Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of cyclic adenosine 3':5'-monophosphate (cAMP) upon the synthesis and release of carcinoembryonic antigen (CEA) was studied in the human pancreatic ductal cancer cell line, SW-1990. Incubation for up to 24 h with forskolin, an activator of adenylate cyclase, or isobutylmethyl xanthine, a theophylline analog, increased cellular cAMP levels by over 100-fold and significantly increased CEA release and cellular CEA content. Whereas cAMP levels were augmented within 10 min of exposure to these agents, CEA release and CEA cell content were not increased until 90 min and 24 h, respectively. Similar results were obtained using dibutyryl-cAMP, a cAMP analog, but not using sodium butyrate, a metabolite of dibutyryl-cAMP. Cells were incubated with 35S-cysteine and 3H-glucosamine in the presence or absence of forskolin in order to compare the effects of high cAMP levels upon the synthesis and release of total proteins, total glycoproteins, and immunoprecipitable CEA. Both CEA synthesis and release were enhanced by forskolin, but these effects were not specific to CEA since the release of labeled proteins and glycoproteins also increased. In addition, altered CEA expression caused by forskolin was consistently associated with a cessation of cell division, an effect which was reversible upon removing the agent. There was no effect upon cell morphology or viability. The data indicate that increased levels of cellular cAMP in pancreatic cancer cells is associated with decreased cell proliferation and increased expression of CEA and other glycoproteins.
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PMID:Cyclic-AMP-stimulated synthesis and release of carcinoembryonic antigen by pancreatic cancer cells. 283 72

The intracellular concentration and rate of cyclic adenosine monophosphate (cAMP) synthesis, as measured by adenylate cyclase (AC) activity, were measured in dermal fibroblast cultures, colon cancer lines, and cells cultured from colonic epithelium and colonic adenomas. Dermal fibroblasts had higher AC activity and intracellular cAMP levels than the colon cancer lines (p less than 0.05). Benign colonic epithelial cultures (mucosa and adenomas) had AC levels similar to those found in dermal fibroblasts. To characterize further these observed differences, similar measurements were made in cultures incubated in cholera toxin (CT) or epidermal growth factor (EGF). CT stimulated AC activity and cAMP accumulation in both cancers and fibroblasts. EGF had no effect on AC activity in cancers or fibroblasts, and no effect on cAMP concentration in cancer, although EGF incubation did increase intracellular cAMP in fibroblasts. Dermal fibroblasts from colon cancer-prone patients had AC activity and cAMP concentration not significantly different, though greater, than fibroblasts from healthy individuals. Therefore, although the product of the oncogene associated with colon cancer has been shown to be an activator of AC in yeast, in human colon cancer, AC activity and intracellular cAMP concentration were much lower than in dermal fibroblasts. This difference was so great that AC activity and intracellular concentration of cAMP might be biochemical markers that can be used to differentiate colon cancer from benign cells in tissue culture.
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PMID:Adenylate cyclase activity and cyclic adenosine monophosphate levels in colon cancer lines and dermal fibroblasts and the effects of cholera toxin and epidermal growth factor. 283 11

High-performance liquid chromatography-purified 125I-vasoactive intestinal peptide (VIP) bound to T-47D human breast cancer cells in a specific, saturable, and reversible manner. Scatchard plots were compatible with the presence of one class of VIP receptors with high affinity (Kd = 4.5 X 10(-10) M VIP, and Bmax = 293 fmol/mg protein). The neuropeptide and its natural analogues inhibited the binding of 125I-VIP and stimulated cyclic AMP (cAMP) generation in T-47D cells 96-fold (EC50 = 7 X 10(-10) M VIP), in the following order of potency: VIP greater than helodermin greater than human peptide with N-terminal histidine and C-terminal methionine greater than human pancreatic growth hormone-releasing factor greater than human secretin. In contrast, 125I-VIP binding was not displaced by pancreatic glucagon, human oxyntomodulin, truncated glucagon-like peptide-1, glucagon-like peptide-2, the somatostatin analogue SMS 201-995, gastric inhibitory peptide, and a series of steroid hormones or peptides unrelated to VIP. VIP also increased cAMP generation in seven other human breast cancer cell lines: H4-66B, HSL 53, HSL 78, MCF 7, MDA-MB231, T-47D2, and ZR75-1. Adenylate cyclase activity rose from 72.2 +/- 14 to 1069 +/- 66 pmol cAMP/min mg protein after the addition of 10(-7) M VIP to T-47D plasma membranes. In agreement with our pharmacological results and the Scatchard analysis of the binding data, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the solubilized receptor in the T-47D membranes permitted identification of one autoradiographic band with a molecular weight of 69,000. The sensitivity of the Mr 69,000 binding site to GTP and low doses of VIP implies that in T-47D cells, this component constitutes the membrane domain involved in the functional regulation of adenylate cyclase by VIP receptors. Our results indicate a role for the VIP receptor-cAMP system in human breast cancer cells.
Cancer Res 1988 Sep 15
PMID:Pharmacology, molecular identification and functional characteristics of vasoactive intestinal peptide receptors in human breast cancer cells. 284 44

