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)

In vitro and in vivo metastatic variants derived from Lewis lung carcinoma (3LL) were examined for the level of the expression of several growth-regulated genes, oncogenes, and transforming growth factor (TGF) genes. To determine whether the proliferative advantage of metastatic cells is due to an increased growth fraction of the cell population or to a deregulated expression of some growth-regulated genes, the mRNA levels of the S-phase-specific H3 histone gene were compared with that of some cell cycle-related genes (vimentin, calcyclin, c-myc, and p53) and oncogenes (Ki-ras, Ha-ras, c-sis, c-src, c-fes, and c-erb). In addition, to evaluate whether an autocrine pattern of cell proliferation is responsible for the proliferative advantage of metastatic cells, the level of the expression of TGF genes (alpha and beta 1) was studied. Northern blot analysis demonstrated that in 3LL metastatic variants the expression of TGF-alpha as well as the expression of all growth-regulated genes and oncogenes studied are similar. Only the TGF-beta 1 gene is expressed at higher levels in highly metastatic 3LL variants maintained either in vitro or in vivo. Data suggest that the proliferative advantage of 3LL metastatic cells is not due to a deregulated expression of some growth-regulated genes and oncogenes, but more likely is acquired through the expression of genes which might interfere with the ability of the tumor cells to escape hostile microenvironmental conditions.
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PMID:Differential expression of transforming growth factor-beta 1 gene in 3LL metastatic variants. 191 69

In two-stage mouse skin carcinogenesis initiated by 7,12-dimethylbenz[alpha]anthracene (DMBA), cepharanthine inhibited the tumor promoting activity of 12-O-tetradecanoyl phorbol-13-acetate (TPA). Since Ca2(+)-phospholipid-dependent protein kinase (PKC) was shown to be an intracellular target of TPA, effects of cepharanthine on the activity of this enzyme were investigated Cepharanthine also inhibited the phosphorylation of H1 histone by PKC in a concentration dependent manner. While cepharanthine inhibited the association of H1 histone with phospholipid vesicles, autophosphorylation of PKC was not inhibited by this drug. Cepharanthine also inhibited TPA-stimulated phosphorylation of some cytoplasmic proteins of mouse skin epidermis. These results indicated the possibility that anti-tumor promoting action of cepharanthine was the result of inhibition of PKC dependent cytoplasmic protein phosphorylation through the reduction of the interaction of these proteins with the plasma membrane.
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PMID:Inhibition of 12-O-tetradecanoyl phorbol-13-acetate promoted tumorigenesis by cepharanthine, a biscoclaurine alkaloid, in relation to the inhibitory effect on protein kinase C. 198 45

The phorbol ester receptor (PER), which is believed to be identical to protein kinase C (PKC), has been implicated in the control of the sensitivities of tumor cells to certain forms of cancer chemotherapy. We evaluated the effects of regulating the expression of PER/PKC on the sensitivity of the R1B6 subclone of HL-60 human promyelocytic leukemic cells to anthracyclines. This cell line is resistant to the effects of phorbol esters on cellular differentiation by virtue of a down-regulated PER. R1B6 cells were maintained in phorbol 12, 13 dibutyric acid (PDBu). Twenty four to thirty six hours after removal of PDBu from the medium there was a 3-fold increase in the number of receptors compared to baseline values measured by [3H]-PDBu binding and a marked increase in the activity of PKC as measured by calcium-phospholipid dependent incorporation of [32P] into histone. Despite these changes in the number of PER and in the activity of PKC there was no difference in the cellular accumulation of [3H]-daunomycin or in the sensitivity of cells to the toxic effects of doxorubicin. Furthermore, there was no difference between the R1B6 cells and the parental HL-60 line in their intrinsic sensitivities to doxorubicin. These studies demonstrate that alterations in the expression of PER and the activity of PKC alone are not sufficient to influence anthracycline accumulation or toxicity in R1B6 human leukemic cells in contrast to recently reported results using other cell lines.
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PMID:The role of the phorbol ester receptor/protein kinase C in the sensitivity of leukemic cells to anthracyclines. 200 30

