UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among environmental pollutants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is one of the most potent tumor promoters and teratogens known. The molecular mechanisms responsible for the biological activity of TCDD, however, remain largely unknown. In this report, we show that the first observable effects of TCDD in cultured murine hepatoma cells are a rapid, transient increase in Ca2+ influx and a minor but significant elevation of activated, membrane-bound protein kinase C. These changes are then followed by induction of the immediate early proto-oncogenes c-fos, jun-B, c-jun, and jun-D, and by large increases in AP-1 transcription factor activity. Induction of these changes by TCDD is delayed compared with that by phorbol esters, although the magnitude of the effects caused by both treatments is similar, and both induction processes can be blocked by staurosporine, a protein kinase C inhibitor. In cultured cells, proto-oncogene induction by TCDD appears to be independent of the presence of a functional aryl hydrocarbon (Ah) receptor or nuclear translocation protein. These results reveal early events that may lead to the elucidation of the molecular basis of TCDD-induced tumor promotion.
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PMID:Dioxin induces expression of c-fos and c-jun proto-oncogenes and a large increase in transcription factor AP-1. 160 50

The CaSki cell line derived from an epidermoid carcinoma of the uterine cervix produces and releases a tumor associated-antigen, TA-4. The authors have already reported that EGF stimulated the production and secretion of TA-4 by the CaSki cells. EGF receptor is known to be one of the proteins phosphorylated by C-kinase. In order to elucidate a possible role of signal transduction systems (cAMP-A-kinase, diacyglycerol-C-kinase and Ca(2+)-calmodulin) in the regulation of TA-4 production and secretion by human cervical epidermoid carcinoma cells, the effects of cholera toxin (CT), an activator of adenylate cyclase, phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, and Ca2+ ionophore A23187, an activator of Ca2+ modulation on TA-4 production and secretion by CaSki cells were evaluated. TA-4 in the cultured cells and media were measured with a SCC RIA-Kit. The addition of PMA or Ca2+ ionophore to the medium caused increases in the cellular levels of TA-4 and TA-4 levels in the medium in a dose-dependent manner shortly after the addition. Combined treatment with PMA and Ca2+ ionophore did not cause additive increases in TA-4 levels in the cells and medium compared to the treatment with PMA alone or Ca2+ ionophore alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The role of signal transduction systems in the regulation of production and secretion of TA-4 by cultured cervical epidermoid carcinoma cells (CaSki)]. 160 73

Protein kinase C (PKC), the major receptor for tumor-promoting phorbol esters, consists of a family of at least eight distinct lipid-regulated enzymes. How the various PKC isozymes are regulated in vivo and how they couple to particular cellular responses is largely unknown. We have examined the expression and regulation of PKC isoforms in R6 rat embryo fibroblasts. Northern and Western blot analyses indicate that these cells express four PKC isoforms, cPKC alpha, nPKC epsilon, nPKC delta, and nPKC zeta; of which nPKC epsilon and nPKC delta are the most abundant. In agreement with the simultaneous presence of cPKC and nPKC isozymes, both Ca(2+)-dependent and -independent PKC activities were detected in extracts of these cells. cPKC alpha and nPKC zeta were predominantly localized in the cytosol when subcellular fractionation was carried out in the presence of [ethylenebis(oxyethylenenitrilo)]tetraacetic acid. When cell lysis was carried out in the presence of Ca2+, greater than 50% of cPKC alpha redistributed to the particulate fraction, whereas nPKC zeta remained in the cytosol. In contrast to cPKC alpha and nPKC zeta, 60-80% of nPKC epsilon and nPKC delta were located in a Ca(2+)-insensitive, membrane-bound form. Treatment of R6 cells with 12-O-tetradecanoyl phorbol 13-acetate (TPA), resulted in the translocation of all four PKC isozymes to the membrane fraction, and the subsequent down-regulation of cPKC alpha, nPKC zeta, and nPKC delta, nPKC epsilon, however, was only partially down-regulated in response to long-term TPA exposure. Overproduction of exogenous cPKC beta I in R6 cells conferred partial resistance of nPKC delta to TPA-induced down-regulation and potentiated the resistance of nPKC epsilon to down-regulation. These results demonstrate that the multiple isoforms of PKC which coexist within a single cell type are differentially regulated by extra- and intracellular stimuli and may thereby influence growth control and transformation via distinct mechanisms.
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PMID:Expression of four protein kinase C isoforms in rat fibroblasts. Distinct subcellular distribution and regulation by calcium and phorbol esters. 161 87

