cerebral hemispheres with insulin, somatomedin C (IGF1), thrombin and acidic or basic fibroblast growth factors promoted a rapid activation of a cytosolic protein kinase (S6 kinase) which phosphorylates ribosomal protein S6. The phorbol ester (TPA) also triggered a rapid increase in S6 kinase activity. Two agonists of adenylate cyclase activity (forskolin and isoproterenol) and the cyclic AMP analog (dibutyryl cAMP) also stimulated the same S6 kinase. These observations support the idea that several pathways might promote the activation of the same entity that is regarded as one of the primary targets of signals elicited by growth factors.
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PMID:[A model for studying the transmission of information produced by certain growth factors: activation mechanisms of S6 kinase in cultured astrocytes]. 262 75

To study the maturation of fetal pancreatic B-cells, cell suspensions of pancreas from 21.5-day-old fetuses were cultured in RPMI medium containing 10 mM glucose. Forskolin (1 microM), used to stimulate adenylate cyclase, moderately delayed the neoformation of islets, slightly accelerated the proliferation of endocrine cells, and considerably increased insulin release by the cultures. The latter increase was not completely compensated for by the stimulation of insulin biosynthesis, so that the islet insulin content was decreased. The phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 25 nM), used to stimulate protein kinase-C, had little effect on the evolution of the cultures, but increased insulin release. This increase was almost compensated for by the stimulation of insulin biosynthesis. After 9-10 days of culture, insulin release in response to 15 mM glucose or 10 mM leucine was studied with perifused islets. In control islets, glucose produced a sustained increase in insulin release, which, however, was 6-fold smaller than that produced by leucine. Addition of forskolin or TPA to the perifusion medium markedly amplified the response to glucose without causing a biphasic pattern of release. In islets cultured with forskolin, the insulin response to glucose or leucine was decreased, largely owing to the lower insulin stores. In islets cultured with TPA, the insulin response to glucose or leucine was also decreased, but these differences cannot be explained simply by changes in insulin content. Neither treatment affected the kinetics of release. In conclusion, acute stimulation of adenylate cyclase or protein kinase-C markedly increased insulin release from fetal islets without causing an adult-like biphasic pattern of secretion. Chronic stimulation did not accelerate maturation of B-cells.
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PMID:Effects of stimulation of adenylate cyclase and protein kinase-C on cultured fetal rat B-cells. 267 88

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

A clonal cell line (Saos-2/B-10) derived from human osteosarcoma Saos-2 cells had the same osteoblastic characteristics as the mother line, but lacked sensitivity to parathyroid hormone (PTH) at early passages. At later passages (greater than 70) the cells became very sensitive to PTH (0.1 nmol/l). The absence of PTH-stimulatable adenylate cyclase correlated with the secretion of an adenylate cyclase-stimulatory activity which had the properties of the recently characterized PTH-like peptide (PTH-LP). This activity was inhibited by the PTH antagonist [8norleucyl,18norleucyl,34tyrosinyl]bovine PTH-(3-34)amide and could be neutralized by an antiserum raised against the synthetic PTH-LP-(1-34). Hybridization with a human PTH-LP cDNA showed that these cells produce two PTH-LP mRNAs of approximately 1.5 and 1.8 kb. The production of PTH-LP was stimulated by 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 150 nmol/l) and epidermal growth factor (EGF; 10 ng/ml). The increased accumulation of PTH-LP in conditioned media in response to TPA was seen after 1 h and levelled off at 6 h. In contrast, EGF stimulation was lower at 3 and 6 h but continued for 24 h. Both agents increased PTH-LP mRNA levels in Saos-2/B-10 cells. A TPA analogue which does not stimulate protein kinase C had no effect on PTH-LP production. Cycloheximide blocked the stimulatory effect of both TPA and EGF and the TPA effect was blocked by actinomycin D, suggesting transcriptional control. The regulation of PTH-LP by these agents may offer clues regarding the association of this protein with malignancy.
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PMID:Production of parathyroid hormone-like peptide in a human osteosarcoma cell line: stimulation by phorbol esters and epidermal growth factor. 278 97

