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)

In the rat pituitary gland the mechanism responsible for ERalpha regulation has not been fully elucidated. Using transient transfection assays in alphaT3-1 cells, a cell line of gonadotrope origin, we show that GnRH stimulates estrogen response element-containing promoters in an estrogen-independent manner. This effect was strictly ER and GnRH receptor dependent, as no activation of the reporter gene was observed in presence of the anti-estrogen ICI 182,780 or a GnRH antagonist. These data suggest that the GnRH-triggered signaling pathway results in 17beta-estradiol-independent trans-activation of the ERalpha in alphaT3-1 cells. Furthermore, an additive activation was achieved when cells were treated with both GnRH and 17beta-estradiol. In primary pituitary cells, GnRH alone (100 nM) did not cause a significant stimulation of reporter gene activity, presumingly due to the low amount of gonadotropes. Interestingly, the combination of 17beta-estradiol and GnRH resulted in a significant increase in ERalpha trans-activation compared with that in cells treated with 17beta-estradiol alone. This enhancement was prevented by ICI 182,780, showing an ERalpha requirement. Moreover, we show that the effects of GnRH on ERalpha transcriptional activity in gonadotrope cell lines are mediated by the PKC/MAPK pathway. In conclusion, our data demonstrate that GnRH is an important signal in the regulation of ERalpha trans-activation in gonadotrope cells.
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PMID:Steroid-independent activation of ER by GnRH in gonadotrope pituitary cells. 1145 76

We examined effects of 17beta-estradiol (E(2)) on human vascular smooth muscle cell (VSMC) proliferation under normal (5 mmol/l) and high (25 mmol/l) glucose concentrations. Platelet-derived growth factor (PDGF) BB (20 ng/ml)-induced increases in DNA synthesis and proliferation were greater in high than normal glucose concentrations; the difference in DNA synthesis was abolished by a protein kinase C (PKC)-beta inhibitor, LY-379196 (30 nmol/l). Western blotting showed that PKC-beta(1) protein increased in cells exposed to high glucose, whereas PKC-alpha protein and total PKC activity remained unchanged, compared with normal glucose cultures. In normal glucose, E(2) (1-100 nmol/l) inhibited PDGF-induced DNA synthesis by 18-37% and cell proliferation by 16-22% in a concentration-dependent manner. The effects of E(2) were blocked by the estrogen receptor (ER) antagonist ICI-182780, indicating ER dependence. In high glucose, the inhibitory effect of E(2) on VSMC proliferation was abolished but was restored in the presence of the PKC-beta inhibitor LY-379196. Thus high glucose enhances human VSMC proliferation and attenuates the antiproliferative effect of E(2) in VSMC via activation of PKC-beta.
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PMID:High glucose abolishes the antiproliferative effect of 17beta-estradiol in human vascular smooth muscle cells. 1188 93

17 beta-Estradiol (E(2)) regulates growth plate cartilage cells via classical nuclear receptor mechanisms, as well as by direct effects on the chondrocyte membrane. These direct effects are stereospecific, causing a rapid increase in protein kinase C (PKC) specific activity, are only found in cells from female rats and are mimicked by E(2)-bovine serum albumin (BSA), which cannot penetrate the cell membrane. E(2) and E(2)-BSA stimulate alkaline phosphatase specific activity and proteoglycan sulfation in female rat costochondral cartilage cell cultures, but traditional nuclear receptors do not appear to be involved. This study examined the effect of the anti-estrogen tamoxifen on these markers of chondrocyte differentiation; the gender-specificity of tamoxifen's effect on PKC, if tamoxifen has an effect on vitamin D metabolite-stimulated PKC, which is mediated via specific membrane receptors (1,25-mVDR; 24,25-mVDR) and whether the effect of tamoxifen is mediated by nuclear estrogen receptors. Tamoxifen dose-dependently inhibited the effect of E(2)-BSA on PKC, alkaline phosphatase and proteoglycan sulfation in confluent cultures of female resting zone (RC) cells and growth zone (GC) (prehypertrophic/upper hypertrophic zones) cells, suggesting that its action is at the membrane and not cell maturation-dependent. Neither the estrogen receptor (ER) antagonist ICI 182780 nor the ER agonist diethylstilbesterol affected E(2) or E(2)-BSA-stimulated PKC in female chondrocytes. Tamoxifen also inhibited the increase in PKC activity due to 1 alpha,25-(OH)(2)D(3) or 24R,25-(OH)(2)D(3) in growth plate cells derived from either female or male rats. Inhibition of PKC by tamoxifen may be a general property of membrane receptors involved in rapid responses to hormones.
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PMID:Tamoxifen elicits its anti-estrogen effects in growth plate chondrocytes by inhibiting protein kinase C. 1198 87

