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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum hepatic cell-surface enzymes, isoenzymes, and sialic acid levels may be useful adjuncts in detecting early metastatic disease and in evaluating the tumor burden of patients with uveal melanoma. Hepatic cell-surface enzyme concentrations were elevated in the serum of ten patients with uveal melanoma and liver metastasis and in five patients with other hepatobiliary disorders and in 75 control patients. Five patients in the metastatic group (50%) had serum gamma-glutamyl transpeptidase and 5'-nucleotide phosphodiesterase (5-NPD) bands known to be associated with either primary hepatic carcinoma or carcinoma metastatic to the liver. One patient with uveal melanoma without known metastasis had a positive 5-NPD pattern; metastatic disease was subsequently proved. Higher levels of sialic acid were found in the serum of patients with uveal melanoma and metastatic disease (4 mumole/mL) than in controls (2.4 mumole/mL).
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PMID:Metastatic uveal melanoma. Hepatic cell-surface enzymes, isoenzymes, and serum sialic acid levels in early metastatic disease. 684 71

Treatment of the T47D(A1-2) mammary carcinoma cell line with the nonspecific kinase inhibitor 2-aminopurine (2AP) has an unusual effect on induction of the mouse mammary tumor virus promoter by glucocorticoids. 2AP initially abrogates the dexamethasone-mediated increase, but after about 16-20 h, this effect is reversed, and continued incubation with 2AP potently stimulates the hormone induction. The biphasic kinetics of 2AP action displayed cell specificity. No inhibitory phase was seen in fibroblasts. Cell type specificity is also seen upon treatment of cells with isobutylmethylxanthine (IBMX). Dexamethasone action is inhibited in mammary cells, but potentiated in fibroblasts. Unlike 2AP treatment, IBMX continues to suppress the hormone response through at least 48 h of treatment. IBMX is commonly used as a phosphodiesterase inhibitor, and indeed, it stimulates a cAMP-dependent promoter in both mammary carcinoma cells and fibroblasts. Because elevating cAMP will potentiate dexamethasone-mediated induction in mammary cells, IBMX must be interventing in another pathway that elicits IBMX-dependent suppression of the hormone response. Pharmacological studies suggest that this interaction is not mediated through adenosine receptors, histamine receptors, or imidazoline receptors. The five-member imidazole ring plays a critical role in the suppressive activity; substitutions at the 7 position inhibit suppression. These results give further indication of coupling of steroid receptor action to other cellular signaling pathways. This complex spectrum of interactions may play a central determining role in the tissue specificity of the response to steroid hormones.
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PMID:Modulation of glucocorticoid-regulated transcription by purines: novel characteristics and implications for tissue specificity of steroid responses. 753 78

We have stably introduced expression vectors for the glucocorticoid receptor and a sensitive, hormone-responsive reporter (mouse mammary tumor virus-luciferase) into a human breast carcinoma-derived cell line. Employing this cell line, we have conducted a detailed examination of the induction of glucocorticoid-regulated genes and the phosphorylation of glucocorticoid receptor following pharmacologic manipulation of cell signaling pathways. The hormone response can be enhanced from 2 to 10-fold by activators of protein kinase A, protein kinase C, and inhibitors of protein phosphatase. Forskolin and 8-bromoadenosine 3':5'-cyclic monophosphate (BrcAMP), but not BrcGMP, enhance the hormone effect, yet surprisingly, phosphodiesterase inhibitors, isobutylmethylxanthine and Ro20-1724, strongly inhibit hormone-mediated induction of the reporter gene. These treatments do not alter cellular receptor content, dexamethasone binding, nor hormone-mediated receptor down-regulation. Tryptic peptide analysis of 32P-labeled receptor reveals that neither BrcAMP, isobutylmethylxanthine, nor the tumor promoter and protein kinase C activator, 12-O-tetradecanoyl-phorbol-13-acetate, detectably alter the state of glucocorticoid receptor phosphorylation. The only agent which alters receptor phosphorylation is the protein phosphatase inhibitor okadaic acid, but only at concentrations higher than required for maximum effects on glucocorticoid receptor transactivation. We propose that these effectors do not modify receptor directly but alter its interaction with transcription complexes.
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PMID:Modulation of cell signaling pathways can enhance or impair glucocorticoid-induced gene expression without altering the state of receptor phosphorylation. 769 81

