Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trehalose dimycolate (TDM), a mycobacterial glycolipid, is a powerful macrophage-priming agent. However, its efficiency seems limited in the case of BALB/c mice. Peritoneal macrophages harvested from TDM-treated BALB/c mice did not control BCG growth in vitro as efficiently as similar macrophages from two other mouse strains, (B6 x D2)F1 and C57BL/6, which are respectively Bcgr and Bcgs. BALB/c macrophages elicited by TDM also exhibited a low capacity to produce hydrogen peroxide and, after activation by lipopolysaccharide (LPS), weak cytostatic activity against P815 mastocytoma cells. Finally, alkaline phosphodiesterase, a marker of resident and inflammatory macrophages, was still expressed at a high level in macrophages of BALB/c mice treated with TDM. Low responsiveness of BALB/c macrophages to stimuli was not observed with TDM only; activation for tumor cytotoxicity of thioglycolate-elicited macrophages from BALB/c mice required also higher doses of interferon-gamma, and LPS. L-Arginine-dependent production of nitric oxide was inducible in macrophages from BALB/c mice, but the conditions required for its induction were more stringent. Thus, the reduced antiproliferative effects of BALB/c macrophages may be due to uncomplete induction of NO synthase after suboptimal stimulation.
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PMID:Low response of BALB/c macrophages to priming and activating signals. 138 43

DNA from Ehrlich ascites tumor (EAT) cells and from human placenta was examined for covalent bonds between hydroxy amino acid residues in peptides and nucleotide phosphate groups. The residual proteinaceous material in highly purified DNA was radiolabelled with 125Iodine and the linking-groups between peptides and nucleotides released by combined protease and nuclease treatment were investigated with respect to their chemical and enzymatic stabilities. The residual nucleotide(s)-peptide(s) fraction from DNA isolated after prolonged alkaline cell lysis and phenol extraction contains mainly alkali and acid-stable but phosphodiesterase-sensitive peptide-nucleotide complexes which indicates phosphodiesters between tyrosyl residues in peptides and nucleotide phosphates. In contrast, the linking-group fraction from DNA isolated under native conditions contains additional peptide components. (a) Phospho-peptides that co-purify with DNA but that are not covalently bound to nucleotides. (b) A fraction of peptides that is released from nucleotides by alkali in a time and concentration-dependent reaction. Evidence is presented indicating that the latter fraction involves phospho-triesters between hydroxy amino acid residues in peptides and internucleotide phosphates. The phosphodiesters between hydroxy amino acids and nucleotide phosphates representing the predominant class of peptide-nucleotide complexes in alkali-denatured DNA are most likely side products of peptide-nucleotide phospho-triester hydrolysis.
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PMID:Chemical and enzymatic analysis of covalent bonds between peptides and chromosomal DNA. 166 8

The glycoprotein hormone common alpha-subunit can be induced in HeLa and other nontrophoblastic tumor cell lines by sodium butyrate. This report demonstrates that production of alpha-subunit can be further modulated by theophylline, especially in conjunction with butyrate. This synergism was not observed with other phosphodiesterase inhibitors such as xanthine, caffeine, theobromine, or methylisobutylxanthine. Induction by a combination of the short chain fatty acid plus the methylxanthine results from a decrease in the lag time after effector addition as well as a change in the rate of subunit accumulation. The increase in alpha-subunit is correlated with an increase in the levels of alpha-subunit mRNA, suggesting that induction is manifest at a pretranslational stage. The production of alpha-subunit was only marginally affected in cultures treated with 8-Br-cAMP or forskolin. Intracellular levels of cAMP were increased approximately threefold by methylisobutylxanthine, twofold by theophylline, fourfold by forskolin, and about 50% by butyrate, yet significant induction was achieved only by butyrate and theophylline. Taken together, these data suggest that the synergism between butyrate and theophylline is not mediated by cAMP.
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PMID:Enhancement by theophylline of the butyrate-mediated induction of choriogonadotropin alpha-subunit in HeLa cells. I. Lack of correlation with cAMP. 169 36

We report that a specific inhibitor of types 1 and 2A phosphatases, okadaic acid (OA), induces germinal vesicle break down (GVBD) and chromosome condensation when microinjected into denuded mouse oocytes maintained in prophase block by analogs of cAMP, inhibitors of phosphodiesterase, or a tumor-promoting phorbol ester. GVBD and chromosome condensation are also observed when incompetent oocytes are similarly injected with OA, this effect being dependent on the oocyte diameter. Marked changes in cell shape, cytoskeletal organization, and chromosome condensation with abnormal or abortive spindle formation are associated with such injections. The polar body is not formed. These results led to the conclusions that in mouse oocytes, OA acts distal to both the cAMP-modulated pathway involved in meiotic arrest and the inhibitory action exerted by tumor-promoting phorbol esters.
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PMID:Induction of M-phase entry of prophase-blocked mouse oocytes through microinjection of okadaic acid, a specific phosphatase inhibitor. 170 30