We have previously reported that beta-adrenergic receptor (beta-AR) stimulation promotes apoptosis in adult ventricular myocytes through PKCepsilon-mediated suppression of ERK. In this study, we investigated differential effects of beta-AR subtypes on this signal pathway. The apoptosis induced by the non-specific beta-AR agonist isoproterenol was largely blocked by the beta(1)-selective antagonist CGP 20712A, but not by the beta(2)-selective antagonist ICI 118551. A pro-apoptotic effect of beta(1)-AR was also blocked by the PKA inhibitor H89, while the protein kinase A (PKA) activators forskolin and dibutyryl-cAMP both induced apoptosis. These results indicate that beta(1)-AR-mediated PKA activation is largely responsible for the apoptosis induced by beta-AR in adult rat cardiac myocytes. This conclusion was also supported by the finding that PKA was preferentially activated by beta(1)-AR over beta(2)-AR. beta(2)-AR selectively induced anti-apoptotic ERK activation in the presence of PKCepsilon suppression, and this ERK activation was sensitive to pertussis toxin. PKCepsilon itself as well as Akt, the other anti-apoptotic factor were activated by both beta-AR subtypes. Thus, beta(1)-AR induces pro-apoptotic signals mainly through PKA activation. In contrast, beta(2)-AR is linked to Gi-mediated ERK activation, which is involved in the anti-apoptotic pathway, and is regulated by PKCepsilon. Therefore, our findings suggest a rather complex role for beta-AR subtypes in the regulation of apoptosis in adult ventricular myocytes.
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PMID:Subtype specific roles of beta-adrenergic receptors in apoptosis of adult rat ventricular myocytes. 1209 21

It has been suggested that the estrogenicity of PAHs could contribute to their carcinogenic effects via increased tissue-specific cell proliferation. Both benzo[a]pyrene (BaP) and benz[a]anthracene (BaA) are known to weakly activate estrogen receptor (ER)-dependent reporter constructs. In this study, several other PAHs, including fluorene, fluoranthene, pyrene, chrysene, phenanthrene and anthracene, were found to act as very weak inducers of ER-mediated activity in the MCF-7 cell line stably transfected with a luciferase reporter gene. The effects of PAHs were time-dependent and they were not completely inhibited by antiestrogen ICI 182,780. In addition, BaP and BaA, as well as weakly estrogenic fluoranthene, significantly potentiated the maximum ER-mediated activity of 17beta-estradiol. Therefore, the effects of inhibitors of several types of protein kinases known to activate ERalpha in a ligand-independent manner were investigated. However, neither inhibitors nor inducers of extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3 kinase, protein kinase C, c-Src, or protein kinase A modified ER-mediated activity in this model. Neither estradiol nor BaA activated ERK1/2, two kinases suggested to play significant roles in ER signaling, suggesting that another kinase is involved in the observed phosphorylation of ERalpha. Similar to 17beta-estradiol, BaA stimulated G(0)/G(1)-S-phase transition in MCF-7 cells, which was fully suppressed by ICI 182,780. In conclusion, some PAHs can potentiate 17beta-estradiol-induced ER activation and stimulate cell cycle entry in vitro. However, their exact mode(s) of action and whether this phenomenon is of in vivo relevance remains to be elucidated.
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PMID:Modulation of estrogen receptor-dependent reporter construct activation and G0/G1-S-phase transition by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells. 1244 64

17beta-Estradiol decreases R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding [an index of serotonin-1A (5-HT(1A)) receptor coupling] through the activation of estrogen receptors. We hypothesize that this occurs as a result of activation of protein kinase A (PKA) and/or protein kinase C (PKC) and phosphorylation of 5-HT(1A) receptors. Hippocampus from ovariectomized rats was incubated with 17beta-estradiol in HEPES buffer (37 degrees C). Cytosolic and membrane fractions were prepared to assess PKA and PKC activities, respectively. In separate experiments, membranes were prepared to measure R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. 17beta-Estradiol (50 nM) increased PKA and PKC activities approximately 2- to 3-fold. PKC activity was elevated at 10, 30 and 60 min, whereas PKA activity was increased at 10 and 30 min. The ability of 17beta-estradiol to increase PKA and PKC was blocked by the estrogen receptor antagonist ICI 182,780 (1 microM). A selective PKA inhibitor (KT 5720, 60 nM) blocked 17beta-estradiol-stimulated PKA but NOT PKC activity. Conversely, the PKC inhibitor calphostin C (100 nM) blocked the increase in PKC activity produced by 17beta-estradiol but NOT the PKA response. The protein kinase inhibitors individually blocked the effects of 17beta-estradiol on R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. By contrast, preincubation with the protein synthesis inhibitor cycloheximide (200 microM) or the mitogen activated protein (MAP) kinase kinase inhibitor PD 98059 (50 microM) was without effect. Incubation of hippocampus with 17beta-estradiol (50 nM, 60 min) caused the phosphorylation of a protein consistent with the 5-HT(1A) receptor. These studies demonstrate that 17beta-estradiol acts on estrogen receptors locally within the hippocampus through nongenomic mechanisms to activate PKA and PKC, phosphorylate 5-HT(1A) receptors and uncouple them from their G proteins.
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PMID:Rapid uncoupling of serotonin-1A receptors in rat hippocampus by 17beta-estradiol in vitro requires protein kinases A and C. 1256 41

