Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of tumor promotion may involve stimulation of prostaglandin production. Previous studies with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) have identified two effects of TPA on prostaglandin production. TPA stimulates both arachidonic acid release and de novo synthesis of prostaglandin H synthase. Activation of protein kinase C by TPA appears to be part of the mechanism to cause arachidonic acid release. However, it is unclear if induction of prostaglandin H synthase also involves activation of protein kinase C. Bryostatin 1 is known to activate protein kinase C and to mimic some of the effects of TPA. We compared bryostatin 1 with TPA for the ability to cause arachidonic acid release and induce synthesis of prostaglandin H synthase. Bryostatin 1 induced arachidonic acid release and caused some prostaglandin production but only marginally induced synthesis of prostaglandin H synthase. Furthermore, we found that bryostatin 1 could inhibit the effect of TPA both in stimulation of arachidonic acid release and in the induction of prostaglandin H synthase.
Carcinogenesis 1988 Aug
PMID:Stimulation of arachidonic acid release and prostaglandin synthesis by bryostatin 1. 313 56

The growth of A65T cells, a mouse thymic leukemia cell line, was strictly dependent on the presence of tumor promoters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), teleocidin and mezerein. In the presence of the tumor promoters, A65T cells proliferated rapidly in a concentration-dependent manner. When the cells were cultured with a synthetic diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG) or 1,2-dicaprylin, cell proliferation was not stimulated. In addition, bihourly cumulative addition of OAG or 1,2-dicaprylin again failed to induce A65T cell proliferation. Phospholipase C (PLC) induced a concentration-dependent stimulation of A65T cell proliferation, though the effect was slight compared with that of the tumor promoters. Protein kinase C activity was detected both in cytosol and particulate fractions of A65T cells. When the cells were incubated in the TPA-free medium for 5 h, the protein kinase C activity in the cytosol fraction increased, whereas the activity in the particulate fraction decreased. Treatment of the cells with the tumor promoters mentioned above resulted in the increased phosphorylation of proteins with apparent mol. wts of 27,000 and 68,000. The effects were concentration-dependent and the half maximal phosphorylation was observed either with 3.6 nM TPA, 4.5 ng/ml teleocidin or 0.33 microM mezerein, respectively. On the other hand, a half maximal effect on cell proliferation was observed either with 0.14 nM TPA, 47 pg/ml teleocidin or 6.3 nM mezerein, respectively. At these concentrations, these tumor promoters never induced the detectable stimulations of the protein phosphorylation. A synthetic diacylglycerol 1,2-dicaprylin failed to stimulate the phosphorylation of 27- and 68-kd proteins, but stimulated the phosphorylation of proteins with apparent mol. wts of 100,000 and 54,000. The effect was concentration-dependent and a half maximal stimulation was observed with 35 micrograms/ml 1,2-dicaprylin. Neither TPA, teleocidin nor mezerein stimulated the phosphorylation of these 100- and 54-kd proteins. OAG and PLC failed to induce any detectable alterations in the protein phosphorylation in A65T cells. Both OAG and 1,2-dicaprylin, which we used, actually activated partially purified mouse brain protein kinase C in a concentration-dependent manner. These results clearly demonstrate that in A65T cells TPA and diacylglycerol mutually stimulate the phosphorylation of the completely different set of endogenous proteins, and also suggest that the cell-proliferating effects of the tumor promoters do not appear to be mediated through the phosphorylation of 27- and 68-kd proteins.
Carcinogenesis 1988 Oct
PMID:Differential effects of diacylglycerols and 12-O-tetradecanoylphorbol-13-acetate on protein phosphorylation and cell proliferation of tumor promoter-dependent leukemia cell line A65T. 313 19

