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)

Cytochrome P-450scc (P-450scc) catalyzes the cholesterol side-chain cleavage reaction, a rate-limiting enzymatic step for progesterone synthesis in trophoblastic and other steroidogenic cells. Adrenodoxin is the iron/sulfur protein donating electrons to P-450scc during this reaction. We examined the effects of cholera toxin (CT), an activator of adenylate cyclase, and 12-O-tetradecanoylphorbol acetate (TPA), a phorbol ester protein kinase C activator, on the levels of mRNAs encoding P-450scc and adrenodoxin in JEG-3 choriocarcinoma cells. CT induced in a concentration- and time-dependent manner P-450scc and adrenodoxin mRNA levels to 8-fold and 1.5-fold above that of control, respectively. TPA also increased P-450scc and adrenodoxin mRNA levels about 3-fold and 1.5-fold above that of control, respectively. Epidermal growth factor (EGF) was found to weakly induce P-450scc mRNA accumulation with a maximal 20% stimulation above basal levels. The effects of CT and TPA were apparently additive on both mRNAs. The protein synthesis inhibitor cycloheximide diminished basal, CT-, TPA-, and EGF-stimulated P-450scc mRNA accumulation whereas the opposite was observed for the adrenodoxin mRNA. Insulin-like growth factor I (IGF-I) appeared to have no effect on either mRNA. These data indicate that: (1) the accumulation of P-450scc and adrenodoxin mRNAs is mainly controlled by the cyclic adenosine 3',5'-monophosphate (cAMP)-dependent pathway but their stimulation by TPA- and EGF-induced signals may also play a weaker synergistic role; (2) the protein synthesis inhibitor cycloheximide inhibits basal, CT-, TPA- and EGF-stimulated P-450scc mRNA levels while it increases the expression of adrenodoxin mRNA suggesting that in the malignant trophoblasts these two enzyme mRNAs are differentially controlled.
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PMID:Regulation of the cholesterol side-chain cleavage cytochrome P-450 and adrenodoxin mRNAs in cultured choriocarcinoma cells. 131 54

We found that 4-beta-phorbol 12-myristate 13-acetate (PMA) caused decreased expression of the polymorphonuclear neutrophil (PMN) surface antigen 31D8. In contrast to the rapid initiation of the oxidative burst caused by PMA, the effect was slow to start but increased during incubation periods up to 50 min. To study this apparent protein kinase C-independent late effect of PMA, we measured 31D8 expression in PMNs after incubation with various concentrations of PMA. The maximum PMA-induced inhibition was 76 +/- 2%, with an ID50 of 3.9 +/- 0.4 ng/ml. Oxidants and prooxidants (hydrogen peroxide, hypochlorite, taurine-chloramine, and ferrous iron, with or without H2O2) had no direct effect on 31D8 antigen expression. The following substances were not protective against the inhibitory affect of PMA: (1) antioxidants (superoxide dismutase, catalase, azide, dimethyl sulfoxide, Desferal, and ascorbate, with the exception of alpha-tocopherol), (2) inhibitors of protein kinase C (H7 and W7), (3) inhibitors of 5-lipoxygenase (A-63162, MK886, and high-dose indomethacin) and (4) inhibitors of cyclooxygenase (low-dose indomethacin). Myeloperoxidase-deficient PMNs had normal 31D8 antigen expression and a decrease of 31D8 antigen expression by PMA, as did normal PMNs. The inactive analog of PMA, 4-alpha-phorbol didecanoate, had no effect on 31D8 antigen expression. alpha-Tocopherol (50 micrograms/ml) and betamethasone (150 micrograms/ml) protected against the PMA effect by 30.5 +/- 7.3 (P less than .0005) and 52 +/- 15 (P less than 0.004) channels, respectively. These results indicate that PMA has a protein kinase C-independent late effect on human neutrophils, which can be prevented by pretreatment with alpha-tocopherol or the steroid betamethasone. These compounds probably exert their protective effect by membrane stabilization.
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PMID:Characterization of a direct effect of phorbol myristate acetate on human neutrophil cell membrane using 31D8 monoclonal antibody. 154 11

