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)

The interaction of okadaic acid and a protein phosphatase, which is the receptor for a tumor promoter, okadaic acid, was studied. [27-3H]Methyl 7-O-(4-azidobenzoyl)okadaate was synthesized and protein phosphatase 2A, which consists of two regulatory subunits of 65 kDa and 42 kDa and a catalytic subunit of 37 kDa, was purified from bovine brain. After UV irradiation of the reaction mixture, [3H]methyl 7-O-(4-azidobenzoyl)okadaate covalently bound to the catalytic subunit, but not to the two regulatory subunits. These results strongly suggest that okadaic acid, a potent inhibitor of protein phosphatases, binds specifically to the catalytic subunit rather than to the other regulatory subunits.
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PMID:Photoaffinity labeling of protein phosphatase 2A, the receptor for a tumor promoter okadaic acid, by [27-3H]methyl 7-O-(4-azidobenzoyl)okadaate. 216 75

Okadaic acid (OA) is a potent non-12-O-tetradecanoyl-phorbol-13-acetate (non-TPA) type tumor promoter on mouse skin. OA acts on cells through inhibiting the activity of protein phosphatases and results in the increase of phosphorylation of proteins. Seventeen OA derivatives were evaluated as possible tumor promoters by means of three biochemical tests: inhibition of specific [3H]OA binding to a particulate fraction of mouse skin containing protein phosphatases, inhibition of protein phosphatase activity, and induction of ornithine decarboxylase in mouse skin. Potency in each of these biochemical tests correlated well for each of these derivatives. We present results indicating that the carboxyl group as well as the four hydroxyl groups at C-2, C-7, C-24 and C-27 of OA are important for activity. Acanthifolicin, which gave positive responses in these three biochemical tests as strong as those of OA and dinophysistoxin-1, is predicted to be an additional member of the OA class of tumor promoters.
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PMID:Structure-activity relationship within a series of okadaic acid derivatives. 217 47

Microcystins and nodularin, isolated from toxic blue-green algae, are hepatotoxic monocyclic polypeptides. Both microcystins and nodularin inhibited in vitro protein phosphatase activity present in a cytosolic fraction of mouse liver, bound to the okadaic acid receptors, protein phosphatases 1 and 2A, and thus resulted in the increase of phosphoproteins; this was referred to as the apparent "activation" of protein kinases. Their concentrations causing 50% of the maximal effects are comparable to that of okadaic acid, a potent protein phosphatase inhibitor and a potent tumor promoter, in the nanomolar range of concentration. The increase of phosphoproteins was observed in rat primary cultured hepatocytes and was subsequently associated with morphological changes, which appeared to be a step in the process of hepatotoxicity. The well-known hepatotoxic compounds, alpha-amanitin and phalloidin, did not show any effects similar to those of microcystins, nodularin and okadaic acid. It is suggested that the hepatotoxicity of microcystins and nodularin may result from inhibition of protein phosphatases and the increase of phosphoproteins.
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PMID:Inhibition of protein phosphatases by microcystins and nodularin associated with hepatotoxicity. 217 96

Calcineurin is one of the calmodulin binding proteins and a Ca2+-dependent and calmodulin-stimulated phosphoprotein phosphatase. We used antisera to the calcineurin as a cell-type-specific marker in order to identify neuronal cells in the rat brain and human neoplasms. In normal rat brain slices, basal ganglia were stained macroscopically, and other areas such as cerebral cortex, corpus callosum, cerebellar cortex, granular layer and pyramidal tract of the spinal cord were lightly identified as well. Under the light microscope, it was found that only the neuronal cells were stained, and astrocytes, oligodendrocytes, ependymal cells and vessels were not. Intracellular distribution of the staining showed various patterns and staining intensity of varying degree. Using the PAP method, localization of the calcineurin in formalin-fixed, paraffin-embedded tissues were studied in 65 human intracranial neoplasms, and in 11 human extracranial neoplasms. The neuronal elements of neuroblastoma, ganglioglioma, ganglioneuroma and retinoblastoma were clearly stained. In contrast, glioblastoma, astrocytoma, oligodendroglioma, ependymoma, meningioma, neurinoma, pituitary adenoma, craniopharyngioma, hemangioblastoma, hamartoma, lymphoma and mesenchymal tumor were all negative. Two cases out of 5 medulloblastomas were stained, but others were not. Although positive tumors disclosed various staining patterns and intensities, these results indicated that calcineurin could be a new neuronal marker in human brain tumors.
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PMID:Calcineurin as a neuronal marker of human brain tumors. 242 51