We have found that maximum stimulation (greater than 10-fold) of kinase activity of a bovine brain preparation of calcium- and phospholipid-dependent protein kinase (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) occurs in the presence of phospholipid, but in the absence of added Ca2+. In effect, nM concentrations of TPA substitute for mM concentrations of added Ca2+, and the two agents are not synergistic. Biologically active analogs of TPA such as phorbol-12,13-dibutyrate (PDBu), 12-O-hexadecanoyl-16-hydroxyphorbol-13-acetate (HHPA) or mezerein were also effective activators of PKC, as were the chemically unrelated tumor promoters teleocidin and aplysiatoxin, when tested at nM concentrations in the absence of added Ca2+. On the other hand, the biologically inactive compounds phorbol, 4-alpha-phorbol-12,13-didecanoate (4-alpha-PDD), HHPA-13,20-diacetate and 1,2-dihydro-20-deoxy-HHPA did not affect PKC activity in the absence or presence of Ca2+. Our results are consistent with a stereochemical model in which the hydrophilic domains of certain diterpenes, teleocidin and aplysiatoxin interact specifically with PKC apoenzyme, while their hydrophobic domains interact with phospholipid, thus forming an enzymatically active ternary complex.
Carcinogenesis 1985 Feb
PMID:Activation of protein kinase C by tumor promoting phorbol esters, teleocidin and aplysiatoxin in the absence of added calcium. 315 4

A new type of phorbol ester, which has a macrocyclic dicarboxylic acid diester structure, was isolated from the seed oil of Jatropha curcas L. (Euphorbiaceae). Based on the results of spectroscopic analyses of the compound and its chemical degradation products, its structure is proposed to be an intramolecular 13,16-diester of 12-deoxy-16-hydroxyphorbol, 12-deoxy-16-hydroxyphorbol-4'-[12',14'-butadienyl]-6'-[16',18',20' - nonatrienyl]-bicyclo[3.1.0]hexane-(13-O)-2'-[carboxylate]-(16-O)-3 '- [8'-butenoic-10']ate (DHPB). DHPB showed slightly weaker biological and biochemical activities than 12-O-tetradecanoylphorbol-13-acetate (TPA). DHPB induced ornithine decarboxylase in mouse skin (2.8 nmol CO2/30 min/mg protein/34 nmol application), inhibited the specific binding of [3H]-12-O-tetradecanoylphorbol-13-acetate to phorbol ester receptors (50% effective dose, 17.0 nM), and activated protein kinase C in vitro (50% effective dose, 36.0 nM). Also, a weak tumor-promoting activity of DHPB was found in a two-stage carcinogenesis experiment on mouse skin. One week after initiation of mice with 100 micrograms of 7,12-dimethyl-benz(a)anthracene, topical application, twice a week, of 2 micrograms of DHPB until week 17, followed by application of 5 microgram of DHPB until week 30 at the same rate, resulted in 46.7% incidence of tumors by week 30. The groups treated with 7,12-dimethylbenz(a)anthracene alone or DHPB alone did not produce significant numbers of tumors. These results indicate that the new phorbol ester, DHPB, is a tumor promoter with weaker activity than 12-O-tetradecanoylphorbol-13-acetate.
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PMID:A new tumor promoter from the seed oil of Jatropha curcas L., an intramolecular diester of 12-deoxy-16-hydroxyphorbol. 316 37

We found that staurosporine, a potent inhibitor of protein kinase C, inhibits induction of ornithine decarboxylase (ODC) and tumor promotion caused by 12-O-tetradecanoylphorbol-13-acetate (TPA) in CD-1 mouse skin. When applied 5 min either before or after treatment with TPA, 1 microgram of staurosporine cause about 56% inhibition of ODC-induction by 5 micrograms of TPA. However, staurosporine did not inhibit TPA-induced epidermal hyperplasia. In two-stage carcinogenesis, staurosporine at 1 microgram was applied 5 min before application of 5 micrograms of TPA to the initiated skin: number of tumors was suppressed by about 40% although the incidence was not affected. No tumors developed when staurosporine alone was applied to the initiated skin.
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PMID:Inhibition of phorbol ester-caused induction of ornithine decarboxylase and tumor promotion in mouse skin by staurosporine, a potent inhibitor of protein kinase C. 319 53