We investigated the effects of iron deficiency in mice on protein kinase C (PKC) activation, an enzyme required for optimal lymphocyte proliferation. C57BL/6 mice were fed either an iron-deficient diet (ID; 10 mg Fe/kg diet), a control diet (C; 50 mg/kg diet), or were pair fed (PF) to ID mice for 34 d. PKC activity was studied in spleen cells by histone phosphorylation. Iron deficiency significantly reduced cytosol activity in unstimulated cells and membrane-bound activity in cells stimulated by concanavalin A (Con A) or phorbol-12-myristate-13-acetate (PMA), and the ratio of membrane-bound over cytosol activity in mitogen-stimulated cells. In PF mice the ratio of membrane-bound activity to cytosol activity was greater than normal in Con A-treated cells and only slightly decreased in PMA-treated cells. PKC activity positively correlated with iron status. We conclude that reduced PKC activity and poor translocation results in aberrant signal transduction, which in turn might be responsible for the impaired lymphocyte proliferation associated with iron deficiency.
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PMID:Impaired protein kinase C activation as one of the possible mechanisms of reduced lymphocyte proliferation in iron deficiency in mice. 195 Nov 69

Iron-transferrin (FeTF) is an essential growth factor required for proliferation of lymphoid cells. FeTF activates protein kinase C (PKC) in the lymphoblastoid T-cell line, CCRF-CEM. We have treated CEM cells with human FeTF, then examined levels of PKC mRNA by hybridization analysis using cDNA probes specific for alpha-, beta-, and gamma-PKC subspecies. CEM cell mRNA hybridized with the beta-subspecies probe but not with probes for alpha- or gamma-subspecies. After exposure to FeTF an increase in PKC-beta mRNA was detectable at 10 minutes, peaked at 12 hours, and was sustained for 72 hours. Nuclear transcription assays demonstrated that rates of PKC-beta mRNA transcription were increased in FeTF-treated cells. By contrast, steady state levels of PKC-beta mRNA did not increase after treatment of cells with apotransferrin or gallium TF. Similarly, treatment with soluble iron as ferric ammonium citrate did not increase steady state levels of PKC-beta mRNA, despite producing a marked increase in cellular ferritin content. Ferritin increased from a baseline value of 63 ng/10(6) cells to 98 and 100 ng/10(6) cells in CEM cells treated for 1 hour with ferric ammonium citrate or FeTF, respectively. FeTF did not increase cytoplasmic-free calcium in CEM cells loaded with fura-2, indicating that binding of FeTF to transferrin receptors did not open membrane Ca2+ channels or release intracellular Ca2+. In addition, pretreatment of cells with desferrioxamine, but not ferrioxamine, blocked the FeTF-induced increase in PKC-beta transcripts. Therefore, iron as FeTF (not soluble iron or nonferric TF) stimulates transcription of the CEM cell PKC-beta gene. Transcriptional rate of the PKC-beta gene does not correlate with cellular iron content as judged by ferritin measurements. Furthermore, the requirement for FeTF does not appear to reflect activation of a classic agonist pathway as judged by stable cellular Ca2+. These data suggest that delivery of iron by FeTF to one or more specific cellular compartments may stimulate PKC-beta gene transcription in CEM cells.
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PMID:Induction of protein kinase C mRNA in cultured lymphoblastoid T cells by iron-transferrin but not by soluble iron. 200 52

