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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the regulation of the secretion and cytoplasmic RNA levels of calcitonin (CT) and Chromogranin-A (CgA) to determine if the biosynthesis and secretion of these two substances are controlled in a coordinated fashion. The studies were conducted in two cell lines, a medullary thyroid carcinoma (MTC) cell line and a lung tumor (BEN) cell line. Both cell types secrete CT and CgA. Forskolin treatment resulted in a significant increase in the secretion of CT and CgA in each cell line and in CT-specific cytoplasmic RNA in the MTC cell line. Treatment with calcium ionophore A23187 resulted in significantly increased secretion of both substances in the lung tumor cells but not in the medullary thyroid carcinoma cells. A significant increase in CT-specific or CgA-specific cytoplasmic RNA was not seen in either cell line. We conclude that the secretion of CT and CgA are regulated in a coordinated fashion in these cell lines through processes that are calcium-mediated and processes that involve cyclic AMP-dependent protein kinase A. However, each of these regulatory pathways is not always operative in a given tissue. The coordinate regulation of the secretion of CT and CgA supports the hypothesis that CgA participates in the secretory process of its associated hormones.
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PMID:The effects of forskolin and calcium ionophore A23187 on secretion and cytoplasmic RNA levels of Chromogranin-A and calcitonin. 314 98

Induction of urokinase-type plasminogen activator (uPA) in response to either reagents activating cAMP-dependent protein kinase (cAMP-PK) or the calcium ion phospholipid-dependent kinase (C-kinase) was compared in the LLC-PK1 and T47D cell lines. The two cell lines exhibited quantitatively different responses to calcitonin, to the phosphodiesterase inhibitor isobutylmethylxanthine, and to the adenylate cyclase activator forskolin. Both showed activation of cAMP-PK in response to all these reagents, with T47D cells displaying a greater extent of activation. T47D cells, however, failed to produce uPA in response to calcitonin, forskolin, or the cAMP analog 8-bromo-cAMP, whereas LLC-PK1 cells produced high levels of uPA in response to all these agents. Both cell lines responded to phorbol esters in terms of uPA induction, though to differing extents. Phorbol myristate acetate (PMA) was shown conclusively not to activate cAMP-PK in either cell line, even at concentrations 10-fold higher than those promoting maximal uPA induction. It was concluded that phorbol ester-mediated induction of uPA does not involve cAMP or cAMP-PK activation. These results are discussed in relation to proposed models concerning the role of cAMP-PK in uPA induction.
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PMID:Pathway of urokinase-type plasminogen activator induction in the T47D and LLC-PK1 cell lines. 365 59

The clonal cell line UMR 106, which was originally derived from a rat transplantable osteogenic sarcoma with an osteoblastic phenotype, was subcloned after the emergence of a calcitonin-responsive adenylate cyclase was noted in late passages. Detailed studies on the stimulation of adenylate cyclase and activation profile of the cyclic AMP-dependent protein kinase isoenzymes in response to parathyroid hormone (PTH) and salmon calcitonin (SCT) were conducted on two subclones (UMR 106-01 and UMR 106-06). Both subclones responded in an identical manner to PTH, which stimulated adenylate cyclase and activated both isoenzyme I and isoenzyme II of cyclic AMP-dependent protein kinase. In contrast, only UMR 106-06 cells responded to calcitonin. At 3 X 10(-8)M SCT, there was a sevenfold stimulation of adenylate cyclase, 84% activation of isoenzyme I, and 44% activation of isoenzyme II. The activation profiles of the isoenzymes to PTH and SCT in UMR 106-06 were similar. Furthermore, their response to SCT correlates with the presence of specific, saturable binding of 125I-labeled SCT. Binding parameters indicate apparent Kd = 0.8 nM and 6,000 receptors/cell. These data point to a significant phenotypic change having taken place in this clonal cell line with prolonged maintenance in culture, with the emergence of a calcitonin receptor linked to adenylate cyclase and protein kinase activation.
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PMID:Characterization of an osteoblast-like clonal cell line which responds to both parathyroid hormone and calcitonin. 392 97

