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)

Cyclosporin immunosuppression is mediated by a calcium/sodium excess during G0 which inhibits further cell cycle progression. The consequences of cyclosporin on electrolyte content were measured in T-lymphocytes stimulated with concanavalin A. Cyclosporin caused an excessive accumulation of extracellular calcium for the first 4 h of lectin stimulation. The nonpermissive calcium content resulted from a reduction in the rate of calcium efflux from the cell. Because cyclosporin did not affect calcium translocation via ATPase but did permit excessive amounts of sodium to enter the resting cell we hypothesized that the calcium excess is caused by a shut-down of the Ca2+/Na+ antiport during the first hours of lectin stimulation. The subsequent normalization of calcium content is coincident with the onset of mRNA synthesis, which suggests development of compensatory mechanisms to alleviate the calcium burden. The G0 calcium excess did not affect other transductive events such as ligand recognition, phosphatidyl inositol metabolism, or adenylate cyclase activation. This study points to the causative mechanism of cyclosporin immunosuppression and emphasized the dynamic role of ions as modulators of normal cell proliferation.
Cancer Res 1989 Feb 15
PMID:Cyclosporin immunosuppression mediated by calcium/sodium imbalance. 253 94

Malnutrition, as well as malignancy, induces alterations in heart metabolism and performance. Previous studies have implicated adrenergic mechanisms as the cause. The present study was undertaken to investigate if the adenylate cyclase system in the rat heart was affected by malnutrition. Three different animal groups with malnutrition were compared with a control group: rats with acute starvation for 14-96 hours, rats with protein-calorie malnutrition for 2 weeks, and rats with tumors. Stimulation by beta-adrenergic receptors and inhibition by muscarinic receptors of adenylate cyclase activity were not altered by malnutrition. However, conditions used for in vitro adenylate cyclase determinations were, of necessity, not physiological. Neither did the number of beta-adrenergic and muscarinic receptors change. When competition-binding experiments were performed, differences comprising agonist affinity and affinity state distribution were noted among the groups. The myocardial beta-adrenergic receptors formed a reduced number of high-affinity sites in all groups as compared with the control rats. All high-affinity sites displayed a more than 10-fold increase in affinity toward isoproterenol and an impaired sensitivity to guanine nucleotides except in heart membranes derived from rats starved less than 48 hours. While the protein-calorie restricted and the tumor-bearing rats had myocardial beta-adrenergic receptors that were unresponsive to guanine nucleotides, after 48 hours of starvation the rats exhibited an attenuated guanine-nucleotide-induced affinity shift. No changes associated with malnutrition in myocardial membrane levels of the of the stimulatory guanine-nucleotide-binding protein were detected by cholera-toxin-induced ADP-ribosylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of malnutrition on rat myocardial beta-adrenergic and muscarinic receptors. 253 24

We have reported previously that murine mammary tumor cell subpopulations isolated from one spontaneous adenocarcinoma are heterogenous in terms of prostaglandin E2 (PGE2) synthetic capacity. We have also shown that tumor-PGE2 contributes to the ability of these cells to grow and metastasize in vivo (Fulton and Heppner: Cancer Research 45:4779-4784, 1985). In the present study, we have asked whether exogenous PGE2 has direct effects on the proliferation of these cells in vitro and if such responses can be attributed to the capacity of these cells to 1) bind PGE2 and 2) activate adenylate cyclase via the PGE2 receptor. We report that PGE2, at concentrations below 1 x 10(-5) M, does not affect the proliferation rate of these cells. This unresponsiveness is not due to the absence of receptors for PGE2. However, marked heterogeneity in receptor binding and function was detected in these closely related cell lines. Two metastatic lines (66 and 410.4) have high-affinity receptors for PGE2 (average Kd = 4.3 x 10(-9) M/L and 4.2 x 10(-9) M/L, respectively) and similar binding capacities (4.1 x 10(-4) and 2.9 x 10(4) binding sites, respectively). Two nonmetastatic lines, 410 and 67, have receptors with lower affinity (Kd = 8.3 x 10(-9) M/L and 1.6 x 10(-7) M/L, respectively) and binding capacities of 2.8 x 10(5)/410 cell or 7.3 x 10(4)/67 cell. A third nonmetastatic line (168) exhibits no specific binding. PGE2 receptor stimulation leads to elevated intracellular cAMP in lines 66, 410, and 67. Line 410.4 cells appear to have a functional lesion in the PGE2 receptor resulting in a failure to elevate cAMP in response to receptor occupancy. Adenylate cyclase can, however, be activated in these cells by cholera toxin, NaF, or forskolin. In comparison to the other cell lines, line 168 cells respond poorly to all cAMP-stimulating agents. Thus, we have found that PGE2 binding is a heterogenous property for these cells, and, in addition, we have identified an apparent uncoupling of PGE2 receptor to the adenylate cyclase system in one cell line.
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PMID:Prostaglandin E2 receptor heterogeneity and dysfunction in mammary tumor cells. 254 Feb 14