Kinetic analysis of transferrin receptor properties in 6-8 day rat reticulocytes showed the existence of a single class of high-affinity receptors (Kd 3-10 nM), of which 20-25% were located at the cell surface and the remainder within an intracellular pool. Total transferrin receptor cycling time was 3.9 min. These studies examined the effects of various inhibitors on receptor-mediated transferrin iron delivery in order to define critical steps and events necessary to maintain the functional integrity of the pathway. Dansylcadaverine inhibited iron uptake by blocking exocytic release of transferrin and return of receptors to the cell surface, but did not affect transferrin endocytosis; this action served to deplete the surface pool of transferrin receptors, leading to shutdown of iron uptake. Calmidazolium and other putative calmodulin antagonists exerted an identical action on iron uptake and receptor recycling. The inhibitory effects of these agents on receptor recycling were overcome by the timely addition of Ca2+/ionomycin. From correlative analyses of the effects of these and other inhibitors, it was concluded that: (1) dansylcadaverine and calmodulin antagonists inhibit iron uptake by suppression of receptor recycling and exocytic transferrin release, (2) protein kinase C, transglutaminase, protein synthesis and release of transferrin-bound iron are not necessary for the functional integrity of the iron delivery pathway, (3) exocytic transferrin release and concomitant receptor recycling in rat reticulocytes is dependent upon Ca2+/calmodulin, (4) dansylcadaverine, dimethyldansylcadaverine and calmidazolium act on iron uptake by interfering with calmodulin function, and (5) the endocytotic and exocytotic arms of the iron delivery pathway are under separate regulatory control.
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PMID:Calmodulin dependence of transferrin receptor recycling in rat reticulocytes. 231 Mar 76

Using Triton X-100/lipid mixed micellar methods, we observed that the adriamycin-iron(III) complex was a potent inhibitor of protein kinase C while uncomplexed adriamycin itself was a poor inhibitor in the absence of heavy metal contaminants. The 3:1 adriamycin-iron complex was more potent than 2:1, 1:1, and 1:0 complexes. Inhibition of protein kinase C was reversible, and 50% inhibition occurred at 13 microM (adriamycin)3Fe3+. Both the catalytic and the regulatory domain of protein kinase C were affected by adriamycin-iron(III). Adriamycin-iron(III) was a competitive inhibitor of the catalytic domain of protein kinase C with respect to MgATP but not with respect to magnesium (IC50 350 microM). The predominant interaction of adriamycin-iron(III) with native protein kinase C was as a competitive inhibitor with respect to diacylglycerol. Inhibition was not competitive with respect to phosphatidylserine, calcium, magnesium, MgATP, or histone. Interaction with the regulatory domain was demonstrated by the ability of adriamycin-iron(III) to inhibit phorbol dibutyrate binding. Other adriamycin transitional metal complexes showed little inhibition of protein kinase C activity. Acetylation of the amine on the daunosamine moeity of adriamycin did not preclude the formation of a ferric complex but resulted in total loss of inhibitory activity. These results suggest that the presence of free amines in a highly structured adriamycin-iron complex is necessary for inhibition. The implications of inhibition of protein kinase C by adriamycin-iron(III) are discussed.
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PMID:The adriamycin-iron(III) complex is a potent inhibitor of protein kinase C. 254 37

A hypothesis is presented to account for the dietary induction and promotion of colorectal cancer. The principal agents are the secondary bile acids, lithocholic and deoxycholic acids, the vitamin K group and ferrous iron complexes. These metabolites may interact to subvert the normal free radical generating mechanisms involved in mucosal defence. Diets high in fat and red meat and low in fibre support a Bacteroides-dominated colonic microflora, which both synthesis and utilises vitamin K2 isoprenalogues or menaquinones as enzyme co-factors. Iron(II) complexes such as haemin from the breakdown of dietary haemoglobin and myoglobin also serve as growth factors for these bacteria and provide a rich source of haem-iron for intestinal uptake. Biliary secretion is stimulated by dietary fat and bile acids are essential for the intestinal uptake of vitamin K and possibly of iron complexes such as haemin. In the mature colonocyte, vitamin K and haemin may initiate redox cycling reactions which liberate superoxide (O2-.). Bile acids can activate the membrane bound phospholipase to liberate arachidonate and diacylglycerol. This leads in turn to the production of more O2-. which can enter the microcirculation and acts as a potent chemoattractant for the neutrophils that line the lamina propria. The released diacylglycerol can activate protein kinase C in the neutrophil membrane to switch on the respiratory burst oxidase system generating yet more O2-. and may stimulate the proliferation of transformed stem cells by a similar protein kinase C mediated mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Free radical generating mechanisms in the colon: their role in the induction and promotion of colorectal cancer? 279 47