The immunomodulator AS101 has recently been found to have radioprotective properties when injected prior to sublethal and lethal doses of irradiation. In addition, this compound was found to protect mice from hemopoietic damage caused by sublethal doses of cyclophosphamide (CYP) and to increase the rate of survival of mice treated with lethal doses of CYP. AS101 was previously shown to exert a synergistic effect with the PKC-inducer bryostatin in cytokine secretion in vitro. The present studies were designed to evaluate the effects of in vivo combined treatment with AS101 and bryostatin on bone marrow and spleen cellularity and on the number of committed progenitors in the bone marrow at various points of time after their treatment with a sublethal dose of CYP or irradiation. In addition, the combined effect was tested on the survival of mice irradiated with a lethal dose of irradiation. Our data show the presence of synergism which greatly enhances the number of bone marrow and spleen cells 48 hr and 9 days after CYP treatment or irradiation. The combined effect was also demonstrated when bone marrow colony-forming units granulocyte-macrophage (CFU-GM) progenitor cells were evaluated. Moreover, AS101 and bryostatin synergized in their protective effects against lethal damages of irradiation. These results strongly suggest that bryostatin, which lacks tumor-promoting activity, is a particularly good candidate in combination with AS101 for treatment in vivo in counteracting chemotherapy- or radiation-induced hematopoietic suppression or in generally improving the restoration of immune response under conditions involving immune or hemopoietic damage.
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PMID:In vivo synergistic effect of the immunomodulator AS101 and the PKC inducer bryostatin. 162 62

Several cis-unsaturated fatty acids such as oleic, linoleic, linolenic, eicosapentaenoic, and docosahexaenoic acids added directly to intact human platelets greatly enhance protein kinase C activation as judged by the phosphorylation of its specific endogenous substrate, a 47-kDa protein. This enhancement absolutely requires the presence of a membrane-permeant diacylglycerol, 1,2-dioctanoylglycerol, or a tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate. In the presence of ionomycin and either 1,2-dioctanoylglycerol or phorbol 12-myristate 13-acetate, the release of serotonin from the platelets is also remarkably increased by cis-unsaturated fatty acids. The effect of these fatty acids is observed at concentrations less than 50 microM. Saturated fatty acids and trans-unsaturated fatty acids are inactive. Titration of ionomycin to induce a release reaction and measurement of the intracellular Ca2+ level by the fura-2 procedure indicate that cis-unsaturated fatty acids increase an apparent sensitivity of the platelet response to Ca2+. The results suggest that cis-unsaturated fatty acids, which are presumably produced from phosphatidylcholine by signal-dependent activation of phospholipase A2, may take part directly in cell signaling through the protein kinase C pathway.
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PMID:Platelet activation by simultaneous actions of diacylglycerol and unsaturated fatty acids. 163 Nov 41