The signal transducing regulatory protein (Gs alpha) was examined in B16 melanoma clones of low (F1C29) and high (F10C23) experimental metastatic potential. Incorporation of the photoaffinity analogue, [8-azido-gamma-32P]GTP, into Gs alpha was decreased in F10C23 extracts when compared to F1C29. This difference disappeared when the photolabeling reaction was carried out at an elevated temperature which enhanced the rate of GTP exchange, suggesting functional differences in the ability of Gs alpha to bind or release GTP rather than dissimilar intracellular Gs alpha concentrations. Differential Gs alpha photolabeling occurred only during the period of rapid growth when F10C23 cells proliferated faster than F1C29 cells. During the recovery phase of growth immediately following plating and at confluence, periods in which F1C29 and F10C23 growth rates are similar, Gs alpha photolabeling between the two clones was equal. CMT lung carcinoma clones of differential metastatic potential grew at a uniform rate at all stages of growth and also exhibited equal Gs alpha photolabeling. F10C23 cells were more responsive to alpha-melanocyte-stimulating hormone stimulation of adenylate cyclase activity than F1C29 cells at all growth stages. These results confirm previously observed functional differences in Gs alpha between B16 metastatic variants and show that photolabeling differences in Gs alpha are related to growth rate.
Cancer Res 1989 Jun 15
PMID:Growth rate dependence of differential incorporation of a guanosine triphosphate photoaffinity probe into the alpha subunit of a guanine nucleotide binding protein, Gs, from metastatic variants of B16 melanoma cells. 254 98

Adenylate cyclase activation through adrenergic receptors in rat ascites hepatoma (AH) 130 cells in response to adrenergic drugs was studied, and receptor binding and displacement were compared with those of normal rat hepatocytes. Epinephrine (Epi) and norepinephrine (NE) activated AH130 adenylate cyclase about half as much as isoproterenol (IPN) but equaled IPN after treatment with the alpha-antagonist phentolamine or islet-activating protein (IAP). The three catecholamines in hepatocytes were similar regardless of phentolamine or IAP. These catecholamines activated adenylate cyclase in order of IPN greater than NE greater than Epi in AH130 cells but IPN greater than Epi greater than NE in hepatocytes. We then used the alpha 1-selective ligand [3H]prazosin, the alpha 2-selective ligand [3H]clonidine, and the beta-ligand [125I]iodocyanopindolol [( 125I]ICYP), and found that AH130 cells had few prazosin-binding sites, about eight times as many clonidine-binding sites with high affinity, and many more ICYP-binding sites than in hepatocytes. The dissociation constant (Ki) of the beta 1-selective drug metoprolol by Hofstee plots for AH130 cells was lower than that for hepatocytes. The inhibition of specific ICYP binding by the beta 2-selective agonist salbutamol for AH130 cells gave only one Ki value which was much higher than both high and low Ki values of the drug for hepatocytes. These findings indicate that the alpha- and beta-adrenergic receptors in hepatocytes are predominantly alpha 1-type and beta 2-type, but that those in AH130 cells are predominantly alpha 2-type and beta 1-type, and the low adrenergic response of AH130 cells is due to the dominant appearance of alpha 2-adrenergic receptors, linked with the inhibitory guanine-nucleotide binding regulatory protein, instead of alpha 1-adrenergic receptors, and beta 1-adrenergic receptors with low affinity for the hormone.
Cancer Res 1989 Nov 15
PMID:Altered adrenergic response and specificity of the receptors in rat ascites hepatoma AH130. 255 51

The hypercalcemia caused by malignancy factor, also called parathyroid hormone-related protein (PTHrP), exhibits most of the biological activities of parathyroid hormone (PTH) in kidney and bone. On the basis of the well-documented vascular action of PTH, we characterized the vasodilator action of human (h) PTHrP-(1-34) on a preparation of the isolated rat kidney, and its activity to stimulate adenylate cyclase in microvessels isolated from rabbit kidney cortex. Injection of sequential cumulative doses of hPTHrP-(1-34) into the isolated kidney preparation produced increasing vasodilatation up to 10(-8) M (EC50 of 3 x 10(-9) M) and decreasing responses thereafter. The maximal effect represented 26% of the reference relaxation induced by papaverine. Single injections of hPTHrP-(1-34) resulted in a greater (over 60%) vasodilatation. These results were reminiscent of the tachyphylaxis that occurs after repeated exposure to the peptide. The (3-34) PTH antagonist inhibited the hPTHrP-induced vasodilatation. Human PTHrP-(1-34) was equipotent with hPTH-(1-34) (EC50 values of 3 x 10(-9) M) but 5-fold less potent than rat (r) PTH-(1-34) in stimulating microvessel adenylate cyclase. GTP enhanced the enzyme responses to the peptides but reduced their potency. Both (3-34) and (7-34) PTH antagonists were inhibitors of hPTHrP- or PTH-stimulated microvascular adenylate cyclase. Synthetic hPTHrP-(1-16) had neither vasodilator nor adenylate cyclase-stimulating activity. This hPTHrP fragment exhibited some inhibitory effect on the hPTHrP-(1-34)-induced stimulation of microvessel adenylate cyclase. These results indicate that hPTHrP possesses PTH-like activity to cause vasorelaxation and to stimulate microvascular adenylate cyclase in the kidney.
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PMID:Renal vasodilatation and microvessel adenylate cyclase stimulation by synthetic parathyroid hormone-like protein fragments. 263 Feb 97