The binding of epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) to cell membranes was determined in 14 renal cancers and in 13 normal kidney tissues adjacent to the tumors. The soluble 34K IGF binding protein (34K IGF-BP) content and the phosphotyrosyl-protein phosphatase activity in renal cancer tissue and adjacent normal tissue were also determined. The specific EGF receptor binding in renal cancers was 12.7 +/- 2.5% (mean +/- SEM) as compared to 2.6 +/- 0.2% (mean +/- SEM) in normal tissues (p less than 0.01). Phosphotyrosyl-protein phosphatase activity in renal cancer tissue was less than half of that observed in normal renal tissue (p less than 0.01). The highest IGF-I binding was observed in 5 renal cancers although no consistent differences between IGF-I binding to tumor and normal tissues were observed. Both EGF and IGF binding to kidney tissue were higher than binding to gastro-intestinal tissue irrespective of whether normal or malignant tissues were compared. All normal kidney tissues and 7 of 8 kidney tumors contained measurable amounts of 34K IGF-BP as determined by RIA and the cross-linking technique. In 2 tumor tissue samples the 34K IGF-BP content was increased 8- and 15-fold over that seen in adjacent normal kidney tissue, whereas in the 6 other renal cancers the 34K IGF-BP was similar to that observed in normal kidney tissue.
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PMID:Binding of epidermal growth factor and insulin-like growth-factor I in renal carcinoma and adjacent normal kidney tissue. 254 41

Many oncogene products are protein kinases and signals are transduced via phosphorylation of proteins. Similarly, protein-dephosphorylation may play a critical role in malignant cell transformation. We have cloned two catalytic subunits of ser/thr protein phosphatase (PP) type 2A, PP2A alpha, and PP2A beta, from a rat liver cDNA library. Both cDNAs encode peptides of 309 amino acids with a difference of only 8 amino acids between the two. All primary hepatocellular hyperplastic nodules or carcinomas, which were induced by a food carcinogen, 2-amino-3-methylimidazo[4,5-f]quinoline, showed up-regulation of expression of the mRNAs of both PP2A alpha and PP2A beta. NIH3T3 cell transformants obtained by introducing activated c-raf, ret-II or Ki-ras oncogenes also showed high levels of PP2A alpha transcripts. Okadaic acid, a non-TPA type tumor promoter, was found to be a potent inhibitor of PP1 and PP2A. Its IC50 for PP1 was much higher than that for PP2A with phosphorylase a as a substrate. When raf and ret-II transformants were cultured with okadaic acid at 8 ng/ml for 2 days, both transformants became flattened and showed strict contact inhibitions. This flat cell morphology was stable for at least one month in the presence of okadaic acid, but in its absence, the cells reverted to their original transformed shape within 7-10 days. Colony formation by raf and ret-II transformants in soft agar was inhibited dose-dependently by okadaic acid; very few colonies grew in the presence of the acid at 8 ng/ml. Okadaic acid had less effect on a transformant of the Ha-ras gene, causing only 50% inhibition of colony formation at 8 ng/ml. The role of protein phosphatases in cellular transformation by certain oncogenes is suggested.
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PMID:Role of protein phosphatases in malignant transformation. 256 81

Superoxide anion (O2-) is an active oxygen species found in virtually all cells grown in the presence of oxygen. In vivo, the highest concentration of this oxygen radical is found after granulocytes have been exposed to particles or the tumor promoter, phorbol myristate acetate. O2- is released from the cell as a "respiratory burst," which is followed shortly by the appearance of strand breaks in the DNA of the producing cell. In the present report, we have continued our investigation into the mechanism by which extracellular O2- causes breakage of intracellular DNA. Although hydrogen peroxide is present and could also cause strand breaks, its effects are eliminated by the addition of catalase. When the amount of O2- is increased threefold by adding glucose to the medium, the number of breaks increases only slightly, suggesting that the number of breaks that could be induced is limited. The strand-break process is abruptly interrupted by the addition of metabolic poisons such as ionophore A23187, fluoride, or 2-deoxyglucose, but ATP does not appear to be involved. The number of O2(-)-induced strand breaks is increased in the presence of sodium orthovanadate and decreased by A23187. Orthovanadate prevents the inhibition caused by A23187. Reaction of O2- with orthovanadate itself appears not to be responsible for the enhancement of breaks by orthovanadate. We propose that orthovanadate exerts its effect by acting as an inhibitor of a phosphoprotein phosphatase and that A23187 acts to deplete intracellular Ca2+. These data support our hypothesis that the O2- radical causes strand breaks not by attacking the DNA but rather by activating a specific metabolic DNA strand-break pathway.
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PMID:A superoxide anion induced DNA strand-break metabolic pathway in human leukocytes: effects of vanadate. 284 51

