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)

Dramatic smooth muscle cell (SMC) growth occurs in the uterine artery during pregnancy. The potential for pregnancy-associated growth may also exist at other vascular sites. We tested the hypothesis that increased growth of uterine artery SMC isolated from pregnant (vs. nonpregnant) guinea pigs would be detectable in culture, that pregnancy-associated phenotypic changes would also be found in nonuterine vascular cells (aortic SMC), and that the enhanced growth would be dependent on estrogen, peptide growth factors like platelet-derived growth factor (PDGF), and protein kinase C (PKC). Growth responses were measured by [3H]-thymidine incorporation and cell counts. Uterine artery SMC from pregnant guinea pigs grew to a higher plateau density with serum stimulation, had increased spontaneous DNA synthesis and persistent growth following serum with-drawal, and were more responsive to 3-30 ng/ml PDGF-BB than nonpregnant cells. Aortic SMC from pregnant animals also grew to a higher plateau density and had enhanced responsiveness of PDGF-BB. This increased response to PDGF-BB by pregnant uterine artery and aortic SMC (40-233% increase over nonpregnant PDGF result) was reproduced in nonpregnant cells by pretreatment for 1-24 h with 17-beta(beta)-estradiol (30-100 nM). Neither the pregnancy-induced difference nor the estradiol pretreatment was associated with increased PDGF-BB binding activity. The synergistic effect of 17 beta-estradiol was partially (62%) reproduced with 17-alpha(alpha)-estradiol, an isomer which does not bind the estrogen receptor. This suggested that 17 beta-estradiol modulates the PDGF-BB response by both estrogen-receptor- and nonreceptor-mediated mechanisms. To test if the estrogen effects were dependent on PKC, two different antagonist strategies (3 microM dihydrosphingosine and phorbol-ester-induced downregulation) were applied prior to 17 alpha- or beta-estradiol and blocked the enhanced responses to PDGF. The synergistic effect of 17 beta-estradiol on PDGF was then reproduced by 1 h pretreatment with the cell-permeable PKC activator, 10 nM PMA. We conclude that pregnancy stimulates increased growth of uterine and aortic SMC in vitro which is dependent on estrogen, PDGF, and PKC and may be important in vascular remodeling during pregnancy.
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PMID:Pregnancy-stimulated growth of vascular smooth muscle cells: importance of protein kinase C-dependent synergy between estrogen and platelet-derived growth factor. 855 71

Epidermal growth factor reproduces many of the effects of estrogen on the murine female reproductive tract and may partially mediate estrogen-induced growth and differentiation. The mechanism by which the actions of estrogens and epidermal growth factor (EGF) converge is unknown. The studies described herein were performed to investigate the possibility that some of the actions of EGF may be mediated through the estrogen receptor. A specific estrogen receptor (ER) antagonist inhibited estrogenlike effects of EGF in the mouse uterus, specifically induction of DNA synthesis and phosphatidylinositol turnover. In addition, EGF elicited enhanced nuclear localization of uterine ER and formation of a unique nuclear form of ER that is present after estrogen treatment. These in vivo observations indicated that EGF may elicit some of its actions by activation of nuclear ER. Thus, the effect of peptide growth factors on activation of a consensus estrogen response element was assessed in Ishikawa human endometrial adenocarcinoma cells, which contain negligible ER levels, and in BG-1 human ovarian adenocarcinoma cells, which contain abundant ER. EGF and TGF alpha induced transcriptional activation of a consensus estrogen response element (ERE) in an ER-dependent manner in both cell types. In addition, insulinlike growth factor I (IGF-I) was as potent as 17 beta-estradiol in BG-1 cells. Synergism between growth factors and estrogen was observed in both cell types, although synergism was not observed between the different classes of growth factors [i.e., transforming growth factor alpha (TGF alpha) and IGF-I] in BG-1 cells. The most potent activator of ERE-dependent transcription was a protein kinase C activator (TPA), which acted synergistically with 17 beta-estradiol. A protein kinase C inhibitor abolished the effect of TPA but not that of 17 beta-estradiol, IGF-I, or TGF alpha. A protein kinase A activator elicited ER-dependent activation of transcription and did not synergize with estrogen or growth factors. In conclusion, some physiologic actions of peptide growth factors are dependent on ER. Indeed, growth factors are capable of eliciting ER-dependent activation of an ERE. Both the protein kinase A and protein kinase C pathways can elicit ER-dependent transcriptional activation; however, it is unlikely that these pathways mediate the effects of peptide growth factors on the ER in BG-1 cells.
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PMID:Cross talk between peptide growth factor and estrogen receptor signaling systems. 859 72

