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 present study investigated the mechanisms involved in the mitogenic action of epidermal growth factor (EGF) in cultured human myometrial smooth muscle cells. The cells contained EGF/transforming growth factor-alpha (TGF-alpha) receptors as well as EGF and TGF-alpha mRNA transcripts and the corresponding proteins. Culturing with human EGF resulted in concentration- and time-dependent increases in cell density. The maximal increase was seen at 1 nM followed by a decrease to control levels at 100 nM EGF. The EGF increased cell density from 4 to 8 days followed by a plateau coinciding with the cells reaching confluence. EGF treatment concomitantly decreased the average size of cells. TGF-alpha mimicked EGF and there was no synergism between the two, suggesting a common mechanism of action. Although the presence of 10% fetal bovine serum enhanced overall cell growth, it was not required for EGF and TGF-alpha action. The receptor antibody, which is directed against the extracellular domain and can inhibit ligand binding to the receptors, dramatically inhibited the basal cell growth and exogenous EGF reversed the antibody effect. While TGF-alpha antibody was only marginally effective, EGF antibody had no effect on basal cell growth. Lavendustin (a tyrosine kinase inhibitor), calphostin (a protein kinase C inhibitor), but not H-89 (a protein kinase A inhibitor), inhibited EGF action. Indomethacin, a cyclo-oxygenase inhibitor, completely inhibited, whereas nordihydroguaiaretic acid, a lipoxygenase inhibitor, slightly inhibited EGF action. While estradiol-17 beta modestly inhibited basal as well as EGF-stimulated myometrial smooth muscle cell density, progesterone had no effect. In summary, mitogenic action of EGF in human myometrial smooth muscle cells does not require serum components and it involves tyrosine kinase and protein kinase C signaling and eicosanoids from the cyclooxygenase pathway of arachidonic acid metabolism.
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PMID:Analysis of epidermal growth factor action in human myometrial smooth muscle cells. 756 38

The stimulation of both phospholipase A2 (PLA2) enzymic activity and the production of prostaglandin E2 (PGE2) by transforming growth factor-alpha (TGF-alpha) and Ca2+ ionophore A23187 in TEA3A1 rat thymic epithelial cells were studied. TGF-alpha by itself at various concentrations (5-200 ng/ml) had no effect on the stimulation of PGE2 production. A23187 (1 microgram/ml) by itself stimulated PGE2 production on average by 18-fold over the control. When TGF-alpha (50 ng/ml) was added to the cells in the presence of A23187, a synergistic stimulation (on average 45-fold) of PGE2 production was observed. Synergistic stimulation was also observed at the level of arachidonic acid released from phospholipid pools, suggesting the activation of PLA2 enzymic activity. We have found that this synergistic activation of PLA2 enzymic activity and subsequent stimulation of PGE2 production required the activation of epidermal growth factor (EGF) receptor tyrosine kinase and Ca2+ influx. This was shown by the fact that genistein, an inhibitor of tyrosine kinase, blocks the synergistic stimulation by TGF-alpha and A23187 and by the fact that the stimulation of PGE2 production by TGF-alpha and A23187 is dependent on the culture-medium Ca2+ concentrations. The requirement for Ca2+ influx instead of intracellular mobilization of Ca2+ was shown by the fact that PGE2 production was not stimulated when cells were treated with TGF-alpha and thapsigargin. Moreover, the synergistic stimulation of PGE2 production by TGF-alpha and A23187 was not affected in protein kinase C down-modulated cells. In addition, the synergistic stimulation was not observed in cells treated with either phorbol 12-myristate 13-acetate (PMA) and TGF-alpha or PMA and A23187, and in cells treated with TGF-alpha and thapsigargin. The requirement for the activation of receptor tyrosine kinase seems to be specific to the EGF receptor, since a synergistic stimulation of PGE2 production was not observed when cells are treated with either insulin-like growth factor-I or fibroblast growth factor-I in the presence of A23187.
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PMID:Activation of phospholipase A2 and stimulation of prostaglandin E2 production by transforming growth factor-alpha in rat thymic epithelial cells requires influx of calcium. 768 26

