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)

Various chlorinated hydrocarbons, many of which are known hepatic tumor promoters, have been evaluated for their ability to stimulate protein kinase C (PKC) activity in vitro. Chlordane, kepone, toxaphene, heptachlor, 2,2-bis(4-chlorophenyl)-1,1-dichloroethane, the polychlorinated biphenyl Aroclor 1254, aldrin, 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT) and gamma-hexachlorocyclohexane (lindane) were the most potent stimulators of PKC activity. Of these compounds, chlordane was the most potent organochlorine pesticide. Chlordane (100 microM) stimulated mouse brain PKC activity in the 10(5) g supernatant to a maximum velocity equal to that obtained when the enzyme was maximally stimulated with the skin-tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). Chlordane concentrations as low as 1 microM significantly stimulated PKC activity. Chlordane-stimulated PKC activity was calcium-dependent, and in the presence of exogenous calcium, chlordane-stimulated PKC activity was at least 5-fold greater than in the absence of added calcium. In contrast, the addition of calcium only minimally affected (less than 30% increase) the TPA-stimulated PKC activity. Concentrations of TPA and chlordane which maximally stimulate PKC did not produce an additive effect on PKC activity. Chlordane- and TPA- stimulated PKC activity was phospholipid-dependent and could be inhibited by quercetin, a known inhibitor of PKC activity. Chlordane in the presence of calcium also stimulated mouse epidermal and hepatic PKC as well as purified rat brain PKC. These results demonstrate that a wide variety of chlorinated hydrocarbons, which are considered hepatic tumor promoters, stimulate protein kinase C activity in vitro.
Carcinogenesis 1989 May
PMID:Hepatic tumor-promoting chlorinated hydrocarbons stimulate protein kinase C activity. 270 41

Okadaic acid (OA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) are both potent tumor promoters in a mouse skin carcinogenesis experiment. OA was much more toxic than TPA for murine embryo cell lines such as Swiss 3T3 cells or C3H10T1/2 cells. TPA is a potent mitogen for 3T3 cells; in contrast OA was unable to stimulate DNA synthesis in these cells. TPA induces a family of primary response genes, the TPA induced sequence (TIS) genes, in a wide variety of cells. Although OA induced modest levels of TIS mRNA expression, the time course of the induction of TIS1 and TIS8 mRNA was delayed when compared to induction by TPA or peptide mitogens such as fibroblast growth factor (FGF). In addition TPA-mediated down-regulation of protein kinase C attenuated TIS gene induction by OA, but not by FGF.
Carcinogenesis 1989 Aug
PMID:The tumor promoters 12-O-tetradecanoylphorbol-13-acetate and okadaic acid differ in toxicity, mitogenic activity and induction of gene expression. 275 24

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induces a disorganization of the actin cytoskeleton and its redistribution at the periphery of the cells in SV40-transformed human keratinocytes. This phenomenon is induced by other diterpene esters, such as 4-O-methyl TPA, 12-O-ethacrynylphorbol-13-acetate (EPA), 12-O-retinoylphorbol-13-acetate (RPA) and mezerein, which exert either convertogenic or promoting effects in skin tumor development in vivo. Two diacylglycerols: oleyl-acetyl glycerol (OAG) and dioctanoyl-glycerol (DOG) do not induce the disorganization of actin. Thus, the effects of these compounds, as they are found in SV40-transformed human keratinocytes, do not exhibit clear-cut correlations to either their protein kinase C activating abilities, or their effects on different stages of multistage carcinogenesis in mouse skin in vivo.
Carcinogenesis 1988 Feb
PMID:Effect of diterpene esters on actin cytoskeleton of SV40-transformed keratinocytes is not reproduced by diacylglycerols. 282 5