Benzoyl peroxide (BP), used widely in dermatologic therapy and by the food industry, is considered a tumor promoter in chemically induced skin. Tumor promoters of both the phorbol and non-phorbol type interact with protein kinase C (PKC). This enzyme, therefore, is regarded as the intracellular receptor for a number of tumor promoters. BP bears some structural resemblance to diacylglycerol (DAG) and thus may exert its action through the PKC system. Based on these observations, we have investigated the effect of BP on PKC from mouse skin. Our data show that unlike phorbol esters, which stimulate PKC (in vivo and in vitro), BP inhibits PKC. Concentration-dependent inhibition by BP is observed when PKC is stimulated by phorbol esters, diacylglycerol, phosphatidyl serine (PS), or a combination of the latter two. BP also inhibits PKC stimulated by (-) Indolactam V, a nonphorbol compound resembling the teleocidins. 3H-phorbol ester binding experiments reveal that inhibition by BP may be due to its interference with the phorbol ester binding site and consequently diacylglycerol binding. The binding data and the inability of BP to inhibit either cyclic AMP-dependent protein kinase I or II imply that BP interacts with PKC, and not with the histone substrate. Results presented here clearly indicate that unlike phorbol and certain non-phorbol type of tumor promoters BP does not stimulate PKC in vitro.
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PMID:Inhibition of mouse skin protein kinase C by benzoyl peroxide. 200 87

The present study provides evidence that rat brain protein kinase C elicits a phosphotransferase activity towards histone and undergoes autophosphorylation in the absence of phosphatidylserine. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate binds to and activates protein kinase C in a phospholipid-free reaction. The apparent activation constant (Ka = 2.7 nM) is not modified by the absence of phospholipid but the maximum velocity is greatly decreased. The phosphotransfer reaction to exogenous substrates occurs in 0.5 mM ethylene-bis(oxyethylenenitrilo)tetraacetic acid, although autophosphorylation in these conditions requires the presence of Ca2+. The protein kinase C inhibitor (1-(5-isoquinolinesulfonyl)-2-methylpiperazine inhibits the reaction, whereas the cAMP-dependent protein kinase inhibitor is ineffective. In contrast to diacylglycerol, which is a poor activator, unsaturated fatty acids potently activate the phospholipid-free reaction. Moreover, the substrate specificity is markedly changed, e.g., myelin basic protein and histone types VI-S and VII-S appear to be relatively better substrates in the phospholipid-free reaction. The data presented indicate that protein kinase C (or some individual isoforms) may function, at least partially, without binding to membrane phospholipid and suggest that this novel characteristic of phorbol esters may account for their tumor-promoting activity.
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PMID:Phorbol esters mediate phospholipid-free activation of rat brain protein kinase C. 210 68

In view of the critical role that the Ca2+- and phospholipid-dependent enzyme protein kinase C (PKC) plays in mediating proliferative responses to a number of growth factors, hormones, and tumor promoters, it is thought that selective PKC inhibitors may provide a new class of antiproliferative drugs. Established PKC inhibitors include three major classes of agents: agents that compete with the substrate ATP, agents that compete with the protein substrate, and agents that both compete with ATP and interact with the cofactor phosphatidylserine (PS). In this report, we have characterized the interactions between PKC and N-myristyl-Lys-Arg-Thr-Leu-Arg, a myristylated analogue of a synthetic peptide substrate of PKC. We determined that the myristylated peptide was a novel PKC inhibitor that interacted with PS as well as competed with the protein substrate of PKC. The inhibitory activity of the peptide was conferred by myristylation. We found that the myristylated peptide antagonized Ca2+- and PS-activated PKC with an IC50 of 75 microns, whereas the nonmyristylated peptide lacked this inhibitory activity. A fully active, Ca2+- and PS-independent catalytic fragment of PKC can be generated by limited proteolysis. Although the myristylated peptide was a very poor PKC substrate, this peptide inhibited the catalytic fragment of PKC by apparent competition with the phosphoacceptor substrate histone IIIS with an IC50 of 200 microM, whereas the nonmyristylated peptide showed no inhibitory activity against the catalytic fragment. Thus, the myristylated peptide may serve as a model for the development of selective PKC inhibitors, because its inhibitory mechanism exploits the substrate specificity of PKC, as well as the novel regulation of the enzyme. Furthermore, since endogenous PKC substrates include acylated proteins, the observations that we report here concerning a myristylated synthetic peptide suggest that acylation of proteins may be important in the regulation of PKC activity in vivo.
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PMID:N-myristyl-Lys-Arg-Thr-Leu-Arg: a novel protein kinase C inhibitor. 215 82