During the last decade, progress in chemical carcinogenesis research has been substantial, and understanding the cellular changes and molecular causes of initiation, promotion, and malignant conversion appears to be within reach. Cancer begins as a carcinogen-induced genetic change in a single cell. The interaction of a particular carcinogen with specific genetic sites results, in part, from selectivity of metabolically activated carcinogens for particular nucleosides or gene sequences. In turn, modification of the molecular structure at specific genetic loci will have tissue-specific and species-specific consequences dependent on the expression of a particular gene, its sequence, and the function of the gene product in the target cell. It is likely that inactivation of regulatory regions, genomic rearrangements, and point mutations in coding sequences all can result in an altered cell phenotype. The rasH gene (and perhaps other members of the ras gene family) appears to be a common target for coding sequence mutations in the initiation of carcinogenesis in several organ sites and species by specific carcinogens. Whatever genetic mechanisms are involved, an initiated cell phenotype common to many epithelial cell types is observed. Initiated cells have an altered program of terminal differentiation, are resistant to cytotoxic substances or show altered requirements for specific growth factors or nutrients. These cells would have a selective growth advantage in cytostatic or cytotoxic situations or under conditions favoring terminal differentiation. Tumor promoters, some acting through specific cellular receptors, produce a tissue environment conductive to the selective clonal outgrowth of the initiated cell population resulting in a clinically evident premalignant lesion. The tissue specificity for most promoters depends on the ability of a particular agent to produce the selective conditions required for the initiated phenotype of that organ. At the molecular level, phorbol ester tumor promoters bind to and activate protein kinase C and transduce signals through this second-messenger pathway. Heterogeneity in the species of protein kinase C molecule expressed by normal and initiated epidermal cells could account for the differential response pattern observed in these cell types during skin tumor promotion. Malignant conversion of benign tumors requires further genetic changes in the tumor cell. Such changes could result from inherent instability in the genome of initiated cells, from spontaneous mutations more likely to occur in the expanding population of proliferating benign tumor cells, or by additional exposure to exogenous genotoxic agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chemical carcinogenesis: from animal models to molecular models in one decade. 328 45

Epidemiological studies provide evidence that environmental factors (external agents such as chemicals, radiation, and viruses) play a major role in the causation of the majority of human tumors. This is a highly optimistic message, since it implies that cancer is largely a preventable disease. To meet this challenge we must, however, understand the mechanisms of cancer causation at the cellular and molecular levels and, in a parallel effort, develop new laboratory methods that can be used to identify specific causative agents in humans. The approach must be comprehensive since it is likely that human cancers are due to complex interactions between multiple factors, including the combined actions of chemical and viral agents. This paper reviews recent studies from our laboratory and studies by other investigators related to these themes. A major principle in studies on mechanisms of carcinogenesis is that the process proceeds through multiple discernible stages, including initiation, promotion, and progression. It is likely that the transition between these stages is driven by different environmental and endogenous factors and involves different biochemical mechanisms and genetic elements. Several types of chemicals initiate the carcinogenic process by yielding highly reactive species that bind covalently to cellular DNA. Our group has elucidated the details of this process with two groups of compounds, aromatic amines and polycyclic aromatic hydrocarbons, emphasizing how these agents distort the conformation of DNA and its functions during DNA replication and transcription. The implications of these findings with respect to oncogene activation, DNA amplification, gene transposition, and chromosome translocations are discussed. Our studies on tumor promotion have concentrated on the mechanisms of action of the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Studies from several laboratories indicate that this agent and related compounds produce their effects by activating a specific cellular enzyme, protein kinase C (PKC). This produces a cascade of events which include alterations in the function of membrane-associated ion channels and receptors, alterations in gene expression and, ultimately, changes in cellular differentiation and proliferation. Recent studies on the isolation and stable overexpression of a cloned DNA sequence that encodes PKC are described. The results obtained provide direct evidence that PKC plays a critical role in growth control. The possible role of PKC, and other mediators of signal transduction pathways, in the origin of certain human cancers is also discussed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The origins of human cancer: molecular mechanisms of carcinogenesis and their implications for cancer prevention and treatment--twenty-seventh G.H.A. Clowes memorial award lecture. 329 40