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

Nonsteroidal agent tamoxifen (Tam), a therapeutic/chemopreventive agent for breast cancer, inhibits protein kinase C (PKC), which is considered to be one of its extra-estrogen receptor sites of action. This drug is required at higher (>100 microM) concentrations to inhibit PKC in the test tube, whereas it is required at lower (1-10 microM) concentrations to induce inhibition of cell growth in estrogen receptor-negative cell types. To identify additional mechanisms of action of Tam on PKC and cell growth, studies with MDA-MB-231, an estrogen receptor-negative breast carcinoma cell type, have been carried out. Upon treatment with 5-20 microM Tam, a cytosol to membrane translocation of PKC occurred within 30 min, which was then followed by a down-regulation of the enzyme within 2 h. A transient generation of Ca2+/lipid-independent activated form of PKC was observed during this period. Rapidly growing cells require nearly 2-3-fold lower concentrations (2-5 microM) of Tam than do confluent cells to induce changes in PKC. Furthermore, phorbol ester binding observed with intact cells also decreased in Tam-treated cells only under the conditions PKC was inactivated. Unlike phorbol esters, Tam did not directly support the membrane association of PKC. The release of arachidonic acid correlated with the PKC membrane translocation. Studies carried out with [3H]Tam revealed that Tam partitioned into the membrane, and there was no appreciable covalent association of [3H]Tam with cellular proteins within this limited time period (2 h). Various antioxidants (vitamin E, vitamin C, beta-carotene, catalase, and superoxide dismutase) inhibited all these cellular effects of Tam. Moreover, vitamin E strikingly blocked Tam-induced growth inhibition. To determine whether oxymetabolites of Tam can affect PKC permanently, OH-Tam was tested with purified PKC. In contrast to Tam, which reversibly inhibited PKC, OH-Tam permanently inactivated the enzyme by modifying the catalytic domain at lower concentrations. The vicinal thiols present within this domain were found to be required to induce this inactivation. This effect was partially blocked by various antioxidants. This is the first report showing the role of oxidative stress in mediating the actions of Tam. Taken together these results suggest that Tam, by initially partitioning into the membranes, induces a generation of transmembrane signals and an oxidative stress to elicit the membrane association of PKC, followed by an irreversible activation, and subsequent down-regulation of this enzyme, which, in part, may lead to cell growth inhibition.
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PMID:Tamoxifen modulates protein kinase C via oxidative stress in estrogen receptor-negative breast cancer cells. 866 63

Insulin is a well known mitotic agent for neuroblastoma cells. Human SK-N-BE neuroblastoma cells stably transfected with the estrogen receptor, however, undergo growth arrest and differentiation when treated with insulin. These effects were shown to be due to an insulin-dependent activation of the unliganded estrogen receptor. Here, we demonstrate that this activation involves the AF-2 COOH-terminal domain of the estrogen receptor and that the communication between estrogen and insulin receptor systems occurs via selected and specific transduction signals. In fact, by the use of dominant negative and dominant positive mutants we demonstrate that p21ras is essential for insulin and estrogen receptor coupling. With pharmacological tools, we prove that PI 3'kinase does not contribute to this cross-talk and that protein kinase C triggers transduction signals that act in synergism with p21ras. These results prove the intricacy of all these intracellular paths of communication. The finding that, in neuroblastoma cells, selected signal transduction systems are involved in the insulin-dependent activation of estrogen receptor is of particular interest considering that estrogen receptor might restrict the role played by insulin during the differentiation of neural cells and interfere with its proliferative potential while allowing its regulation of other functions related to cell survival.
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PMID:Cross-coupling between insulin and estrogen receptor in human neuroblastoma cells. 873 81

To address the isoenzyme-specific involvement of protein kinase C (PKC) in breast cancer biology, hormone-responsive MCF-7 breast cancer cells were infected with either PKC-alpha or -beta 1 cDNAs subcloned in the retroviral expression vector pMV7. Several stable clones of PKC-overexpressing cells were generated. Western analysis revealed cross-regulation between the alpha and beta isoforms, because induction of overexpression of one up-regulated the other. Overexpression of the alpha and beta isoenzymes, on the other hand, did not affect the already high endogenous expression of the novel delta, epsilon, eta, and zeta isoforms. Compared with control clones, PKC-alpha- and -beta-overexpressing MCF-7 cells exhibited more drastic morphological changes in response to phorbol 12-myristate 13-acetate administration characterized by cellular flattening and vacuolization. More importantly, induction of PKC-alpha and -beta overexpression induced a less aggressive biological behavior, which was characterized by reduced in vitro invasiveness and markedly diminished tumor formation and growth in nude mice. These in vivo findings can probably best be explained by the dramatic down-regulation of estrogen receptor levels observed in tumors derived from PKC-alpha-infected MCF-7 cells. Our data clearly show that it is possible to induce a less aggressive breast cancer phenotype by altering PKC isoenzyme expression.
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PMID:Induction of a less aggressive breast cancer phenotype by protein kinase C-alpha and -beta overexpression. 887