2-Lysophosphatidylcholine (lysoPtdCho), a product of the hydrolysis of phosphatidylcholine catalyzed by phospholipase A2, greatly potentiates the activation of human resting T lymphocytes that is induced by a membrane-permeant diacylglycerol plus a calcium ionophore, as determined by the expression of the alpha subunit of the interleukin 2 receptor and thymidine incorporation into DNA. LysoPtdCho per se is inactive unless both diacylglycerol and a calcium ionophore are present. This effect of lysoPtdCho is also observed when diacylglycerol is replaced by a tumor-promoting phorbol ester. Other lysophosphatides including lysophosphatidylserine, lysophosphatidylinositol, and lysophosphatidic acid are inert except for lysophosphatidylethanolamine, which is far less effective than lysoPtdCho. Tracer experiments with radioactive choline indicate that, when T lymphocytes are stimulated with an antigenic signal, lysoPtdCho is indeed produced in a time-dependent fashion, although the concentration of this lysophospholipid accumulated remains to be quantitated. It suggests that phospholipase A2 is directly involved in the signal transduction pathway through protein kinase C to induce long-term cellular responses.
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PMID:Role of lysophosphatidylcholine in T-lymphocyte activation: involvement of phospholipase A2 in signal transduction through protein kinase C. 163 Nov 42

The effect of activation of calcium- and phospholipid-dependent protein kinase (protein kinase C) on human chorionic gonadotropin (hCG) release by cultured trophoblast cells was studied and a role of protein kinase C in the GnRH-mediated hCG release was also evaluated. Both GnRH and 1-oleoyl-2-acetylglycerol (OAG), a protein kinase C activator, stimulated hCG release after 3 h incubation in a dose-dependent manner with ED50 of 55 nmol/l and 4.0 nmol/l, respectively. A tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) also stimulated hCG release while two non-tumor-promoting compounds, phorbol and 4 alpha-phorbol, failed to stimulate hCG release. hCG release by maximal effective dose of GnRH (10 mumol/l) or OAG (1 mumol/l) was further stimulated when cells were incubated with same concentrations of GnRH and OAG. OAG-stimulated hCG release was completely inhibited by a protein kinase C inhibitor, H-7, with ID50 of 23 nmol/l while H-7 did not affect GnRH-mediated hCG release. These results indicate that GnRH-stimulated hCG release is not mediated by protein kinase C pathway, however, the secretion of hCG is also regulated by the mechanism that involves protein kinase C activation.
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PMID:Effects of diacylglycerol and gonadotropin-releasing hormone on human chorionic gonadotropin release by cultured trophoblast cells. 163 9

To investigate the role of protein kinase C (PKC) in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-dependent growth of human melanocytes, we analyzed the effects of phorbol ester treatment on both PKC expression and growth control in these cells. We found that established cultures of normal melanocytes contain the PKC alpha, PKC beta, and PKC epsilon isoforms. The abilities of various phorbol ester compounds to stimulate DNA synthesis in these cultured melanocytes correlated with their known potencies for activation of PKC and tumor promotion. Dose-response studies revealed that the most effective TPA concentration for stimulation of DNA synthesis and growth of melanocytes (10 ng/ml TPA) also supported a relatively high level of PKC enzyme activity, increased membrane association of the PKC alpha and PKC epsilon isoforms, and led to a high level of phosphorylation of a major PKC substrate, the myristoylated alanine-rich C kinase substrate (MARCKS) protein. Melanocytes incubated for 48 h with TPA at a higher concentration (100 ng/ml TPA) exhibited suboptimal TPA-stimulated DNA synthesis (28% of maximal) and decreased phosphorylation of the MARCKS substrate protein (50% of maximal). Furthermore, treatment of melanocytes with 100 ng/ml TPA for 48 h resulted in a marked decrease in total PKC enzyme activity and the loss of expression of the PKC alpha and PKC epsilon isoforms in both the cytosol and membrane-bound fractions, when examined by immunoblot analysis. These results, taken together, suggest that continuous activation of PKC by TPA, rather than the loss of PKC due to TPA-induced down-regulation, is responsible for the growth-stimulatory effects of phorbol esters on normal human melanocytes. Additionally, the conditioned medium from TPA-treated human melanocytes stimulated DNA synthesis in quiescent melanocytes and human melanoma cells, thus suggesting that activation of the PKC signaling pathway in melanocytes leads to the production of an autocrine growth factor. These findings may be relevant to the autonomous growth of malignant melanomas.
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PMID:Growth of human melanocyte cultures supported by 12-O-tetradecanoylphorbol-13-acetate is mediated through protein kinase C activation. 164 43

