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)

This review consists of the following parts: plasma membranes of cells in normal and cancer tissue; adenylate cyclase complex (ACC) and tumour development; ACC regulation and phase state of lipids in the membranes of tumour cells; interrelations of ACC with the other signal-receiving systems of normal and tumour cells; the role of ACC in providing, changing and analyzing the hormone sensitivity of tumour tissue, regulation of the hormone sensitivity of tumour tissue by means of influences on ACC.
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PMID:[Adenylate cyclase complex, lipids and the regulation of the hormonal sensitivity of tumor tissue]. 302 8

Monolayer cultures of human thyrocytes from normal tissue (n = 10), and adenomas (n = 7), differentiated (n = 4), poorly differentiated (n = 2), and undifferentiated (n = 3) thyroid cancers were established to assess the significance of thyrotropin (TSH) and cAMP (adenosine 3',5'-cyclic monophosphate) on cell growth and DNA (deoxyribonucleic acid) synthesis. Cell growth of thyrocytes from normal and adenomatous tissues increased more rapidly (p less than 0.01) after TSH (0.1 IU/ml) was added but was unaffected by cAMP (10(-4) mol/L). In these cells, TSH also enhanced DNA synthesis twofold to twelvefold (p less than 0.01). The adenylate cyclase (AC) inhibitor, 2',3' dideoxyadenosine (ddA), increased DNA synthesis 1.3 to 6 times at a concentration of 2 X 10(-4) mol, whereas the membrane/passable cAMP analogue, dibutyryl-cAMP, and the AC stimulator, forskolin, failed to show any effect on DNA synthesis up to a concentration of 10(-5) mol/L (p less than NS). When administered simultaneously, TSH (1/2 maximum) and ddA (20 mumol) had no cumulative effect on DNA synthesis (p = NS). TSH stimulation in cancerous thyroid tissue (n = 11) demonstrated a lack of TSH response in seven of 11 monolayer cultures with no apparent correlation to cancer differentiation, patient age, or sex. Thus TSH was demonstrated to stimulate DNA synthesis and cell growth of human thyrocytes in monolayer cultures independent of the AC system. However, the TSH effect on cell growth and DNA synthesis was unpredictable in thyrocytes from cancerous tissues.
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PMID:The effect of thyrotropin and cAMP on DNA synthesis and cell growth of human thyrocytes in monolayer culture. 302 42

Retinoids and cAMP-elevating agents markedly inhibited the proliferation of human mammary tumor cells. Their response has been previously correlated with the presence of estrogen receptor (ER) positivity. MDA-MB-231 cells were ER negative and insensitive to the antiproliferative effects of retinoids. However, their growth was markedly inhibited by agents that elevated intracellular cAMP levels, i.e., 8-bromo-cAMP, cholera toxin (CT), forskolin, and the phosphodiesterase inhibitor papaverine. The CT and forskolin inhibition of the ER-positive cells (MCF-7) was associated with an elevation of adenylate cyclase activity and intracellular cAMP levels; however, similar elevations in intracellular cAMP levels were not observed following CT or forskolin inhibition of MDA-MB-231 cells but only following the addition of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine.
J Natl Cancer Inst 1987 Jun
PMID:Inhibition of human mammary carcinoma cell proliferation by retinoids and intracellular cAMP-elevating compounds. 303 64

This study examines the osteoblastic properties of the established human osteosarcoma cell line Saos-2. Saos-2 cells inoculated into diffusion chambers, which were implanted i.p. into nude mice, produced mineralized matrix in 4 of 6 chambers at 8 weeks. In 5 of 6 chambers there was a strong positive alkaline phosphatase reaction. In culture the alkaline phosphatase levels increased with time and cell density, reaching very high levels at confluence: 4-7 mumol/mg protein/min. The cells show a sensitive adenylate cyclase response to parathyroid hormone, 50% effective dose = 2.8 nM, which increases with cell density and is further raised by dexamethasone treatment. They also exhibit typical binding of 1-25-dihydroxyvitamin D3 to 3.2S receptor protein with an apparent Kd of 0.21 nM; the numbers of sites per cell were 3,300 at 50,000 cells/cm2 and 1,800 at 280,000 cells/cm2. The presence of osteonectin was visualized with a monoclonal antibody which revealed a reticular pattern on the cell surface. Osteonectin was also detected in the medium by Western blots, migrating at around Mr 40,000 in nonreduced gels and Mr 44,000 in reduced gels. The Saos-2 cells thus possess several osteoblastic features and could be useful as a permanent line of human osteoblast-like cells and as a source of bone-related molecules.
Cancer Res 1987 Sep 15
PMID:Characterization of a human osteosarcoma cell line (Saos-2) with osteoblastic properties. 304 Feb 34