Human colon carcinoma cell lines secrete transforming growth factor-alpha (TGF-alpha). Previous work indicated that the apparent m.w. of the TGF-alpha secreted by these cells ranged between 5 and 25 kDa. The more differentiated GEO cell line secreted a higher percentage of high m.w. TGF-alpha than did the poorly differentiated HCT 116 cell line. In addition, the HCT 116 cells secreted 5-fold more TGF-alpha. Treatment of HCT 116 and GEO cells with a phorbol ester (TPA) resulted in a 4-fold increase in TGF-alpha in the conditioned media of both cell types. The TPA-induced release of TGF-alpha was blocked by an inhibitor of elastase-like enzymes. This suggested a role for protein kinase C (PKC) in TGF-alpha processing in colon carcinoma cells. Direct measurement of PKC activity indicated that the HCT 116 cells (which secrete more fully processed TGF-alpha) had 10-fold more PKC activity than GEO cells. The presence of an elastase-like activity in detergent extracts and the ability of an elastase inhibitor to block the TPA-induced secretion of TGF-alpha suggests that PKC and an elastase-like enzyme are involved in the processing and secretion of TGF-alpha by human colon carcinoma cell lines.
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PMID:Involvement of protein kinase C and an elastase-like enzyme in the processing of transforming growth factor-alpha in human colon carcinoma cell lines. 801 8

The anti-proliferative activity of the DNA-interactive anti-cancer agent cis-diamminedichloroplatinum(II) (cDDP) can be modulated by intracellular signaling systems. We have investigated the effects of growth factors on the sensitivity of human cervical carcinoma (HeLa) cells to cDDP. A 24-hr pretreatment of HeLa cells with 10 ng/ml epidermal growth factor (EGF) or transforming growth factor-alpha increased the anti-proliferative activity of cDDP by 2- to 4-fold. A similar pretreatment of HeLa cells with EGF did not alter cellular sensitivity to doxorubicin or vincristine. A brief exposure (15 min) to growth factors was not sufficient for cDDP sensitization. EGF caused a modest and transient increase in cellular diacylglycerol, the endogenous activator of protein kinase C. Bryostatin I, a partial agonist of protein kinase C, antagonized phorbol ester-mediated cDDP sensitization but had no effect on EGF-mediated sensitization to cDDP. Both EGF and phorbol 12,13-dibutyrate (PDBu) enhanced the rate of [195mPt]cDDP uptake but had no effect on the rate of [195mPt]cDDP efflux in HeLa cells. Bryostatin I reversed the increase in [195mPt]cDDP content by PDBu but failed to block EGF-induced increase in [195mPt]cDDP accumulation. Therefore, although the mechanism of cDDP sensitization by both EGF and phorbol ester appears to involve enhanced drug uptake, they may utilize distinct signal transduction pathways.
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PMID:Comparison of effects of growth factors and protein kinase C activators on cellular sensitivity to cis-diamminedichloroplatinum(II). 805 56

Lactoferrin is present in a variety of tissues and biological fluids; however, the amount differs significantly due to differential expressions. We have previously demonstrated that the mouse lactoferrin gene is regulated by estrogen through an estrogen-response DNA element located at -349, upstream from the transcription start site (+1). In this report, we characterized by deletion and mutation analyses a cluster of mitogen-response elements located between -80 and -40 of the mouse lactoferrin promoter. We demonstrated that the chimeric chloramphenicol acetyltransferase reporter constructs (the -103 to +1 sequence of the mouse lactoferrin gene) containing the mitogen-response unit of the lactoferrin gene were stimulated by cAMP, forskolin, 12-O-tetradecanoylphorbol-13-acetate, and epidermal growth factor/recombinant transforming growth factor-alpha (EGF/TGF-alpha) in a time- and dose-dependent manner. The sequence at position -52 to -40 (mLF-CRE) of the gene conferred transcriptional activation in the presence of forskolin, cyclic AMP, and 12-O-tetradecanoylphorbol-13-acetate in transiently transfected human endometrium carcinoma RL95-2 cells, whereas the region at -80 to -60 responded to EGF/TGF-alpha stimulation. Overexpression of the catalytic unit of protein kinase C or protein kinase A in the RL95-2 cells elevated the chloramphenicol acetyl-transferase activity of the reporter construct 5-6-fold. The mobility shift assay suggested that AP1 and CREB or related proteins participated in complex formation with the mLF-CRE, whereas different proteins bound to the EGF/TGF-alpha-response element.
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PMID:Characterization of a mitogen-response unit in the mouse lactoferrin gene promoter. 817 15