We investigated the effects of the non-phorbol tumor promoter okadaic acid on human leukemia K562 cells. It was found that okadaic acid potently and reversibly inhibited cell growth, with a nearly complete inhibition of thymidine uptake seen at about 10 nM. The cytotoxicity of okadaic acid was characterized by a marked mitotic arrest of the cells exhibiting scattered chromosomes and abnormal anaphase-like structures, a phenomenon distinct from the typical metaphase arrest caused by colchicine. Okadaic acid (10-1,000 nM) greatly stimulated phosphorylation of a number of nuclear proteins in K562 cells. Phosphorylation of many of the same proteins was also stimulated by 12-O-tetradecanoylphorbol-13-O-acetate, a protein kinase C activator. The present findings, consistent with recent reports that okadaic acid is a potent inhibitor of protein phosphatases 1 and 2A (PP1 and PP2A) shown to be essential for normal mitosis, provided evidence for the first time that okadaic acid inhibition of PP1/PP2A resulted in enhanced nuclear protein phosphorylation and subsequent mitotic arrest.
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PMID:Mitotic arrest and enhanced nuclear protein phosphorylation in human leukemia K562 cells by okadaic acid, a potent protein phosphatase inhibitor and tumor promoter. 164 33

Interactive regulation of gene expression by retinoic acid (RA) and adenosine monophosphate (cAMP) in mammary tumor cells was explored using Shionogi mouse mammary carcinoma cells (SC115) as a model and urokinase-type plasminogen activator (uPA) as a target gene product. Twenty-four hour treatment of SC115 cells with 100 nM RA, 1 mM 8-bromo-cAMP (BrcAMP), and 100 nM RA + 1 mM BrcAMP resulted in extracellular uPA activity increases of 1.4-fold, sevenfold, and 20-fold, respectively. These effects were dose-dependent with regard to both interacting members. Similar responses were obtained if 1 nM cholera toxin or 10 microM forskolin was used instead of the cAMP analog. Retinoids lacking the carboxylic acid function were inactive. The changes in uPA activity were accompanied by similar changes in uPA antigen concentration, as seen via Western blot analysis, and uPA mRNA abundance, as seen via Northern blot analysis. Actinomycin D, an inhibitor of RNA synthesis, blocked uPA stimulation by BrcAMP, suggesting that mRNA levels were transcriptionally regulated. The effect of BrcAMP on extracellular uPA activity was first evident at 2 h and peaked at approximately 6 h; the effect of RA alone and the synergistic response to joint treatment, however, followed a slower time course, requiring at least 12 h for initial expression and increasing gradually with time up to at least 48 h. Priming with RA for 48 h followed by extensive washing of the cells resulted in a threefold enhancement of the stimulatory effect of BrcAMP on uPA. Experiments utilizing the casein/plasminogen overlay method for the detection of uPA secretion by increased rate of uPA secretion per cell rather than to an increased fraction of uPA-secreting cells. Initial investigation of the mechanism of RA potentiation of cAMP responsiveness showed that RA did not alter cellular cAMP levels or total cAMP-dependent protein kinase A activity. Finally, the tumor promoter phorbol myristate acetate, an activator of protein kinase C, also increased SC115 cell uPA activity and synergized with RA. This raised the possibility that the enhancement of cAMP responsiveness by RA was indirectly mediated via an effect on protein kinase C. Experiments with protein kinase C-depleted cells, however, showed that this was not the case. In conclusion, RA treatment of SC115 cells potentiates the effect of cAMP on uPA expression at the single cell level via a partially irreversible mechanism independent of protein kinase C. The molecular target of RA and whether SC115 cell differentiation underlies the effect of RA remain to be established.
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PMID:Retinoic acid priming potentiates the induction of urokinase-type plasminogen activator by cyclic adenosine monophosphate in mouse mammary carcinoma cells. 164 61

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