Desensitization of human carcinoma colonic cells in culture (HT-29) to vasoactive intestinal peptide (VIP) has been reported previously (C. Boissard, J. C. Marie, G. Hejblum, C. Gespach, and G. Rosselin, Cancer Res., 46: 4406-4413, 1986). In the present study, we have determined the ultrastructural localization of VIP and its receptor after exposure of HT-29 cells to VIP monoiodinated on tyrosyl residue 10 together with the molecular forms and the activity of the internalized VIP receptor. Quantitative electron microscope autoradiography showed that after binding at the cell surface, VIP is internalized in heterogeneous endosomes. Cross-linking experiments followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis were performed in different experimental conditions allowing us to selectively obtain cell surface-associated, internalized, or recycled receptors. No detectable alteration of the labeled VIP-receptor complex occurred during the internalization and recycling processes. Furthermore, a loss of the forskolin potentiation of the VIP-induced stimulation of adenylate cyclase was observed after VIP exposure. This feature was time and temperature dependent as was the VIP-induced loss of cell surface receptors, indicating that the internalized VIP receptor is dissociated from the adenylate cyclase.
Cancer Res 1988 Nov 01
PMID:Combined ultrastructural and biochemical study of cellular processing of vasoactive intestinal peptide and its receptors in human colonic carcinoma cells in culture. 284 2

The renal response to calcium infusion was compared in ten normocalcaemic patients with squamous cell cancer and in ten normocalcaemic patients with adenocarcinoma. Both groups were comparable with regard to tumour load, renal function, magnesium and 25-hydroxyvitamin D levels. After injection of 3 mg elementary Ca/kg BW nephrogenous cAMP excretion fell significantly in the group of adenocarcinoma patients (1.74 +/- 1.14 nmol/dl GF vs. 2.81 +/- 1.39 nmol/dl GF; P less than 0.01) and TmPO4/GFR rose significantly at 60 and 120 min. No fall in NcAMP excretion was observed in the group of squamous cell cancer patients (2.18 +/- 0.84 vs. 2.24 +/- 0.84 nmol/dl GF; NS) and TmPO4/GFR remained unchanged. Three of ten patients with squamous cell cancer showed a paradoxical rise in NcAMP excretion following calcium administration. The other seven patients with squamous cell cancer showed a decline in NcAMP excretion (delta NcAMP) which was significantly less than in the ten patients with adenocarcinoma (0.52 +/- 0.16 vs. 1.23 +/- 0.74 nmol/dl GF; P less than 0.05). Increased phosphaturia was observed in three of ten patients with squamous cell cancer after calcium was administered. This also occurred in the presence as well as in the absence of a paradoxical activation of the adenylate cyclase system. It is concluded that the abnormal NcAMP response to calcium-infusion in normocalcaemic squamous cell cancer patients might be due to the presence of a non-suppressible PTH-like substance in these patients.
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PMID:Abnormal responsiveness of nephrogenous cyclic AMP excretion following intravenously administered calcium in normocalcaemic squamous cell cancer patients. 284 40

We compared the bioactivities of a synthetic truncated NH2-terminal fragment of the human (h) PTH-like peptide (PLP) associated with malignancies [hPLP-(3-34)], an intact NH2-terminal fragment [hPLP-(1-34)], and an NH2-terminal fragment of PTH [hPTH-(1-34)]. Although hPLP-(1-34) was less potent than hPTH-(1-34) in stimulating adenylate cyclase in rat renal membranes, hPLP-(1-34) and hPTH-(1-34) were equipotent in stimulating adenylate cyclase in OK renal cells as well as in UMR 108 osteosarcoma cells in vitro. In osteosarcoma cells, each of these peptides could desensitize adenylate cyclase responses to itself and to the other peptide, but could not reduce stimulation by prostaglandin E2. Renal membranes of vitamin D-deficient rats with secondary hyperparathyroidism had a reduced PLP-stimulated as well as PTH-stimulated adenylate cyclase response. The truncated analog hPLP-(3-34) was only a weak partial agonist and an antagonist in vitro, produced equivalent inhibition of hPLP-(1-34) and hPTH-(1-34) in renal and osseous cells, and could not desensitize agonist responses. In thyroparathyroidectomized rats in vivo, hPLP-(1-34) and hPTH-(1-34) increased cAMP excretion, enhanced phosphaturia, maintained plasma calcium, and reduced calciuria. Equimolar concentrations of hPLP-(3-34) produced no increases above control levels; however, high concentrations of this peptide mimicked PTH actions on renal and plasma ion handling while modestly augmenting cAMP excretion. These results demonstrate the importance of the first two residues of PLP for bioactivity, indicate that PLP and PTH interact at common receptor sites in vivo as well as in vitro, suggest that PLP may not be less potent than PTH in renal target cells, and indicate that the net result of interaction of these peptides with their common receptor in target tissues may reflect both activation and desensitization of receptor-mediated events.
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PMID:Influence of the amino-terminus on in vitro and in vivo biological activity of synthetic parathyroid hormone-like peptides of malignancy. 284 83