The influence of calcitonin on cell growth was examined in the human breast cancer cell line, T 47D. These cells possess specific high-affinity receptors for calcitonin as well as a sensitive calcitonin-responsive adenylate cyclase. In the T 47D cells, low doses of salmon calcitonin initially stimulated cell growth and the incorporation of [3H]thymidine into acid-insoluble macromolecules. This initial stimulation was followed by an inhibitory effect of calcitonin upon cell proliferation, which occurred during the log phase of growth, was dose dependent, and resulted in prolongation of doubling time from 36 to 90 hr. DNA and protein content correlated well with cell number. By 7 to 9 days of treatment, cell numbers of calcitonin-treated cells reached a mean of 66.5 +/- 3.7% of control (p less than 0.001, n = 8) (range, 51.3 to 82.9%). This biphasic effect of calcitonin on T 47D cells was reproduced by human calcitonin and prostaglandin E2 in the order of potency with which they influence adenylate cyclase. Epidermal growth factor (10(-9)M) and insulin (10(-9)M) stimulated the growth of T 47D cells, but this effect was abolished when either hormone was combined with salmon calcitonin (3 x 10(-10)M). Calcitonin specifically activated type II isoenzyme of cyclic adenosine 3':5'-monophosphate-dependent protein kinase in the T 47D cells. In view of other published data relating activation of this isoenzyme to growth regression in cancer cells, this response to calcitonin may be causally related to the inhibitory effect of the hormone upon cell replication in T 47D cells. The mechanism of the early stimulatory effect of calcitonin upon mitogenesis is not explained, although the possibility of stimulation of activity of type I isoenzyme of cAMP-dependent protein kinase has not been entirely excluded in the present experiments.
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PMID:Calcitonin effects on growth and on selective activation of type II isoenzyme of cyclic adenosine 3':5'-monophosphate-dependent protein kinase in T 47D human breast cancer cells. 618 57

We have previously demonstrated that a cultured porcine kidney cell, LLC-PK(1), maintains the characteristics of a polar renal epithelial cell in culture, and responds to salmon calcitonin and [arginine]vasopressin by increasing cyclic AMP content. To demonstrate the usefulness of this cell line as a model for the study of the biochemical events distal to cyclic AMP production, the activation of cyclic AMP-dependent protein kinase was examined. Intact cells in monolayer demonstrated progressive increases in cyclic AMP content and activation of protein kinase in response to [arginine]vasopressin (2-200nm) and salmon calcitonin (0.03-30nm) with both hormones fully activating the enzyme at a cell cyclic AMP content of 35pmol/mg of protein. Of the total cyclic AMP-dependent protein kinase activity, 80% was found in the 27000g supernatant fraction of sonicated cell material, and this soluble protein kinase could be fully activated by hormone. Conversely, the 27000g pellet contained a significant proportion of cyclic AMP-independent protein kinase and only 20% of total cell cyclic AMP-dependent protein kinase; the latter showed little response to hormone. On the basis of DEAE-cellulose chromatography, type II protein kinase was the predominant isoenzyme in both soluble and particulate fractions of the LLC-PK(1) cells and the soluble fractions of rat and guinea-pig renal medulla. Thus, the LLC-PK(1) cell line can serve as a model for hormonal modulation of protein kinase and as a potential source for defining the endogenous substrates for these enzymes.
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PMID:Modulation of cyclic AMP-dependent protein kinase by vasopressin and calcitonin in cultured porcine renal LLC-PK1 cells. 624 60

Plasminogen activators are highly selective proteases that activate the proenzyme plasminogen to the general protease, plasmin. We studied a porcine kidney cell line, originally isolated as a high producer of plasminogen activator, in which activities of cellular adenylate cyclase and cAMP-dependent protein kinase are increased in response to calcitonin. We found that salmon calcitonin, in the concentration range 0.03-300 nM, increased plasminogen activator production up to approximately 1,000-fold and concurrently inhibited cell multiplication; both of these effects were reversible. Human calcitonin was approximately 0.01 times as potent as salmon calcitonin, corresponding to potency differences observed in other biological systems. Plasminogen activator production was also stimulated by other agents that raise cellular cAMP levels such as cholera toxin, phosphodiesterase inhibitors, and vasopressin, but not to the same extent as by calcitonins. The rapidity and sensitivity of the plasminogen activator determination and other cellular responses may make it possible in the future to use this cell stain in a convenient bioassay for calcitonins and their analogues.
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PMID:Calcitonin stimulates plasminogen activator in porcine renal tubular cells: LLC-PK1. 627 91

The characteristics of the cyclic AMP-dependent protein kinase isoenzyme response to calcitonin have been studied in a calcitonin-secreting human lung cancer cell line (BEN). These cells secrete a high molecular weight calcitonin-like molecule. They have previously been shown to have calcitonin receptors linked to adenylate cyclase. In this study we demonstrate that the cells contain two cyclic AMP-dependent protein kinase iso-enzymes. Using a recently reported method for studying selective activation of these isoenzymes by hormones in intact cells, it is demonstrated that calcitonin causes selective activation of isoenzyme I, with no significant activation of isoenzyme II. Post-extraction activation was excluded by appropriate controls. The response was rapid (2 min) and persisted for 18 hours. Half maximal response occurred at 3 X 10(-10) M salmon calcitonin.
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PMID:Selective activation of cyclic AMP dependent protein kinase by calcitonin in a calcitonin secreting lung cancer cell line. 647 48