Various derivatives of oligoribonucleotides were synthesized by the H-phosphonate method. Different modifications of the ribophosphate backbone were designed in order to protect the derivatives against nucleolytic enzymes present in the biological media. These modifications include coupling of fluorescein moiety to 3'-terminal ribose, 2'-O-methylation of ribose, introduction of phosphorothioate internucleotide bonds throughout the molecule, replacement of the two last 3'-terminal phosphodiester bonds by phosphoroamidates and coupling of the last 3'-terminal nucleotide via the 3'-3'-phosphodiester bond. All modifications were tested for their effect on the stability of the derivatives against phosphodiesterase from snake venom and nucleases of the cell culture media. 2'-O-methylated oligoribonucleotides containing either terminal 3'-3'-linkage or two 3'-terminal phosphoroamidate internucleotide bonds appeared to be the most stable under the most severe conditions used. The results demonstrate a possibility to use protected oligoribonucleotide derivatives for experiments in vivo when the use of deoxy-analogues might be ineffective. The uptake of 2'-O-methylated derivatives and their 5'-cholesterol conjugates (coupled via a disulfide bond) by human carcinoma cells did not differ from that of the corresponding oligodeoxyribonucleotides. 85% of the bound derivatives were found in the membrane-cytosolic fraction, while only 15% were found in the nuclear fraction. The oligonucleotide moiety of 2'-O-methyloligoribonucleotide-cholesterol conjugate was not translocated through the cellular membrane. After cleavage of the linkage between cholesterol and oligonucleotide by dithiothreitol the major portion of the oligonucleotide moiety was released into the media. The derivatives, as well as their 5'-cholesterol conjugates, which entered the cells, were stable and protected from action of dithiothreitol dissolved in culture media. These results demonstrate an endocytosis mechanism of penetration as observed in similar experiments using oligodeoxyribonucleotides.
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PMID:Effect of derivatization of ribophosphate backbone and terminal ribophosphate groups in oligoribonucleotides on their stability and interaction with eukaryotic cells. 803 1

In a human breast carcinoma-derived cell line engineered to contain a hormone-responsive luciferase reporter gene, manipulation of cell growth conditions or cellular signal transduction in a variety of ways can enhance or impair glucocorticoid-mediated induction of a target gene. Induction may be enhanced as much as 10-fold or inhibited 90% by different treatments. For example, two different inhibitors of protein phosphatase-1 and -2A potentiated the hormone-dependent induction of luciferase. Activation of protein kinase-A via addition of 8-bromo-cAMP or forskolin also potentiated the hormonal induction, whereas 8-bromo-cGMP was ineffective. In contrast, activating protein kinase-A by inhibiting cAMP turnover with the phosphodiesterase inhibitors isobutylmethylxanthine or Ro20-1724 inhibited the hormone response rather than potentiated it. The inhibitory activity of isobutylmethylxanthine was evident even when activators of protein kinase-A are administered simultaneously. Isobutylmethylxanthine must, therefore, activate a signal transduction pathway in addition to the protein kinase-A pathway. Activation of protein kinase-C potentiated the hormone response in a cell-specific manner. Treatment with epidermal growth factor and imposition of cell stress by heat shock or inhibition of protein synthesis also enhanced the glucocorticoid response. Thus, our results suggest an elaborate coupling of the steroid response pathway with other cellular signal transduction mechanisms that permits an additional layer of control to be imposed on hormone-mediated transcriptional responses. It is proposed that cell-specific phosphorylation events influence steroid receptor interaction with the basal transcription apparatus, thereby altering receptor-mediated induction mechanisms.
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PMID:The coupling of multiple signal transduction pathways with steroid response mechanisms. 813 36