Variations in catalase, glutathione peroxidase (GP) and adenylate cyclase (AC) activity in murine erythroleukemic (MEL) cells were studied during multiplication and dimethylsulfoxide (DMSO)-induced differentiation. The results demonstrated that, although DMSO favors the incorporation of 3H-thymidine into DNA of treated cells, it slows down cell multiplication. Increased incorporation was also observed in superoxide dismutase (SOD)-treated cells. DMSO also determined an early and significant drop in AC activity and a late fall in catalase activity, whereas there was no significant variation in GP activity in parallel with the decreased cell multiplication that accompanied cell differentiation. We hypothesize that DMSO and SOD favor 3H-thymidine incorporation by neutralizing the reactive forms of oxygen and that the reduction in catalase and AC activity is closely related to the mitotic activity of MEL cells.
Int J Cancer 1989 Jun 15
PMID:Effects of dimethylsulfoxide on Friend erythroleukemic cell proliferation and on the activity of enzymes involved in this process. 273 3

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

Acquired resistance to chemotherapeutic agents is an important clinical problem. One preclinical model, termed multidrug resistance (MDR), is characterized by a complex phenotype of cross-resistance to biochemically unrelated antineoplastic agents, the presence of a high-molecular-weight membrane glycoprotein, and impaired accumulation of drug. To determine whether MDR is mediated in part by altered cyclic 3',5'-adenosine monophosphate (cAMP) levels, the effect of incubation with the adenylate cyclase agonist, forskolin, was investigated in the murine sarcoma S180 cell line and two MDR variants (A5-.8, A5-2.5). Basal cAMP levels in sensitive and MDR lines were not significantly different (range, 0.15 +/- 0.05 to 0.31 +/- 0.09 pmol/mg protein); however, 1-h incubation with forskolin, 10 microM, elevated intracellular cAMP 2-fold in the parent line and 43- and 35-fold in the variants. The adenylate cyclase agonists, prostaglandin E2 and cholera toxin, and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine had no significant effect on cAMP levels. To determine the effect of forskolin on doxorubicin-induced cell lethality, S180 and MDR lines were incubated with doxorubicin plus forskolin for 1 h and cloned in soft agar. Coincubation with forskolin partially reversed doxorubicin resistance in the MDR lines in a dose-dependent fashion. To determine whether this effect was mediated solely by elevation of intracellular cAMP, the inactive 1,9-dideoxy analogue of forskolin (DF) was used. Incubation with DF resulted in no elevation of cAMP levels in the sensitive or resistant cell lines; however, DF also partially reversed doxorubicin resistance in the MDR variants. Furthermore, coincubation of the A5-2.5 cell line with doxorubicin and 8-bromo cAMP, 1 mM, did not result in reversal of resistance to doxorubicin. To determine whether the reversal of resistance by the diterpenes was associated with alteration of doxorubicin transport, uptake and efflux of [14C]doxorubicin were measured. Coincubation with both forskolin and DF, 10 microM, enhanced [14C]doxorubicin uptake in the resistant cells, while drug efflux was significantly affected only in the cell line exhibiting intermediate resistance. Since both forskolin and its inactive analogue are effective in partially reversing resistance to doxorubicin and augmenting anthracycline uptake, a mechanism other than elevation of cAMP is most likely responsible.
Cancer Res 1988 Feb 01
PMID:Partial reversal of doxorubicin resistance by forskolin and 1,9-dideoxyforskolin in murine sarcoma S180 variants. 282 78

S49 cyc- lymphoma cells contain a mutation resulting in loss of a functional guanine nucleotide regulatory protein rendering their adenylate cyclase refractory to most stimuli. S49 wild-type and cyc- clones were used in the present study to investigate the possible association of altered cAMP metabolism with tumorigenicity and metastatic potential. The S49 clones were implanted i.v., i.p., and intracerebrally in both athymic nude mice and syngeneic, immunocompetent BALB/c mice. Both S49 clones gave rise to tumors when inoculated into athymic mice, and no differences were observed in the tumorigenicity or metastatic potential of S49 wild-type and cyc- cells. Implantation of S49 clones in syngeneic BALB/c mice gave rise to few tumors except when administered intracerebrally, where wild-type cells were more tumorigenic than cyc- cells. This raises the possibility of differences in immunogenicity between the S49 clones. Analysis of cell lines derived from tumors grown in athymic mice showed that they retained the phenotype of the S49 clones used for inoculations. The results indicate that, despite differences in adenylate cyclase responsiveness, S49 wild-type and cyc- cells are both highly tumorigenic and metastatic.
Cancer Res 1988 Feb 01
PMID:Tumorigenicity of the cyc- variant of the S49 murine lymphoma deficient in the Gs-alpha subunit of adenylate cyclase. 282 80


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