How do the p21v-ras proteins and their normal cellular counterparts regulate cell function? What is the molecular basis of action of these proteins? Biochemical, structural and functional similarities between the ras proteins and the vertebrate G proteins offer clues that may help to answer such questions. The G proteins couple a wide array of extracellular signals to regulation of a number of enzyme effectors, including adenylate cyclase, retinal cGMP phosphodiesterase and phospholipase-C. The RAS1 and RAS2 proteins of yeast regulate adenylate cyclase, whereas their close mammalian homologues, the p21ras proteins, do not. Both the ras and the G proteins are located at the cytoplasmic face of the plasma membrane and bind and hydrolyse GTP. Patchy amino acid sequence homologies between the two groups of proteins suggest a common evolutionary origin and common structural features, particularly in the GTP binding domain. In the GTP bound state both proteins are 'on' or activated, and each exhibits an intrinsic GTPase activity that turns off the active state. The analogies between the G and ras proteins suggest that the latter may also couple signal detector and enzymatic effector elements, and suggest strategies for identifying them.
Cancer Surv 1986
PMID:Mammalian G proteins: models for ras proteins in transmembrane signalling? 309 65

Members of the ras multigene family have been found in virtually all eukaryotes, from yeast to mammals. ras is required for normal cell growth in the yeast Saccharomyces cerevisiae and in at least some mammalian cells. These genes induce tumorigenic transformation of established NIH 3T3 cells by increased expression of a normal ras gene, certain point mutations or amino acid deletion. In tumours, point mutation appears to be the most common mechanism of activation. The ras proteins are found at the plasma membrane, bind guanine nucleotides GDP and GTP and possess a GTPase activity. At least some ras proteins that have been activated by single amino acid substitutions possess a GTPase activity that is lower than that of the normal version. These results are consistent with the hypothesis that ras protein stimulates its putative target(s) when GTP is bound to it, as is true for the G regulatory proteins or elongation factor Tu. In Saccharomyces cerevisiae, ras has been shown to stimulate adenylate cyclase. However, there does not appear to be a direct interaction between ras and adenylate cyclase in mammalian cells.
Cancer Surv 1986
PMID:The ras gene family. 309 66

We have determined that the primary reason for the frequently encountered poor survival of human scirrhous breast carcinomas in short-term (4 days) organ culture is mechanical injury to the tumor tissue during explant preparation. It was possible to minimize this injury by preparing 0.5-mm-thick slices using very sharp blades. This resulted in much improved preservation of tissue structure and function, as assessed by histology, DNA content, and enzyme synthesis and secretion. With the exception of insulin, which was always present in the culture medium, exogenous hormones, including estrogen, or serum did not further improve explant preservation. In rodent mammary tumors, growth in vivo and production of the serine protease plasminogen activator (PA) in organ culture are coordinately regulated by hormones, suggesting that PA may be a valuable indicator of tumor hormone responsiveness. We have now tested the effect of estrogen and other hormones on PA secretion in organ cultures of primary human breast carcinomas. We found that: modulation of PA by 17-beta-estradiol (10-8) M) occurred only in carcinomas which were positive for both estrogen and progesterone receptors; of 21 such tumors, 11 (52%) were responsive. Plasminogen activator was not modulated by estradiol in any of the 22 tumors which were negative for one or both receptors; hydrocortisone (10(-7) M) effectively inhibited, and 3,5,3'-L-triiodothyronine (10(-8) M) and adenylate cyclase activators effectively stimulated PA in most breast tumors, regardless of their estrogen and progesterone receptor status. Prolactin (5 micrograms/ml) had no effect when tested alone; urokinase-type PA was found to be the principal PA produced by human breast tumors. Changes in its rate of synthesis and secretion and not in the content of PA inhibitors appeared to be the prevailing mechanism of enzyme regulation by hormones. In summary, short-term organ culture coupled with the use of PA as an index of response appears to be a promising approach to the study of hormone sensitivity of primary human breast carcinomas.
Cancer Res 1987 Jul 01
PMID:Hormonal modulation of plasminogen activator: an approach to prediction of human breast tumor responsiveness. 310 11