Recent clinicopathologic studies have shown that many prostatic adenocarcinomas express focal neuroendocrine differentiation and that neuroendocrine differentiation is most apparent in advanced anaplastic tumors. While studying growth-regulatory signal transduction events in human prostate carcinoma cell lines, we found that in two of four cell lines, the androgen-sensitive line LNCaP and the highly metastatic androgen-independent line PC-3-M, elevation of cAMP through addition of cAMP analogues or phosphodiesterase inhibitors induced a markedly neuronal morphology. Also in LNCaP cells ultrastructural analysis showed that cAMP induced the appearance of neurosecretory cell-like dense-core granules. Phenotypic analysis of untreated LNCaP and PC-3-M cells showed that both cell lines express markers of the neural crest including S-100, chromogranin A, pp60c-src, and neuron-specific enolase as well as the epithelial marker KS1/4 and stage-specific embryonic antigen 4. In PC-3-M cells, cAMP markedly elevated neuron-specific enolase protein and caused an increase in the specific activity of the neuroendocrine marker pp60c-src, and in both cell lines expression of KS1/4 and stage-specific embryonic antigen 4 was down-regulated. In addition to effects on lineage markers, cAMP treatment induced G1 synchronization, growth arrest, and loss of clonogenicity, indicating terminal differentiation. Our data provide direct evidence of plasticity in the lineage commitment of adenocarcinoma of the prostate. We have shown that cell-permeant cAMP analogues can induce terminal differentiation, suggesting that hydrolysis-resistant cyclic nucleotides may present an additional approach to the treatment of advanced prostate cancer.
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PMID:Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP. 820 89

A preliminary investigation of enzymes functioning at the cell surface indicates that when Walker 256 carcinoma cells growing ascitically are induced to grow as a solid tumour there is a marked increase in the activities of Na+, K(+)-ATPase, Mg(2+)-ATPase, 5'-nucleotidase, alkaline phosphatase and phosphodiesterase I; 5'-nucleotidase and alkaline phosphatase being particularly affected. These enzyme changes occur in the absence of any major alteration in the protein composition of the plasma membrane.
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PMID:Protein and enzyme content of plasma membranes derived from Walker 256 carcinoma cells grown as ascitic or solid tumours. 838 3

Isoenzymes of 3',5'-cyclic nucleotide phosphodiesterase (PDE) have been characterized in B16 murine melanoma cells and MCF-7 human mammary carcinoma cells. Separation of soluble phosphodiesterase activity by fast protein liquid chromatography on a Mono-Q column resolved three isoenzymes, MCF-7 cells contained a cyclic GMP-specific isoenzyme (PDE-V), a cyclic GMP-activable isoenzyme (PDE-II), and a cyclic AMP-specific isoenzyme (PDE-IV). B16 cells contained a cyclic GMP-specific isoenzyme (PDE-V), a Ca2+/calmodulin-activated isoenzyme (PDE-I), and a cyclic AMP-specific isoenzyme (PDE-IV). A series of PDE inhibitors was tested for their activity spectrum on PDE isoenzymes. Inhibition of PDE activity in B16 cells by the new compound DC-TA-46, was found to result specifically from PDE-IV inhibition [50% inhibition (IC50) = 0.03 microM]. Much lower inhibitory activity was observed for DC-TA-46 toward PDE-I (IC50 = 5 microM) and PDE-V (IC50 = 14 microM). DC-TA-46 was found to inhibit growth of B16 melanoma and MCF-7 mammary carcinoma cells dose dependently (B16: IC50 = 1.7 microM, MCF-7: IC50 = 2 microM). At 2 microM concentration, growth inhibition of B16 melanoma cells was 60%, concomitant with a decrease in PDE activity of 63% and an increase in cAMP level of 59%. In contrast, incubation with inhibitors specific for PDE-I and PDE-V resulted only in marginal or undetectable growth inhibition. The results suggest a correlation between PDE-IV inhibition and growth inhibition. PDE-IV thus appears to be a potential new target for antiproliferative treatment.
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PMID:3',5'-Cyclic nucleotide phosphodiesterase in tumor cells as potential target for tumor growth inhibition. 839 85