Studies were conducted to evaluate the regulation of steroid production in dispersed cells from ovarian stromal tissue from 5- to 8-week-old-pullets (IM cells) and laying hens (MAT cells). Short-term incubation of IM and MAT cells with ovine (o) LH resulted in a dose-dependent increase in progesterone, androstenedione and oestradiol production; progesterone production was greater in MAT cells than in IM cells (P < 0.05) in response to 2-200 ng oLH ml-1, whereas androstenedione and oestradiol production was greater in MAT cells following treatment with 20 and 200 ng oLH ml-1 (P < 0.05). In both cell populations the cyclic adenosine monophosphate (cAMP) analogue, 8-bromo-cAMP (1 and 10 mmol l-1) stimulated progesterone and androstenedione production, whereas oLH (200 ng ml-1) and forskolin (1-10 mumol l-1) promoted cAMP accumulation (P < 0.05 compared with basal values). However, treatment with the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), did not alter basal or oLH-stimulated cAMP accumulation or progesterone production in either IM or MAT cells (P > 0.10). PMA did, however, inhibit agonist-induced androstenedione production (P < 0.05); co-treatment with the calcium ionophore A23187 potentiated this inhibitory effect. Finally, treatment with transforming growth factor-alpha (TGF-alpha; 1.8-18 pmol l-1) did not affect basal or oLH-stimulated progesterone or androstenedione production by IM cells, MAT cells, theca cells from 6-8 mm follicles or theca cells from the second largest (F2) follicle (P > 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of steroid production in ovarian stromal tissue from 5- to 8-week-old pullets and laying hens. 818 89

In the mouse keratinocyte line HEL-30 the epidermal mitogen transforming growth factor-alpha (TGF-alpha) stimulated the rapid release of arachidonic acid in a dose- and time-dependent manner. The liberation of arachidonic acid was due to the activation of a Ca(2+)-dependent cytosolic phospholipase A2 (cPLA2). The activation mechanism critically depended on a functionally active epidermal growth factor receptor tyrosine kinase and occurred independently of phospholipase C-mediated increases in cellular diacylglycerol and inositol 1,4,5-trisphosphate concentrations and protein kinase C activation. The activation included an increase in cytosolic PLA2 (cPLA2) activity and an association of the enzyme with the membrane fraction. Both activation steps apparently occurred in the presence of basal cytoplasmic Ca2+ concentrations. Moreover, cPLA2 or a closely associated protein was found to be phosphorylated on tyrosine upon TGF-alpha challenge of the cells. The data suggest that tyrosine phosphorylation is involved in the TGF-alpha-induced activation of cPLA2.
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PMID:Activation of cytosolic phospholipase A2 by transforming growth factor-alpha in HEL-30 keratinocytes. 834 57

Treatment of normal primary human keratinocytes with phorbol 12-myristate 13-acetate (PMA) or phorbol 12-13 dibutyrate (PDBu) (100 ng/ml, 6-40 h) followed by two-dimensional (2-D) gel electrophoresis (isoelectric focusing) and microsequencing identified three polypeptides (phorbolin 1, M(r) = 19.9 kDa; phorbolin 2, M(r) = 19.7 kDa; and interleukin-1 (IL-1) receptor antagonist, IL-1ra, M(r) = 19.5 kDa) that are upregulated eight times or more by the phorbol esters and that are highly expressed in noncultured psoriatic keratinocytes. The response was not elicited by other effectors tested including second messengers (Bt2cAMP, Bt2cGMP), cytokines (basic fibroblast growth factor, transforming growth factor-alpha, IGF-II, tumor necrosis factor-alpha, and -beta, interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-3, IL-6, IL-7, IL-8, interferon-alpha, and -gamma), and other substances (Ca++, dexametasone, retinoic acid, lipopolysaccharides) and it was partially reversed by staurosporine, a strong inhibitor of protein kinase C. The results are taken to imply that the protein kinase C signaling pathway may be altered in psoriatic keratinocytes.
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PMID:Evidence for an altered protein kinase C (PKC) signaling pathway in psoriasis. 840 24