Somatostatin (SRIF) reduces growth hormone releasing hormone (GRF)-stimulated growth hormone (GH) release from avian and mammalian adenohypophyseal cells. The present studies examined the intracellular mechanisms mediating SRIF inhibition of GRF-stimulated GH release from chicken pituitary cells. Increases (P less than 0.05) in GH release were observed in the presence of (1) GRF; (2) the adenylyl cyclase stimulator, forskolin; (3) a cAMP analog, 8-bromo-cAMP; (4) the phosphodiesterase inhibitor 3-isobutyl-l-methyl-xanthine (IBMX) combined with GRF; (5) a tumor-promoting phorbol ester and protein kinase C activator, phorbol 12-myristate, 13-acetate (PMA); (6) a diacylglycerol analog, 1,2-dioctanoyl-glycerol (DiC8); and (7) a calcium ionophore, A23187, alone and in combination with PMA. Somatostatin (10 ng/ml) reduced the release of GH stimulated by GRF, forskolin, and 8-bromo cAMP and the GRF-provoked release of GH in the presence of IBMX (P less than 0.05). Somatostatin, however, did not influence GH release in the presence of the protein kinase C activators, PMA or DiC8, or the calcium ionophore A23187. These data suggest that SRIF inhibits GRF-provoked GH release by reducing the ability of the cAMP-protein kinase A but not of the calcium or protein kinase C intracellular message pathways to stimulate GH release.
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PMID:Possible involvement of adenylyl cyclase-cAMP-protein kinase a pathway in somatostatin inhibition of growth hormone release from chicken pituitary cells. 170 26

In order to assess the effect of increased cAMP degradation on the responsiveness on an endocrine cell, we have obtained stable transfectants of MA-10 Leydig tumor cells that overexpress a mammalian cAMP-phosphodiesterase. Two novel cell lines, designated MA-10(P+8) and MA-10(P+29), that express high levels of the transfected enzyme were characterized. Although the basal levels of cAMP in the mutant cell lines are comparable to those of the wild-type cells, the increase in cAMP accumulation elicited by human choriogonadotropin (hCG) is severely blunted. Further studies with MA-10(P+29) show that the ability of hCG to stimulate adenylyl cyclase activity is normal. The failure of MA-10(P+29) cells to accumulate cAMP in response to hCG can be correlated with a similar reduction in hCG-stimulated steroidogenesis. On the other hand, the maximal steroidogenic response of MA-10(P+29) cells to dibutyryl cAMP, a cAMP analogue that is fairly resistant to phosphodiesterase degradation, is normal. We also show that the ability of these cells to respond to hCG with increased cAMP accumulation and steroid synthesis can be restored with a specific phosphodiesterase inhibitor. These results demonstrate that overexpression of a cAMP-phosphodiesterase in MA-10 cells limits the levels of cAMP attained under hCG stimulation and supresses the steroidogenic response of these cells to hCG. Since gonadotropins increase the cAMP-phosphodiesterase activity in their target cells, these findings also provide evidence that this regulation plays a major role in the modulation of cell responsiveness. Last, these new cell lines should be valuable in the study of the actions of cAMP because they express a conditional and reversible cAMP-resistant phenotype.
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PMID:Attenuation of cAMP-mediated responses in MA-10 Leydig tumor cells by genetic manipulation of a cAMP-phosphodiesterase. 171 81

A series of studies was conducted to evaluate the ability of several second messengers/second messenger systems to stimulate LH secretion from dispersed chicken pituitary cells. [Gln8]-LHRH-(cLHRH) stimulated LH secretion in a dose-dependent fashion; this effect was potentiated in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, and was mimicked by the cAMP analog, 8-bromo-cAMP. These data indicate that the production of cAMP in response to cLHRH can stimulate LH secretion, but do not necessarily provide evidence that such production is prerequisite. The tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), and diacylglycerol analogs, 1-oleoyl-2-acetylglycerol (OAG) and 1,2-dioctanoyl-sn-glycerol (DOG), also stimulated LH release; however, only PMA (and not cLHRH or DOG) promoted an accumulation of cAMP. The putative protein kinase C inhibitor, staurosporine, completely blocked LH release stimulated by PMA, but failed to block cLHRH-induced LH secretion. Such results indicate that protein kinase C activation can promote LH secretion, but also suggest that additional second messengers may exist to fully mediate the effects of cLHRH. Both the calcium ionophore, A23187, and the intracellular calcium mobilizing agent, thapsigargin, caused a dose-dependent increase in LH secretion; furthermore, thapsigargin augmented the stimulatory effects of PMA. These data are consistent with a role for calcium in the regulation of LH release, and indicate that the mobilization of intracellular calcium alone can affect such an action.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Second messenger pathways mediating chicken luteinizing hormone secretion from dispersed pituitary cells. 171 94