Increased cytosolic phospholipid-sensitive, Ca2+-dependent protein kinase C (PK-C) activity is correlated with the highly tumorigenic potential of rat embryo fibroblasts transformed by herpes simplex virus type 2 (HSV-2). Treatment of the cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) caused a decrease in the cytosolic PK-C with a concomitant increase in PK-C recovered in the membrane fraction. Translocation of the PK-C was dependent upon length of exposure to the phorbol diester. PK-C activity in the cytosolic fraction could be stimulated by TPA without the addition of phosphatidylserine and diacylglycerol. It is tempting to speculate that HSV-2 induction of cellular PK-C activity may be important in phosphorylation of proteins needed for promotion of HSV-2-induced carcinogenesis.
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PMID:Phospholipid-sensitive, Ca2+-dependent protein kinase activity in rat embryo fibroblasts transformed by herpes simplex virus type 2. 283 20

Protein kinase C catalyzes phosphorylation of purified rat brain guanylate cyclase. The phosphorylation is marked by concomitant increase in guanylate cyclase activity. TPA further enhances both phosphorylation and activity of guanylate cyclase. Data seem to provide clues to the molecular mechanism of one of the transformation-like responses mimicked by 12-O-tetradecanoylphorbol-13-acetate, i.e. the elevation of cyclic GMP. It is envisaged that protein kinase C may have a central role in the understanding of molecular events triggering carcinogenesis.
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PMID:Protein kinase C catalyzes phosphorylation of guanylate cyclase in vitro. 285 74

Ten new tumor promoters which are structurally different from TPA but of similar biological activity were found. Based on their binding to the phorbol ester receptors of cell membranes, these new tumor promoters were classified as TPA-type tumor promoters, teleocidin and aplysiatoxin, which like TPA, activated protein kinase C in vitro, whereas two non-TPA-type tumor promoters, palytoxin and thapsigargin did not induce ODC activity in mouse skin, adhesion of HL-60 cells or activation of protein kinase C, but did show tumor-promoting activity in a two-stage carcinogenesis experiment. Although these two types of tumor promoter exert their tumor-promoting activities through different pathways, production of prostaglandin E2 by rat macrophages was induced by both the TPA-type and non-TPA-type promoters. Therefore, stimulation of arachidonic acid metabolism is suggested to be one of the important biological activities for tumor promotion.
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PMID:[The actions of TPA-type as well as non-TPA type tumor promoters and their mechanism(s) in tumor promotion]. 287 Jun 84

Palytoxon, which is a toxin with a molecular weight of 2681 daltons isolated from a marine coelenterate, is a potent skin irritant. However, it did not induce ornithine decarboxylase in mouse skin, or adhesion of human promyelocytic leukemia cells (HL-60). Moreover, it did not inhibit the specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to a mouse skin particulate fraction or activate protein kinase C isolated from mouse brain in vitro. Since palytoxin showed strong irritation on mouse ear in one short-term screening test for a promoter, it was examined in a two-stage carcinogenesis experiment. The incidence of tumors in a group of mice treated with 7,12-dimethylbenz[a]anthracene plus palytoxin was 62.5% in week 25. These tumors were identified histologically as seven papillomas and one carcinoma. This paper reports the potent tumor-promoting activity of palytoxin, which is classified as a non-TPA-type tumor promoter.
Carcinogenesis 1986 May
PMID:Palytoxin is a non-12-O-tetradecanoylphorbol-13-acetate type tumor promoter in two-stage mouse skin carcinogenesis. 287 Aug 23

To help clarify whether elevation of gamma-glutamyltranspeptidase (GGT) in hepatocytes is associated with particular pattern(s) of liver differentiation, adult rat hepatocytes in primary culture were maintained for up to 5 days under conditions considered to alter differentiation in liver or other cells: basal GGT activity in untreated cultures and inducibility of the enzyme by known inducers such as dexamethasone, p,p'-dichlorodiphenyltrichloroethane or pregnenolone 16 alpha-carbonitrile were measured. Basal and induced GGT activities were maximal in confluent cultures and declined with decreasing cell density, an effect probably mediated by cell contact rather than factors in the culture medium. Opposite effects of cell density on GGT and DNA synthesis suggest that increased GGT activity is not linked with growth. Epidermal growth factor (EGF) increased basal GGT and augmented the action of xenobiotic inducers in lower density cultures, giving GGT activities approaching the levels in confluent cells. EGF had no effect on confluent cultures. Activators of protein kinase C such as tetradecanoyl phorbol acetate had significant but small inducing effects on GGT. Agents including all-trans retinoic acid, butyrate and dimethylsulfoxide which are considered to favour terminal differentiation in many cell types, all partly blocked induction of GGT by dexamethasone, EGF or xenobiotics. The results are consistent with (but do not prove) the view that elevated GGT activity may be associated with liver phenotype(s) distinct from terminal differentiation but not necessarily linked with growth.
Carcinogenesis 1987 Dec
PMID:Modulation of gamma-glutamyltranspeptidase in normal rat hepatocytes in culture by cell density, epidermal growth factor and agents which alter cell differentiation. 289 Apr 44