Products from the hydrolysis of phosphatidylinositol 4,5-bisphosphate (IP3) can increase and/or potentiate cAMP accumulation in a variety of cells. Antibody to surface immunoglobulins activates IP3 hydrolysis in B-lymphocytes. In this study we have examined whether anti-Ig also stimulated and/or potentiated increases in the cAMP levels of splenocytes from athymic nude mice. Furthermore, since TPA potentiates anti-Ig-induced DNA synthesis and cAMP modulates DNA synthesis, the effects of TPA on any anti-Ig-induced changes in cAMP were also studied. Antibody (25 micrograms/ml) stimulated a rapid ris in cAMP which increased from 250 fmol/10(6) cells to 400 fmol/10(6) cells within 1 min and then subsided to 310 fmol/10(6) cells by 10 min. TPA (96 nM) suppressed the anti-Ig-induced cAMP accumulation at 1 min by 60%, but potentiated the forskolin (114 microM)-induced rise by 151%. Two other activators of protein kinase C, dioctanoylglycerol (5 microM), and anti-Ig (25 micrograms/ml), also potentiated the forskolin response by 198% and 52%, respectively. These results suggest that modulation of the adenylate cyclase system by anti-Ig may act in concert with cytokines and/or prostaglandins secreted by other lymphoid cells to define the state of proliferation or differentiation in B-cells.
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PMID:Antibody-induced cAMP accumulation in splenocytes from athymic nude mice. 282 42

ACTH1-24 stimulated the parenchymal cells in cultures of rat adrenal cortex in serum-free synthetic HiWoBa 2000 medium to replicate DNA, enter mitosis and divide. But ACTH's principal mediator, cyclic AMP, was not a complete mitogen: the adenylate cyclase-stimulating cholera toxin and dibutyryl cyclic AMP stimulated parenchymal cells to replicate DNA but not to enter mitosis. Thus, there must have been an additional mediator of the response to ACTH1-24 that enabled the parenchymal cells to enter mitosis. This additional mediator might have been protein kinase C because a protein kinase C activator and cyclic AMP elevator, TPA, stimulated the adrenocortical parenchymal cells to replicate DNA, enter mitosis and divide.
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PMID:The effects of corticotrophin (ACTH1-24), cyclic AMP and TPA (12-O-tetradecanoyl phorbol-13-acetate) on DNA replication and proliferation of primary rabbit adrenocortical cells in a synthetic medium. 282 83

One hour of exposure to cholera toxin is sufficient to elicit a significant delay in the initiation of DNA synthesis and cell division in lactogenic hormone-dependent Nb2-11C lymphoma cells. The inhibitory effect occurs already at very low concentrations of cholera toxin (5-50 fM), at which it is not accompanied by a detectable increase in intracellular cAMP, or ADP-ribosylation of the alpha subunit of Gs, the stimulatory guanine nucleotide binding protein of adenylate cyclase; IBMX, the phosphodiesterase inhibitor, acts synergistically to cholera toxin, indicating that a minute increase in cAMP may be sufficient for the inhibition. This indication is substantiated by the finding that dibutyryl cAMP also inhibits cell proliferation. Phorbol diester reverses partially the inhibitory activity of cholera toxin. It is most likely that this effect does not result from blocking the increase in cAMP, but rather from some subsequent, yet unidentified, events. The inhibitory effect of cholera toxin is not dependent on the concentration of the proliferation-stimulating lactogenic hormone and cannot be abolished or reduced by excess of the hormone. Cholera toxin also inhibits the autonomous proliferation of a lactogenic hormone-independent cell line (Nb2-SP); however, in this case the inhibition is not affected by TPA.
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PMID:Inhibition of the proliferation of Nb2 cells by femtomolar concentrations of cholera toxin and partial reversal of the effect by 12-O-tetradecanoyl-phorbol-13-acetate. 283 25


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