The characteristics of the cyclic AMP-dependent protein kinase isoenzyme response to calcitonin stimulation have been studied in two human breast cancer cell lines, T47D and MCF 7. Both cell lines possess calcitonin receptors, a calcitonin-responsive adenylate cyclase and the two isoenzymes of the cyclic AMP-dependent protein kinase, types I and II. The adenylate cyclase also responds to prostaglandin E2. Acute activation of the cyclic AMP-dependent protein kinase isoenzymes was determined by using a modification of a multiple small anion exchange column method [Livesey, Kemp, Re, Partridge & Martin (1982) J. Biol. Chem. 257, 14983-14987]. Control experiments showed that post-extraction activation did not influence the data. Calcitonin caused a rapid, selective activation of isoenzyme II in the T 47D cells with half-maximal response at 10(-10)M, and persisting for at least 24h. In MCF 7 cells calcitonin also caused a highly selective activation of isoenzyme II with half-maximal response at 5 X 10(-11) M, but the response was transient with a return to basal isoenzyme activity by 4-6 h. At this time further addition of calcitonin did not restimulate the cyclic AMP-dependent kinase activity. In neither cell line did calcitonin treatment result in activation of isoenzyme I. Prostaglandin E2, on the other hand, the only significant alternative agonist of adenylate cyclase in T 47D cells, activated isoenzymes I and II to an equal extent in these cells, illustrating that two hormones activating adenylate cyclase in the one cell type might exert different effects by their selective actions upon protein kinase isoenzymes.
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PMID:Characteristics of selective activation of cyclic AMP-dependent protein kinase isoenzymes by calcitonin and prostaglandin E2 in human breast cancer cells. 659 96

Experiments were designed to examine whether calcitonin gene-related peptide (CGRP), a potent adenosine 3',5'-cyclic monophosphate (cAMP)-dependent vasodilator, affects the production of NO evoked by interleukin-1 beta) (IL-1 beta) in cultured rat aortic smooth muscle cells (SMC). CGRP, in a concentration-dependent manner, enhanced the release of nitrite (a stable oxidation product of NO) and the formation of L-citrulline from L-arginine caused by IL-1 beta. Two cAMP-dependent vasodilators, forskolin and isoproterenol, and the activator of the cAMP-dependent protein kinase, Sp-cAMPS, also enhanced the release of nitrite and the formation of L-citrulline evoked by IL-1 beta. The enhancing effect of isoproterenol required the presence of the vasodilator during the induction of NO synthase (NOS). IL-1 beta-treated vascular SMC inhibited the aggregation of indomethacin-treated platelets. Inhibition of platelet aggregation was more marked with SMC exposed to a combination of IL-1 beta and either CGRP or isoproterenol than with cells exposed to IL-1 beta alone. This inhibition was prevented by methylene blue and oxyhemoglobin. IL-1 beta induced the expression of inducible NOS mRNA in vascular SMC, which was enhanced by coincubation of IL-1 beta with either CGRP, isoproterenol, or forskolin. These observations indicate that CGRP via a cAMP-dependent mechanism potentiates the IL-1-beta-induced production of NO by enhancing the expression of inducible NOS. Therefore CGRP may contribute to the substantial production of NO in the vasculature during septic shock, which accounts, at least in part, for the collapse of the vascular system.
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PMID:CGRP enhances induction of NO synthase in vascular smooth muscle cells via a cAMP-dependent mechanism. 752 98

The two-microelectrode voltage-clamp technique was used to monitor K+ channel activity in Xenopus oocyte follicular cells, which are electrically coupled to the oocyte itself by gap junctions. Endogenous vasodilators such as calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), prostaglandin E2 (PGE2) and adenosine activate glibenclamide-ATP-sensitive K+ (KATP) channels in Xenopus oocyte follicular cells. The mechanism of action of CGRP was studied in detail. CGRP effects undergo a rapid desensitization. CGRP acts via CGRPI receptors. Its effects are antagonised by the amino-truncated CGRP analog hCGRP(8-37). The second messenger for CGRP activation of KATP channels is cAMP. Phosphodiesterase inhibition by 3-isobutyl-1-methylxanthine enhances the CGRP response while adenyl cyclase inhibition by either 2',5'-dideoxyadenosine or progesterone nearly completely depresses the CGRP response. Vasoconstrictors such as ACh and angiotensin II also have receptors in follicular cells. ACh strongly inhibits the CGRP activation of K+ channels as it inhibits the activation of KATP channels by P1060, but angiotensin II does not. It is concluded that as in vascular smooth muscle cells, CGRP and probably other hyperpolarizing vasodilators open KATP channels in follicular cells by protein kinase A activation.
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PMID:CGRP-induced activation of KATP channels in follicular Xenopus oocytes. 753 Aug 40


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