Prostaglandin E (PGE) receptors and PGE-adenylate cyclase responsiveness were measured in tumor samples from a hormone-dependent subline of the transplantable MTW9 rat mammary tumor and from an autonomous subline derived from the hormone-dependent tumor. Scatchard analysis of the equilibrium binding data suggested that the hormone-dependent, slow-growing (MTW9A) tumors contain two major types of binding sites for PGE2: a high-affinity component (Kd less than 10(-9) M) and a low-affinity component [Kd greater than 10(-8) M]. The hormone-autonomous, fast-growing tumors (MTW9D), however, have lost more than 80% of the PG binding sites and exhibited mainly a predominant PGE lower affinity component (Kd greater than 10(-8) M). Loss of PGE receptors in autonomous tumors was not due to in vivo down-regulation of these receptors by excessive production of PGE, since both the hormone-dependent and autonomous tumors endogenously produce and release approximately the same amounts of PGE. Incubation of tumor tissues in vitro with PGE caused a significant stimulation of adenylate cyclase activity in the MTW9A tumors, whereas adenylate cyclase activity was not stimulated in the MTW9D tumors even in the presence of the nonhydrolyzable analogue of GTP, Gpp[NH]p. The results suggest that loss of PGE receptors and PGE-adenylate cyclase responsiveness occurs during progression of mammary tumors from hormonal dependence to autonomy and that the subsequent loss of cyclic AMP is associated with the uncontrolled growth characteristics of the autonomous tumors.
J Natl Cancer Inst 1986 Jan
PMID:Loss of prostaglandin E receptors during progression of rat mammary tumors from hormonal dependence to autonomy. 286 40

The cyclic adenosine 3':5'-monophosphate (cyclic AMP) metabolism of stratified normal rat urothelium propagated in vitro on a floating collagen matrix was characterized and used as a basis for identifying potential biochemical lesions in tumorigenic cell lines. The four neoplastic urothelial cell types studied (AY-27, AY-32, AY-33, and AY-34) were derived from Fischer 344 rats fed the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide. Epinephrine or prostaglandin E1 caused a rise in the cyclic AMP content of normal cultures which was potentiated in the presence of the cyclic nucleotide phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine or by forskolin, a diterpene activator of adenylate cyclase in intact cells. The expected, normal profile of cyclic AMP accumulation in response to beta-adrenergic receptor agonists was epinephrine greater than norepinephrine greater than phenylephrine. By every measure, the tumorigenic AY-27 cells demonstrated an overall decrease of functional adenylate cyclase activity. This was evidenced most by the low accumulation of cyclic AMP observed in response to forskolin. While prostaglandin E1 elicited a heightened cyclic AMP level in these cells, their vanishingly low response to catecholamines also suggested a potential lack of functional beta-adrenergic receptors. Cyclic AMP phosphodiesterase activity was elevated in soluble enzyme preparations obtained from cultures of AY-27 cells. Observations of AY-32 cells were diametrically opposite to the findings with AY-27 cells. In AY-32 cells, prostaglandin E1 receptors appeared to be functionally absent. The beta-adrenergic receptor agonist response profile was abnormal in AY-32 cells. Norepinephrine produced a greater accumulation of cyclic AMP than epinephrine, and phenylephrine stimulated a much greater than normal response. Forskolin stimulation indicated an average level of adenylate cyclase activity in AY-32 cultures. Soluble preparations from AY-32 cells demonstrated a normal amount of cyclic AMP phosphodiesterase activity. AY-33 cells were comparable to normal urothelial cells in all respects save one. These tumorigenic cells had elevated levels of cyclic AMP phosphodiesterase activity. AY-34 cells, like AY-32 cells, were deficient in their responsiveness to prostaglandin E1. However, unlike the other tumorigenic lines, AY-34 cells had an excess of adenylate cyclase as demonstrated by their extraordinary responsiveness to forskolin. In addition, the accumulation of cyclic AMP in AY-34 cells in response to stimulation by epinephrine and norepinephrine, but not phenylephrine, was unusually great.(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Res 1985 Jan
PMID:Aberrant cyclic adenosine 3':5'-monophosphate metabolism in cultures of tumorigenic rat urothelium. 298 Nov 57