The ability of a series of B16 melanoma clones to form experimental lung metastases in syngeneic mice has been shown to correlate positively with adenylate cyclase activity. (Sheppard et al, Int. J. Cancer 37 (1986) 713-722). To begin to identify the components of the adenylate cyclase complex that account for enhanced enzyme activity in highly metastatic tumor populations, cholate extracts containing the GTP-binding protein GS from B16 melanoma clones of different metastatic capacities were reconstituted with membranes prepared from S49 cyc-, a variant lymphoma cell line that lacks GS function. The results revealed that extracts from a highly metastatic B16 clone (F10-C23) reconstituted significantly greater adenylate cyclase activities in S49 cyc- membranes than parallel preparations from a B16 clone (F1-C29) of low metastatic capacity. The data suggest that aberrations in GS function may contribute to the heightened responsiveness of adenylate cyclase observed in B16 melanoma clones of increased metastatic potential.
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PMID:Reconstitution of the Gs protein from B16 melanoma clones of high and low experimental metastatic potential into S49 cyc-membranes. 311 61

The purpose of this study was to elucidate the changes of the TSH receptor-adenylate cyclase system in differentiated thyroid carcinomas, and their relationships with nuclear DNA content, cell kinetics and clinical stage. The results showed that the papillary carcinomas had an impaired TSH receptor-adenylate cyclase system. The production of cAMP stimulated by TSH was decreased when compared with non-cancerous tissue and high-affinity TSH receptors were reduced in number or even completely lost (nine in 24 cases). Follicular carcinomas also showed a reduction in, or even complete loss, of high-affinity TSH receptor (one in five cases). However, the responses to the stimulation of TSH, Gpp (NH)p and forskolin were not different from those in non-cancerous tissue. Papillary and follicular cancer cells showed more proliferative activity than those in non-cancerous tissue. Follicular carcinomas contained more hyperploid cells (DNA content greater than 2.5 C) than papillary carcinomas. There were no differences in cell kinetics, DNA content or the effects of Gpp (NH)p or forskolin on adenylate cyclase activity between those papillary carcinomas with high-affinity TSH receptor and those without. However, the presence of high-affinity TSH receptors had higher cAMP generation stimulated by TSH. The patients having papillary carcinomas in the absence of high-affinity TSH receptors were all in clinical stage III. These studies suggest that TSH receptors are the major sites influenced in the TSH receptor-adenylate cyclase system in papillary carcinomas. The TSH receptor-adenylate cyclase system of papillary carcinomas differs more from normal than does that of follicular carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cell kinetics, DNA content and TSH receptor-adenylate cyclase system in differentiated thyroid cancer. 325 29

Cancer is a malfunction of cellular growth control. The discovery of oncogenes, first in transforming retroviruses, and later in human and animal tumors, may have uncovered the key to understanding one of the most elusive subjects of basic cell biology, namely, the controlling mechanisms of cell growth. The ras gene family encodes a group of closely related 21,000 dalton (p21) proteins with special affinity for guanine nucleotides. Other cellular proteins with similar biochemical properties, collectively known as G-proteins, include the regulatory G proteins of adenylate cyclase, the alpha subunit of transducin of retina rod outer segments, the recently identified rho gene proteins, and perhaps also the elongation factors, EF-Tu and EF-G, of the protein synthesis system. These G-proteins have roles in cellular signal transduction; by analogy p21 may have a similar cellular function in mediating the flow of growth control signals. Recent progress in the cloning and sequencing of these genes, overproduction of gene products in E. coli, protein engineering, detailed biochemical characterization, and the molecular structure determined by high resolution X-ray crystallography, have helped to elucidate in great detail the structure and function of p21 ras proteins. p21 appears to have a small membrane binding domain at the C-terminus, which contains a palmitylation site at cysteine-186, four amino acid residues from the end. Separated by a variable "hinge" region, most of the rest of ras amino acid sequences are highly conserved in nature. Four regions of extensive sequence homology among G-proteins constitute the GTP/GDP binding domain. In the crystal structure of EF-Tu, four peptide loops connecting beta sheets and alpha helices form the pocket for binding GDP. Studies using site-directed mutagenesis and immnochemical probes, indicate that the basic structure of the GDP binding site is conserved between p21 and EF-Tu. Furthermore, these studies also conclude that GTP binding is crucial for p21 ras cellular function. Although the precise target molecules for p21 are still unknown, the finding of the on/off switch function for ras genes have provided a better understanding of the mechanism of proto-oncogene activation, and may also provide further impetus to explore means of cancer intervention by interfering with the switch function.
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PMID:Structure and function of p21 ras proteins. 333 61


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