Protein kinase C (PKC) was detected in the yeast Saccharomyces cerevisiae with bovine myelin basic protein as the phosphate acceptor. The enzyme was purified at least 500-fold by a four-step column chromatographic procedure (phenyl-Sepharose CL-4B, Mono Q, Heparin-5PW, and hydroxyapatite). The molecular mass was approximately 90 kDa, as estimated by gel-filtration analysis. Yeast PKC was activated by the simultaneous addition of Ca2+, diacylglycerol, and phosphatidylserine. Free arachidonic acid alone could activate the enzyme to some extent. However, yeast PKC did not respond significantly to tumor-promoting phorbol esters. GTP did not serve as phosphate donor. The yeast enzyme showed substrate specificity distinctly different from that of mammalian PKCs. H1 histone and protamine were poor substrates. With myelin basic protein as a model substrate, yeast PKC phosphorylated threonyl residues preferentially, whereas rat brain PKCs phosphorylated seryl residues preferentially. Further studies should elucidate the role of yeast PKC in cellular regulation and cell cycle control.
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PMID:Protein kinase C in Saccharomyces cerevisiae: comparison with the mammalian enzyme. 216 17

The activity of cAMP-dependent histone kinases (HK) and cAMP-independent casein kinases (CK) as well as cAMP level were assessed in gastric mucosa affected by various forms of gastritis as well as in gastric tumor and adjacent normal tissue. CK activity was higher whereas that of HK and cAMP level were lower in tumor and at a distance of 5-20 cm from its edge as compared to gastritis. CK/HK cAMP ratio in adenocarcinoma was 6 times that in normal tissue and 2-2.5 times that in gastritis. The data obtained and those published earlier suggest the relative increase in cAMP-independent protein phosphorylation with respect to its cAMP-dependent counterpart to be characteristic of human tumors.
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PMID:[The enhanced relative intensity of cAMP-dependent protein phosphorylation in stomach tumors]. 216 40

Okadaic acid is a potent and specific inhibitor of protein phosphatases 1 and 2A, and is a strong tumor promoter that is not an activator of protein kinase C. Treatment of quiescent cultures of rat fibroblastic 3Y1 cells with okadaic acid induced marked activation of a kinase activity that phosphorylated microtubule-associated protein (MAP) 2 and myelin basic protein, but not histone or casein, in vitro. This activated kinase eluted at approximately 0.15 M NaCl on a DEAE-cellulose column and its apparent molecular mass was determined to be approximately 40 kDa by gel filtration. Detection of the kinase activity in polyacrylamide gels containing substrate proteins after sodium dodecyl sulfate gel electrophoresis revealed that the okadaic-acid-activated kinase activity resided mainly in two closely related polypeptides with apparent molecular mass approximately 40 kDa. The characteristics of this kinase were indistinguishable from those of the mitogen-activated MAP kinase in the same cells. The okadaic-acid-activated MAP kinase was deactivated by protein phosphatase 2A treatment in vitro. These results suggest that MAP kinase is negatively regulated by protein phosphatases 1 and/or 2A in quiescent cells and therefore can be activated by inhibiting these protein phosphatases. Interestingly, the okadaic-acid-induced activation of MAP kinase was transient and epidermal-growth-factor-induced activation was also transient, even in the presence of okadaic acid. These data may imply that protein phosphatases 1 and 2A are not involved in the deactivation of MAP kinase in cells.
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PMID:Okadaic acid activates microtubule-associated protein kinase in quiescent fibroblastic cells. 217 62

(R)-Trichostatin A (TSA) is a Streptomyces product which causes the induction of Friend cell differentiation and specific inhibition of the cell cycle of normal rat fibroblasts in the G1 and G2 phases at the very low concentrations. We found that TSA caused an accumulation of acetylated histone species in a variety of mammalian cell lines. Pulse-labeling experiments indicated that TSA markedly prolonged the in vivo half-life of the labile acetyl groups on histones in mouse mammary gland tumor cells, FM3A. The partially purified histone deacetylase from wild-type FM3A cells was effectively inhibited by TSA in a noncompetitive manner with Ki = 3.4 nM. A newly isolated mutant cell line of FM3A resistant to TSA did not show the accumulation of the acetylated histones in the presence of a higher concentration of TSA. The histone deacetylase preparation from the mutant showed decreased sensitivity to TSA (Ki = 31 nM, noncompetitive). These results clearly indicate that TSA is a potent and specific inhibitor of the histone deacetylase and that the in vivo effect of TSA on cell proliferation and differentiation can be attributed to the inhibition of the enzyme.
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PMID:Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. 221 19


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