The Rous sarcoma virus (RSV)-transforming protein, pp60src, is a plasma membrane-associated tyrosine-specific protein kinase. A 36,000-Da cellular polypeptide (p36) which is phosphorylated at tyrosine in RSV-transformed chicken embryo fibroblasts (RSV-CEF) is also plasma membrane associated. To determine if p36 is directly phosphorylation and kinase activity in situ in the plasma membrane, src-dependent protein phosphorylation in membranes isolated from RSV-CEF has been characterized. These membrane preparations contained high ATPase and phosphoprotein phosphatase activities; but when sufficient concentrations of [gamma-32P]ATP were used, the phosphorylation of pp60src and the phosphorylation of p36 were linear for 1 min or more, and the initial rates of phosphorylation could therefore be determined. In membranes from RSV-CEF pp60src and p36 became phosphorylated predominantly at tyrosine, while in membranes from uninfected cells p36 was phosphorylated at low levels at serine. When membranes from RSV-CEF were preincubated with tumor-bearing rabbit (TBR) serum, the IgG became phosphorylated while the phosphorylation of p36 was inhibited, suggesting that p36 is directly phosphorylated by pp60src. Phosphorylation of pp60src, p36, and TBR-IgG was dependent on growth temperature in membranes from cells infected by a temperature-sensitive mutant, tsNY68, although some dependence on growth temperature was observed even with membranes from wild-type RSV-infected cells. However, at the nonpermissive temperature, tsNY68 pp60src retained 20-40% of its kinase activity, providing supporting for the proposal (B. M. Sefton, T. Hunter, and K. Beemon (1980, J. Virol, 33, 220-229) that transformation may result from a small quantitative change in pp60src activity. The phosphorylation of pp60src and its kinase activity were not coordinately affected by growth temperature or mutations within src, indicating that different factors affect the phosphoacceptor capacity and kinase activity of the protein.
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PMID:pp60src-dependent protein phosphorylation in membranes from Rous sarcoma virus-transformed chicken embryo fibroblasts. 299 19

Biochemical events that follow the engagement of cytotoxic T lymphocytes (CTL) with an Ag-bearing target cell (TC) or triggering by the crosslinking of the Ag-receptor (TcR) by immobilized anti-TcR mAb were studied using cloned CTL and a novel CTL activation assay. The approach described here was undertaken to shed light on the molecular mechanisms of "ON", "STOP" and "OFF" signalling that allow CTL to be activated, kill TC and disengage from the target cell after delivery of the "lethal hit" and then to proceed with the destruction of the next Ag-bearing target encountered. Biochemical studies of TcR-regulated and TcR-triggered constitutive exocytosis in CTL provided a detailed description of the molecular requirements for this important phenomenon in T lymphocytes and provided an alternative CTL activation assay; this assay measures the TcR-dependent response in the absence of a TC. These studies also helped to envision CTLs screening activities as a cycle of engagements-disengagements with the TC, where every surrounding cell is treated by the CTL as a potential Ag-bearing TC. Both constitutive and regulated exocytosis in CTL are triggered through a transmembrane signalling pathway which involves protein kinase C and extracellular Ca2+ that, most likely, is translocated through Ca2+ channels. This is followed by the involvement of calmodulin (CaM)-binding proteins, e.g., calcineurin, a CaM-dependent phosphatase, which was shown to be a major CaM-binding protein in murine lymphocytes. Unexpectedly, these biochemical studies demonstrated that the granule exocytosis model of CTL-mediated cytotoxicity cannot account for the mechanism of target cell lysis by CTL, at least in in vitro conditions in the absence of extracellular Ca2+. These results indicate the existence of an extracellular Ca2+-independent, TcR-regulated CTL response and raise the possibility that second messenger(s) other than Ca2+ and/or products of phosphoinositide turnover are involved in T-cell lysis. Predominance of "non-lethal" engagements between some CTL and TC, revealed during time-lapse cinematographic studies, together with comparative studies of TcR-regulated exocytosis of granules and of constitutive exocytosis of gamma-interferon, suggested that TC destruction by CTL may not be their only or even their most important function in vivo. It is possible that CTL, triggered by Ag recognition to exocytose storage granules and to synthesize and constitutively exocytose macrophage-activating factors, in turn promote tumor destruction by macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanistic, functional and immunopharmacological implications of biochemical studies of antigen receptor-triggered cytolytic T-lymphocyte activation. 313 92

Plasma-membrane-bound kinases of AS-30D ascites from transplantable rat hepatocarcinoma were shown to extensively catalyze the phosphorylation of plasma membrane proteins and membrane lipids, using [gamma-32P]ATP or [gamma-32P]GTP as a phosphate donor. In contrast, plasma membranes from normal adult rat liver or fast-growing regenerating liver (24 h after partial hepatectomy) produce significantly less activity for protein phosphorylation and little phosphorylation of the lipids. However, neonatal (24 h old) rat liver plasma membrane preparations show levels of phosphorylation of proteins and lipids intermediate between those in the tumor cell line and normal adult plasma membrane preparations. Phosphatidic acid was identified as one of the 32P-labelled lipids in the tumor plasma membrane chloroform-methanol (2:1, v/v) extract. Phosphorylation of protein was not affected by cAMP or cGMP. However, calcium ion (in the presence or absence of calmodulin) significantly modifies the 32P labelling of a series of proteins in normal tissue but has little effect with the neoplastic preparations. Some plasma membrane proteins were capable of nucleotide binding, instead or in addition to being phosphorylated. Finally, the presence of membrane-bound phosphoprotein phosphatase(s) was also demonstrated in all the preparations examined by means of chase experiments with nonlabelled ATP or GTP, and (or) by the use of the phosphoprotein phosphatase inhibitor, orthovanadate.
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PMID:Endogenous hyperphosphorylation in plasma membrane from an ascites hepatocarcinoma cell line. 337 Jan 39


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