It has been reported that keratinocytes possess phospholipase C (PLC)-mediated signal transduction system(s), that can be triggered by histamine, bradykinin, thrombin, platelet-activating factor (PAF), and epidermal growth factor (EGF)/transforming growth factor-alpha (TGF-alpha). Since the activation of PLC results in release of 1,2-diacylglycerol (DAG), the physiologic activator of protein kinase C (PKC) that modulates the epidermal adenylate cyclase, we investigated the effects of these PLC activating chemicals on the adenylate cyclase responses of dispase-separated normal pig epidermis. Among these chemicals and factors only histamine decreased the successive histamine-induced cyclic AMP accumulation and increased forskolin-, and cholera toxin-induced AMP accumulations. These effects were similar to those of PKC activators. However, in contrast to the PKC-activator-induced partial and receptor-non-specific desensitization, the histamine-induced desensitization was completely-inducible and specific to the histamine receptor system, and was not affected by the PKC inhibitor, H-7. Similar modulation of the epidermal adenylate cyclase was induced by other adenylate cyclase stimulators (epinephrine, adenosine and prostaglandin E2), but not by bradykinin, thrombin, PAF, or EGF. The combined addition of bradykinin, thrombin, PAF and EGF to the culture medium had no effect on the adenylate cyclase responses, either. Thus no evidence for receptor-agonist dependent PLC-induced modulation of the adenylate cyclase was obtained in the normal pig epidermis. Although keratinocytes might contain PLC-mediated signal transduction systems, that are triggered by histamine, bradykinin, thrombin, PAF, and EGF/TGF-alpha, none of the activators singly or in combination appear to activate PKC sufficiently for the modulation of adenylate cyclase responses of the normal pig epidermis.
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PMID:Activators of protein kinase C but not of phospholipase C modulate adenylate cyclase-responses of normal pig epidermis. 856 94

Modulation of steroid receptor-dependent transcription by extra- cellular ligands represents a novel mechanism of steroid receptor regulation. We have assessed the effects of epidermal growth factor (EGF), transforming growth factor-alpha (TGF alpha), and insulin-like growth factor I (IGF-I) on transcription from consensus estrogen response elements (ERE) in estrogen receptor (ER)-positive BG-1 human ovarian adenocarcinoma calls. EGF, TGF alpha, IGF-I, and estradiol (E2) enhanced transcription in a dose-dependent manner using either a strong or a minimal promoter, and ICI 164,384, a specific ER antagonist, inhibited these responses. Combinations of E2 with TGF alpha or IGF-I induced synergistic activation of transcription from an ERE, whereas as additive response was observed with combinations of IGF-I and TGF alpha of EGF. Tetradecanoyl 12-phorbol 13-acetate (TPA), a protein kinase C (PKC) activator, stimulated ERE-mediated transcription, and this effect was inhibited by ICI 164,384. Bisindolylmaleimide, a relatively specific inhibitor of PKC, completely antagonized TPA-induced transcription, but did not affect the response to TGF alpha, IGF-I, or E2. The combination of TPA with E2 in transcriptional synergism was inhibited by ICI 164,384; conversely, the combination of TPA with either TGF alpha of IGF-I elicited a response only equal to the maximal TPA response. Thus, peptide growth factors elicit ER-dependent transcription independently of PFC; however, there may be a common mechanistic component, as saturation of response was observed. Finally, activation of ERE-dependent transcription in Chinese hamster ovary cells by IGF-I was observed in the presence of a mutant receptor that lacks estrogen-binding activity. The effect of both IGF-I and E2 were dependent on the ability of the ER to bind to DNA. IGF-I elicited only weak transcriptional activation in the presence of a deletion mutant that lacked the entire A/B domain; however, synergism between IGF-I and E2 was observed with this mutant. Therefore, ligand-independent activation of ER-dependent transcription by IGF-I is predominantly mediated through activation function I by a mechanism distinct from that of E2.
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PMID:Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol. 861 9


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