Using an 18 week two-stage protocol we have compared the tumour-promoting properties of a range of phorbol and daphnane esters on female CD-1 mice. The induction of epidermal hyperplasia in this mouse strain by these compounds has also been assessed by comparison with the standard phorbol ester, 12-O-tetradecanoylphorbol-13-O-acetate (TPA). Two compounds, sapintoxin D (SAP D) and thymeleatoxin A (TA) (a daphnane structurally related to the second-stage promoter mezerein) were shown to be second-stage promoters using 5 nmol TPA as a first-stage promoter and 0.2 mumol 7,12-dimethylbenz[a]anthracene (DMBA) as initiator. Both compounds at a dose of 17 nmol were hyperplasiogenic. Two further derivatives, sapintoxin C (SAP C) and 4 alpha-sapinine (alpha-SAP) were inactive as promoters and hyperplastic agents. 4 alpha-sapinine, which prevents in vitro stimulation of protein kinase C (PKC), by 12-O-tetradecanoylphorbol-13-O-acetate (TPA) failed to inhibit significantly TPA-induced promotion and hyperplasia at a dose of 20 nmol and 100 nmol respectively. Sapintoxin A (SAP A), a potent activator of PKC, was neither a complete nor second-stage promoter at doses of up to 20 nmol. A series of in vivo and in vitro experiments which were carried out to determine the metabolic fate of this compound under experimental conditions showed that SAP A was not metabolized to any significant extent up to 48 h. When SAP A was co-administered with sub-hyperplastic doses of the calcium ionophore A23187 (5 micrograms and 10 micrograms) tumours appeared in a dose-dependent manner. This combination was also hyperplasiogenic in mouse skin. SAP A may be a useful probe for studying the involvement of PKC isozymes in tumour promotion and cell proliferation.
Carcinogenesis 1989 Feb
PMID:Tumour-promoting and hyperplastic effects of phorbol and daphnane esters in CD-1 mouse skin and a synergistic effect of calcium ionophore with the non-promoting activator of protein kinase C, sapintoxin A. 291 80

Phorbol esters and the structurally dissimilar teleocidins and ingenols bind to and activate protein kinase C (PKC) during the course of tumour promotion. These compounds are referred to as TPA-like tumour promoters (from 12-O-tetradencanoyl phorbol-13-acetate, the most active of the class) and are amongst the most potent tumour promoters known. Despite their structural dissimilarity, all three groups of molecules have been shown to bind to the diacylglycerol site of PKC with high affinity. It is thought that this binding to and consequent activation of PKC is the crucial step in tumour promotion by these compounds. The aim of this work was to provide a description of the binding site by comparing structural features (in particular the electrostatic potential) with the activity of numerous derivatives of the three classes. Initially the description was obtained by consideration of the phorbol derivatives, and then refined using the teleocidins and ingenols. The activity data were collected from a variety of sources and the structures calculated using the semi-empirical MNDO approximation embodied in the MOPAC program. Where possible, the crystal structure was obtained from the Cambridge Crystallographic Database, and used as a starting point for the calculation. In other cases, a preliminary calculation was carried out using the molecular mechanics program AMBER. Electrostatic potentials were calculated and displayed using an in-house program 3D2, while superpositions of molecules were carried out using CHEM-X.
Carcinogenesis 1989 Mar
PMID:The conformations and electrostatic potential maps of phorbol esters, teleocidins and ingenols. 292 97


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