The effect of tetradecanoylphorbol acetate (TPA) on follicle-stimulating hormone (FSH)-induced synthesis of the cholesterol side-chain cleavage (SCC) enzyme complex was studied in rat ovarian granulosa cells cultured for 48 h in serum-free medium. Cell proteins were radiolabeled with [35S]methionine, followed by immunoprecipitation of cholesterol side-chain cleavage cytochrome P-450 (P-450SCC) as well as the iron-sulfur protein adrenodoxin. Polyacrylamide gel electrophoresis and fluorography of the immunoprecipitates showed that TPA, when added in combination with FSH (50 ng/ml) or dibutyryl cAMP (Bt2cAMP; 1 mM), suppressed the stimulatory effects of these compounds on the synthesis of the SCC components in a concentration-dependent fashion. The effect of TPA was accompanied by decreased progesterone formation and decreased cAMP accumulation. The structural analog of TPA, phorbol-4 alpha-didecanoate, which does not activate protein kinase C (Ca2+/phospholipid-dependent enzyme), had no effect on the FSH- or Bt2cAMP-stimulated synthesis of SCC and progesterone or on cAMP formation. In addition to inhibiting the synthesis of these proteins, TPA greatly reduced the FSH- and Bt2cAMP-induced increase in levels of mRNA encoding the precursor form of P-450SCC. It is concluded that the effect of the phorbol ester TPA to inhibit FSH-stimulated progesterone formation in cultured ovarian granulosa cells of the rat involves decreased synthesis of the components of the SCC enzyme complex due to reduced levels of mRNA encoding the precursor forms of these proteins. The results are indicative that TPA not only inhibits FSH-mediated stimulation of cAMP formation but also may block cAMP-mediated induction of SCC synthesis. It is postulated that the effects of TPA may reflect the physiological role of protein kinase C in the regulation of ovarian steroidogenesis.
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PMID:Tetradecanoyl phorbol acetate suppresses follicle-stimulating hormone-induced synthesis of the cholesterol side-chain cleavage enzyme complex in rat ovarian granulosa cells. 288 36

The dinitrosyl iron complexes (DNIC) with thiosulphate, cysteine or phosphate were shown to inhibit in vitro (in citrate plasma) the human platelet aggregation induced by ADP, collagen or adrenaline. This effect cannot be explained by the toxic action of DNIC on the platelet membrane, since DNIC-pretreated platelets are capable of aggregating under the action of 10(-8) M/ml of phorbol ester, which is known to cause direct activation of protein kinase C. The antiaggregatory activity of DNIC exceeds that of Na-nitroprusside and seems to be due to nitric oxide capable to activate guanylate cyclase of platelets. Using the EPR method, it was shown that addition of DNIC to platelet-enriched plasma results in a rapid transfer of Fe(NO)2 groups to the coupled RS(-)-groups proteins of plasma and, apparently, of platelet membrane proteins. These protein DNIC seem to be the source of NO which inhibits human platelet aggregation.
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PMID:[Inhibition of platelet aggregation by dinitrosyl iron complexes with low molecular weight ligands]. 302

Promastigotes and amastigotes of Leishmania mexicana amazonensis, incubated in the presence of 20 ng/ml of 12-O-tetradecanoyl phorbol-13-acetate (TPA), an exogenous protein kinase C activator, developed several membrane and cytoplasmic alterations. Increased exocytic activity was observed especially in the amastigotes which had an enlarged flagellar pocket. Treatment with TPA induced protrusions of the plasma membrane where cytoplasmic elements (ribosomes and sub-pellicular microtubules) were not seen. Freeze-fracture replicas of TPA-treated parasites showed reduction in the density of the intramembranous particles (IMP), which were not seen on either fracture face of the membrane lining the protrusion. Cytochemical observations showed that sterols and anionic sites which bind to filipin and cationized ferritin particles, respectively, can be detected in the membrane lining the protrusions. However, the pattern of distribution of anionic sites, which bind colloidal iron hydroxide particles, and acid phosphatase in the membrane lining the protrusion region differed from the other portions of the plasma membrane.
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PMID:Effects of phorbol ester on Leishmania mexicana amazonensis: an ultrastructural and cytochemical study. 317 96


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