Chinese hamster ovary cells (CHO cells) do not exhibit any Ca2+/calmodulin-stimulated cAMP phosphodiesterase (PDE1) activity. Challenge of CHO cells with agonists for endogenous P2-purinoceptors, lysophosphatidic acid receptors and thrombin receptors caused a similar rapid transient induction of PDE1 activity in each instance. This was also evident on noradrenaline challenge of a cloned CHO cell line transfected so as to overexpress alpha 1B-adrenoceptors. This novel PDE1 activity appeared within about 15 min of exposure to ligands, rose to a maximum value within 30 min to 1 h and then rapidly decreased. In each case, the expression of novel PDE1 activity was blocked by the transcriptional inhibitor actinomycin D. Challenge with insulin of either native CHO cells or a CHO cell line transfected so as to overexpress the human insulin receptor failed to induce PDE1 activity. Reverse transcriptase-PCR analyses, using degenerate primers able to detect the PDE1C isoform, did not amplify any fragment from RNA preparations of CHO cells expressing PDE1 activity, although they did so from the human thyroid carcinoma FTC133 cell line. Reverse transcriptase-PCR analyses, using degenerate primers able to detect the PDE1A and PDE1B isoforms, successfully amplified a fragment of the predicted size from RNA preparations of both CHO cells expressing PDE1 activity and human Jurkat T-cells. Sequencing of the PCR products, generated using the PDE1A/B primers, yielded a novel sequence which, by analogy with sequences reported for bovine and murine PDE1B forms, suggests that the PDE1 species induced in CHO cells through protein kinase C activation and that expressed in Jurkat T-cells are PDE1B forms.
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PMID:Receptor-mediated stimulation of lipid signalling pathways in CHO cells elicits the rapid transient induction of the PDE1B isoform of Ca2+/calmodulin-stimulated cAMP phosphodiesterase. 900 15

Cells of two human follicular thyroid carcinoma cell lines (FTC133, FTC236) were stably transfected with a cDNA encoding the PDE4A cAMP-specific phosphodiesterase (PDE) splice variant RD1 (RNPDE4A1A) so as to generate the cloned cell lines, FTC133A and FTC236A. This allowed the expression of a novel rolipram-inhibited cAMP-specific PDE activity in these cells. Unlike the parent cell lines in which Ca2+/calmodulin caused a profound activation (approx. 3-4-fold) of homogenate PDE activity, no such stimulation was evident in the RD1-expressing cell lines, indicating loss of PDE1 activity. Reverse transcriptase-PCR analysis indicated that this was due to the down-regulation of the PDE1C isoform. The novel PDE4 activity in transfected cells was located exclusively in the membrane fraction, as was immunoreactive RD1. Low concentrations of the detergent Triton X-100, but not high NaCl concentrations, allowed RD1 to be solubilized. Laser scanning confocal immunofluorescence analyses identified RD1 immunoreactivity in a discrete perinuclear region of these RD1-expressing transfected cell lines. A similar pattern of labelling was observed using the antiserum Tex1, which specifically identified the Golgi apparatus. Treatment of FTC133A cells with the Golgi-perturbing agents monensin and brefeldin A led to a similar redistribution of immunoreactive species detected using both the Tex1 and anti-RD1 antisera. It is suggested that the PDE4A splice variant RD1 contains a membrane-association signal which allows the targeted expression of RD1 within the Golgi complex of these human follicular thyroid carcinoma cell lines.
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PMID:Intracellular localization of the PDE4A cAMP-specific phosphodiesterase splice variant RD1 (RNPDE4A1A) in stably transfected human thyroid carcinoma FTC cell lines. 900 17


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