It is now widely accepted that tumour-promoting phorbol esters activate a Ca2+- and phospholipid-dependent protein kinase (protein kinase C) both in vitro and in intact cells, and that the kinase represents a major cellular phorbol ester-binding protein. The phorbol esters act as analogues of diacylglycerol, a natural regulator of protein kinase C, and stabilize the membrane-association of the kinase. Although other molecular targets may exist, protein kinase C activation is probably important in mediating the diverse responses of cultured cells to phorbol esters and in promoting in vivo tumours. The enzyme comprises a family of closely related proteins and has been detected in extracts from mouse epidermal cells, the likely targets for two-stage carcinogenesis in mouse skin. In this report we show that application of a single dose of TPA (12-O-tetradecanoyl phorbol-13-acetate) to mouse skin results in a rapid and complete loss of protein kinase C activity which is maintained for 3-4 days. This is associated with a loss of immunologically detectable protein kinase C and the accumulation of a smaller protein detectable by antibodies recognizing the regulatory domain of protein kinase C.
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PMID:Application of phorbol ester to mouse skin causes a rapid and sustained loss of protein kinase C. 332 Jul 56

Exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to inhibit gap junctional intercellular communication (GJIC) in many cell types in vitro. Using a scrape loading/dye transfer technique, TPA was shown to cause a dose-dependent and transient inhibition of GJIC in WB-F344, a normal rat liver epithelial cell line. Such a down-modulation of intercellular communication was found to be associated with an increase in protein kinase C (PKC) activity. Translocation of this activity to the particulate fraction occurred 10 min after exposure to 16 nM TPA and was consistent with the time course needed to inhibit GJIC. After 6 h exposure to TPA, essentially all the PKC activity was lost concurrent with the recovery of communication in these cells. During this time, the cells also became refractory to inhibition by further addition of TPA. Blockage of communication induced by TPA in WB cells was prevented by treating the cells with 23 microM palmitoyl carnitine for 1 h or 100 microM 8-N, N-(diethylamino)-octyl-3,4, 5-trimethoxybenzoate for 30 min. The results indicate that TPA transiently modulates GJIC in WB cells and PKC activation is possibly involved in blockage of communication in these cells.
Carcinogenesis 1988 Jan
PMID:Inhibition of gap junctional blockage by palmitoyl carnitine and TMB-8 in a rat liver epithelial cell line. 333 38

When a single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) was performed 12 h before the second application, ornithine decarboxylase (ODC) induction by the second application of TPA was markedly suppressed (refractory state). However, at intervals of 96 h between the first and the second application, the ODC activity induced by the second application of TPA was higher (enhanced state) than the activity induced by the single application. When various anti-tumor promoting agents, i.e. p-bromophenacyl bromide, nordihydroguaiaretic acid, quercetin, 1-tosylamide-2-phenylethyl chloromethyl ketone, retinoic acid and palmitoylcarnitine, were applied concurrently with the first TPA application, the ODC induction in the refractory state was restored only by palmitoylcarnitine, but not by other antitumor promoting agents. None of these anti-tumor promoting agents affected the ODC induction in the enhanced state. Stearoylcarnitine also had the restorative effect but was less effective than palmitoylcarnitine. Acetylcarnitine and palmitic acid were not effective. Pretreatment of mice with TPA 12 h or 96 h before the second TPA application resulted in the reduction or the increase in the Vmax values of ODC both for ornithine and pyridoxal-5'-phosphate, respectively. Palmitoylcarnitine restored these reduced Vmax values to the control values. Twelve hours after TPA treatment, the epidermal protein kinase C activity of both cytosol and particulate fractions decreased moderately. At 96 h after TPA application, protein kinase C activities of both cytosol and particulate fractions were fully or at least partially restored to the control levels. Protein kinase C activities both in the cytosol and the particulate fractions tended to be restored by palmitoylcarnitine, but the effect was not always reproducible. The TPA-induced refractory state and the enhanced state for ODC induction appear to result from the changes in the protein kinase C activities caused by TPA. However, it is not known whether such changes in the protein kinase C activities are the major causes for the TPA-induced refractory and/or enhanced state for ODC induction and whether or not the restorative effect of palmitoylcarnitine is due to its modulating action on protein kinase C activity.
Carcinogenesis 1988 Feb
PMID:Palmitoylcarnitine reverses 12-O-tetradecanoylphorbol-13-acetate-induced refractory state for the TPA-caused ornithine decarboxylase induction in mouse epidermis. 333 15


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