In search of the degree of responsiveness of mammary adenocarcinomas to signals of differentiation, mouse mammary tumors were induced to undergo a course of development leading to multiple foci of squamous metaplasia, and subsequently a differentiation manifested by marked keratinization. The mammary tumors had spontaneously arisen in the preneoplastic mammary outgrowths of the transplantable lines, D1, MH5, and MH9, after their long-term implantation in gland-free mammary fat pads of virgin BALB/c mice. The inductions were produced in cultured fragments of mammary tumors by incubation for 9 days in the cyclic adenine nucleotide, N6-O2'-dibutyryl cyclic AMP, at 0.1 mM, without or with prostaglandins E1, E2, and B1, each at 5 micrograms/ml, and 1 microM papaverine. The N6-O2'-dibutyryl cyclic AMP alone was as active in the mammary tumors derived from the D1 and MH9 preneoplastic outgrowths as was the entire mixture of inducers. Intracellular cyclic adenine nucleotide may presumably be the specific mediator of the inductive process, presumably being elevated synergistically by entry of the N6-O2'-dibutyryl cyclic AMP, by induction of adenyl cyclase by prostaglandin E1 and E2, and through inhibition of phosphodiesterases by papaverine. Epidermidalization occurred to equal extent in well-differentiated and anaplastic mammary adenocarcinomas, indicative that mammary tumor progression did not affect the susceptibility to this course of development and differentiation. Mammary gland epithelium retains its susceptibility to multifocal epidermidalization in organ culture throughout the gradient of neoplastic transformation and progression toward decreasing growth regulation, starting from normal mammary gland, next preneoplasia (both reported previously), then well-differentiated neoplasia, and lastly anaplastic cancer. The findings support the existence of a common or closely associated pool of progenitor cells for the alveolar and epidermoid courses of development and differentiation in mammary gland. Induction of squamous metaplasia and abundant keratinization in both the well-differentiated and anaplastic mammary adenocarcinomas caused some of the cells to differentiate terminally and to die.
Cancer Res 1985 Apr
PMID:Induction of epidermoid differentiation by cyclic adenine nucleotide in cultured mammary tumors of mice. 298 88

This study was conducted to further characterize the previously described phenomenon of growth inhibition of neoplastically transformed C3H/10T1/2 cells (T10T1/2) by nontransformed C3H/10T1/2 clone 8 mouse embryo fibroblast (10T1/2) cells in the presence of inhibitors of cyclic adenosine 3':5'-monophosphate (cAMP) phosphodiesterase. The cAMP phosphodiesterase inhibitor dl-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO20-1724) was shown to be completely nontoxic to T10T1/2 cells at 10(-4) M, yet when added to mixed cultures of T10T1/2 cells and postconfluence growth-arrested 10T1/2 cells, colony formation and [3H]thymidine incorporation into T10T1/2 cells were virtually eliminated. This effect was dose dependent and was reversible upon drug withdrawal. In 10T1/2 cells, RO20-1724 caused a dose-dependent increase in cAMP levels from about 5 to 150 pmol/10(6) cells; in T10T1/2 cells, 10(-4) M drug treatment caused a 5-fold elevation in cAMP without a clear dose dependency. Cyclic guanosine 3':5'-monophosphate levels in 10T1/2 cells fell by 50% with drug treatment but were unmeasurable in T10T1/2 cells. When intracellular cyclic AMP levels were elevated by the adenyl cyclase stimulator forskolin, growth inhibition of T10T1/2 cells was again induced in mixed cultures but was not observed when added to T10T1/2 cells alone. Addition of RO20-1724 to low concentrations of forskolin produced a greater than additive effect on growth inhibition. Growth inhibition of T10T1/2 cells by RO20-1724 was shown to (a) require contact with, or extremely close proximity to, a confluent monolayer of 10T1/2 cells, (b) be maximum when seeded upon a growth-inhibited monolayer and not an actively growing 10T1/2 culture, and (c) not be decreased by continuous agitation of the culture medium, indicating that readily diffusible inhibitory factors are not involved. A model is presented whereby transformed cells can respond to but cannot themselves generate growth-inhibitory signals produced by post-confluence growth-inhibited nontransformed cells. The existence of these cellular interactions may well explain problems in the quantitation of transformed foci encountered in the use of this cell line as an assay system for chemical and physical carcinogens.
Cancer Res 1985 May
PMID:Requirements for and kinetics of growth arrest of neoplastic cells by confluent 10T1/2 fibroblasts induced by a specific inhibitor of cyclic adenosine 3':5'-phosphodiesterase. 298 40


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