Regulation of cholecystokinin (CCK) and the proto-oncogene c-fos mRNA expression was studied in the human neuroblastoma cell line SK-N-MC. Cells were treated either with the tumor promoting phorbol-ester phorbol-12-myristate-13-acetate (PMA), the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX), which results in an elevated intracellular cyclic AMP (cAMP) level, or with a combination of PMA and IBMX. The level of CCK and c-fos mRNA was determined by Northern-blot analysis with CCK and c-fos specific antisense RNA probes after 4-24 h of drug treatment. Treatment with PMA and IBMX for 4-24 hours transiently raised the CCK mRNA level approximately 1.5-3.5 times compared to the controls, and the combination PMA and IBMX had an additive effect and elevated CCK mRNA abundance 1.5-6.5 times. Under the same experimental conditions, both PMA and IBMX elevated the c-fos mRNA level approximately 3-5.5 times. The drug combination showed a pronounced synergistic effect and raised the c-fos mRNA level approximately 3-20 times as compared to controls. Apparently, CCK and c-fos mRNA expression appears to be regulated by similar protein kinase C (PKC) and cAMP-dependent mechanisms in SK-N-MC cells.
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PMID:Phorbol 12-myristate-13-acetate (PMA) stimulates a differential expression of cholecystokinin (CCK) and c-fos mRNA in a human neuroblastoma cell line. 172 Apr 2

Previous experiments have demonstrated that double-stranded RNAs (dsRNAs) can exert an antiproliferative effect on human tumor cells, independent of interferon (IFN) induction. However, the mechanism by which dsRNAs inhibit tumor growth has not been elucidated. As a first step in determining the molecular events responsible for growth arrest, we have explored the role of signal transduction through the cAMP system in the antiproliferative effect of the mismatched dsRNA, r(I)n.r(C12,U)n (Ampligen). These studies utilized the human glioma cell line A1235, which does not produce detectable levels of IFN-alpha, -beta, or -gamma in response to mismatched dsRNA treatment. Treatment of A1235 cells with mismatched dsRNA in combination with either 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), which inhibits cAMP-dependent protein kinase and protein kinase C, or N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004), which preferentially inhibits the cAMP-dependent protein kinase, yielded an antagonism of the mismatched dsRNA-induced antiproliferative effect. Measurement of adenylate cyclase activation showed a dose-dependent increase in activity at antiproliferative mismatched dsRNA concentrations, but not at lower, nonantiproliferative doses. This increase in activity was rapid, seen as early as 30 sec after initiation of treatment, and it was sustained at peak levels for 1-2 hr. Analysis of the intracellular cAMP concentration gave similar kinetics of induction. Exposure of cells to the stable cAMP analogue dibutyryl cAMP yielded dose-dependent inhibition of cell growth. The cAMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also inhibited proliferation. In contrast, neither H-7 nor HA1004 had an effect on growth inhibition induced by human natural IFN-alpha treatment. In addition, antiproliferative doses of IFN-alpha did not increase cAMP concentrations. These results indicate that the cAMP system is utilized by mismatched dsRNA as an early signal transduction mechanism for growth control. Furthermore, the antiproliferative effects induced by mismatched dsRNA and IFN can occur by different mechanisms of action.
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PMID:Cyclic AMP mediates the direct antiproliferative action of mismatched double-stranded RNA. 184 67

Diabetes mellitus is associated with high levels of adenosine 3',5'-cyclic monophosphate in tissue and plasma. Diabetes inhibits and insulin stimulates and restores low Km adenosine 3',5'-cyclic monophosphate phosphodiesterase activity. We recently reported that phorbol ester, a tumor promoting agent known to act through protein kinase C also stimulates phosphodiesterase. Here, we address the issue of whether or not the activation of phosphodiesterase by insulin and phorbol ester is different in streptozotocin diabetic adipose tissue. Rat adipose tissue was incubated with insulin, phorbol ester or other known components or effectors of the protein kinase C pathway, i.e. 1,2 dioleoyl-glycerol, 1- oleoyl, 2- acetylglycerol, Ca(++)-Ionophore A 23187, and nifedipine. After incubation, preparation and assay of adenosine 3',5'-cyclic monophosphate phosphodiesterase was made. As in previous data streptozotocin-diabetes inhibits basal phosphodiesterase by about 50% (P less than .02); insulin and phorbol ester each stimulate phosphodiesterase, in streptozotocin-diabetes less than normal (P less than .025); nifedipine inhibits phorbol stimulated phosphodiesterase in streptozotocin-diabetes but not normal (P less than .001); and nifedipine inhibits insulin stimulated phosphodiesterase in normal (84%) and diabetic (97%) (P less than .005). In normal and diabetic tissue, diacyl glycerol and oleoyl-acyl glycerol stimulate phosphodiesterase, are augmented by ionophore and inhibited by nifedipine. In addition 32P incorporation studies and measurements of tyrosine kinase activity are presented which support these differences between normal and diabetic. In summary then, these data suggest common pathways of activation for low Km adenosine 3',5'-cyclic monophosphate phosphodiesterase by insulin and phorbol ester; imply a relationship between two second messenger systems, phosphoinositides and adenosine 3',5'-cyclic monophosphate; and demonstrate a difference in activation of phosphodiesterase between normal and diabetic adipose tissue.
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PMID:Activation of cyclic AMP phosphodiesterase by phorbol and protein kinase C pathway: differences in normal and diabetic tissue. 196 4


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