We have shown that in an estrogen receptor-negative multidrug-resistant subline of MCF-7 human breast carcinoma cells longer-term (24 h), but not shorter-term (30 min), treatments with clinically relevant (2-5 microM) concentrations of tamoxifen (TAM) inhibited phorbol ester-stimulated phospholipase D (PLD) activity by 50-80%. TAM caused these inhibitory effects without inducing membrane translocation or down-regulation of protein kinase C-alpha, the major mediator of phorbol ester effects on PLD activation. The results raise the possibility that prolonged inhibition of the protein kinase C-alpha-regulated PLD system may contribute to the cytotoxic effects of tamoxifen in estrogen receptor-negative breast cancer cells.
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PMID:Inhibition of phorbol ester-stimulated phospholipase D activity by chronic tamoxifen treatment in breast cancer cells. 900 86

Tamoxifen has been used most commonly to treat breast and endometrial cancer, two malignancies in which the antiestrogenic properties of tamoxifen have substantial therapeutic benefit. However, tamoxifen has been used in the treatment of other cancers as well, some in which an antiestrogen may be effective, but others in which estrogen receptor is not expressed. In estrogen receptor-negative cancers, tamoxifen has been shown to have therapeutic activity at doses approximately fourfold to eightfold above those used for estrogen receptor inhibition. It is thought that the primary mechanism of tamoxifen in estrogen-negative tumors is inhibition of protein kinase C. Clinical trials of tamoxifen in ovarian cancer, hepatocellular carcinoma, desmoid tumors, malignant glioma, pancreatic carcinoma, melanoma, and renal cell carcinoma are reviewed.
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PMID:Tamoxifen for the treatment of malignancies other than breast and endometrial carcinoma. 904 18

To determine what factors regulate gonocyte proliferation in newborn rats, we first examined the expression of several signal transduction molecules by immunocytochemistry in 3-day-old rat testis sections. We found that gonocytes specifically expressed the iota and zeta isoforms of protein kinase (PK) C (PKC) and the phosphatidylinositol 3-kinase (PI3-K). Because both the zeta PKC and PI 3-K have been shown to play a role in platelet-derived growth factor (PDGF)-induced cell proliferation, we examined the effects of PDGF on gonocytes. For this, we developed a method to obtain highly purified and viable gonocytes in culture. After enzymatic digestion, differential adhesion, and two successive gradient fractionations, the gonocyte suspension obtained was over 90% pure, as assessed by light microscopy. The viability of cultured gonocytes exceeded 90% after 48 h in the presence of 2.5% FBS used as a survival factor. Immunodetection studies showed that isolated gonocytes expressed zeta PKC, PI 3-K, and the PDGF receptor. Treatment with 10 ng/ml PDGF induced a 4-fold increase of bromodeoxyuridine incorporation into gonocytes (from 5% proliferative gonocytes under basal conditions to 20% in the presence of PDGF). Because neonatal Sertoli cells secrete high levels of the growth promoting steroid, 17 beta-estradiol, we also tested its effect and found that it induced gonocyte proliferation at a level comparable with that of PDGF and that this effect was blocked by the estrogen receptor antagonist, ICI 164384. The combination of PDGF and estradiol, however, was not additive, suggesting that their effects were mediated by common molecular target(s). These results demonstrate that PDGF and estradiol activate gonocyte proliferation in vitro, suggesting that they may act as the physiological regulators of gonocyte development in vivo.
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PMID:Regulation of rat testis gonocyte proliferation by platelet-derived growth factor and estradiol: identification of signaling mechanisms involved. 904 38

The antiestrogen tamoxifen is widely used for endocrine therapy of breast cancer; however, the mechanisms of estrogen receptor-independent interactions of tamoxifen remain ill defined. Here we examine the effect of tamoxifen on the initial steps of cell signal transduction. To this end, phospholipid metabolism and protein kinase C (PKC) translocation were assessed in CCD986SK human mammary fibroblasts treated with tamoxifen. The addition of tamoxifen resulted in dose-dependent and time-dependent increases in the cellular second messengers phosphatidate (PA) and diacylglycerol (DG). On addition of ethanol to the medium, tamoxifen induced the formation of phosphatidylethanol, demonstrating that tamoxifen activates phospholipase D (PLD). Cellular DG also increased in the presence of ethanol, showing that tamoxifen also activates phospholipase C (PLC). In cells prelabeled with choline and ethanolamine, tamoxifen caused increases in choline, phosphorylcholine, ethanolamine and phosphorylethanolamine. Structure-activity relationship studies for activation of PLD revealed that tamoxifen was the most effective, whereas 4-hydroxy tamoxifen was nearly devoid of activity. Phorbol diesters also activated PLD, but estrogen had no influence. Pretreatment of cells with phorbol dibutyrate (PKC down-regulation protocol) blocked phorbol diester- and tamoxifen-induced PLD activity. Exposure of cells to the PKC inhibitor GF 109203X diminished tamoxifen-induced PLD activity. Addition of tamoxifen to cultures elicited selective membrane association of PKC epsilon. We conclude that tamoxifen exerts considerable extra-nuclear influence at the transmembrane signaling level. These events may contribute to effects beyond the scope of estrogen receptor-dependent actions.
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PMID:Tamoxifen activates cellular phospholipase C and D and elicits protein kinase C translocation. 905 57


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