We examined the hypothesis whether rapid non-genomic effects of oestradiol (E2) on [Ca(2+)](i) are mediated via a membrane-located oestrogen receptor (ER) and further elucidated the signalling pathways involved in rapid non-genomic effects of E2 on [Ca(2+)](i) in distal colonic crypts. Basal [Ca(2+)](i) was significantly increased, within minutes, in response to physiological concentrations of E2. Oestradiol linked to bovine serum albumin (E2-BSA), which renders the E2 membrane impermeable, rapidly increased [Ca(2+)](i) suggesting mediation by a membrane surface receptor. A classical ER is not involved however, as no inhibition of either the E2 or E2-BSA [Ca(2+)](i) response was seen in the presence of the classical ER antagonist ICI 182,780. Treatment with the Galphas inhibitor cholera toxin abolished both E2 and E2-BSA induced Ca(2+) increases. In contrast, treatment with pertussis toxin, an inhibitor of Galphai and Galphao, had no inhibitory effect. Following subsequent additions of E2 and E2-BSA, no further increases in [Ca(2+)](i) were observed, indicating receptor desensitisation. The E2-induced increase in [Ca(2+)](i) was completely abolished by the PKCdelta-specific inhibitor rottlerin, whereas Go6976, an inhibitor of Ca(2+)-sensitive PKC isoforms, was without inhibitory effect. The phospholipase A2 antagonist, quinacrine, and the COX1 inhibitor, indomethacin, abolished the E2-induced increase in [Ca(2+)](i). MAP kinase activation is not involved in rapid stimulatory effects of E2 on [Ca(2+)](i) as the specific inhibitor PD98059 did not inhibit the E2 response. These results demonstrate that rapid E2-induced stimulation of [Ca(2+)](i), in femal rat distal colonic crypts, occurs via a CTx-sensitive Galphas-coupled membrane receptor distinct from the classical ER. PKCdelta and fatty acids are involved in the E2 signalling pathway. In contrast, PKCalpha and MAP kinase are not required.
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PMID:A Galphas protein-coupled membrane receptor, distinct from the classical oestrogen receptor, transduces rapid effects of oestradiol on [Ca2+]i in female rat distal colon. 1258 82

This investigation examined the role of estrogen receptor (ER) on the stimulatory effect of estradiol (E2) on protein phosphorylation in the oviduct as well as on E2-induced acceleration of oviductal oocyte transport in cyclic rats. Estrous rats were injected with E2 s.c. and with the ER antagonist ICI 182 780 intrabursally (i.b.), and 6 h later, oviducts were excised and protein phosphorylation was determined by Western blot analysis. ICI 182 780 inhibited the E2-induced phosphorylation of some oviductal proteins. Other estrous rats were treated with E2 s.c. and ICI 182 780 i.b. The number of eggs in the oviduct, assessed 24 h later, showed that ICI 182 780 blocked the E2-induced egg transport acceleration. The possible involvement of adenylyl cyclase, protein kinase A (PK-A), protein kinase C (PK-C), or tyrosine kinases on egg transport acceleration induced by E2 was then examined. Selective inhibitors of adenylyl cyclase or PK-A inhibited the E2-induced egg transport acceleration, whereas PK-C or tyrosine kinase inhibitors had no effect. Furthermore, forskolin, an adenylyl cyclase activator, mimicked the effect of E2 on ovum transport and E2 increased the level of cAMP in the oviduct of cycling rats. Finally, we measured PK-A activity in vitro in the presence of E2 or E2-ER complex. Activity of PK-A in the presence of E2 or E2-ER was similar to PK-A alone, showing that E2 or E2-ER did not directly activate PK-A. We conclude that the nongenomic pathway by which E2 accelerates oviductal egg transport in the rat requires absolute participation of ER and cAMP and partial participation of PK-A signaling pathways in the oviduct.
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PMID:Estrogen receptor, cyclic adenosine monophosphate, and protein kinase A are involved in the nongenomic pathway by which estradiol accelerates oviductal oocyte transport in cyclic rats. 1260 51

We examined protein kinase C (PKC) in the regulation of breast cancer cells by estrogen. Estrogen receptor (ER)- positive (+) MCF-7 and ER-negative (-) HCC38 cells were treated with 17 beta-estradiol (E(2)) or E(2)-BSA, which cannot enter the cell. E(2) and E(2)-BSA rapidly increased PKC-alpha in both cells via phosphatidylinositol-dependent phospholipase C and G protein, but not phospholipase A(2) or arachidonic acid. In MCF-7 cells, E(2) and E(2)-BSA had comparable effects, maximal at 90 min. In HCC38 cells, PKC was maximal at 9 min, with E(2)-BSA more than E(2). Tamoxifen blocked estrogen-dependent PKC in MCF-7 cells and reduced it in HCC38 cells. ER-antagonist ICI 182780, ER-agonist diethylstilbestrol, and antibodies to ER alpha and ER beta had no effect. E(2) stimulated [(3)H]thymidine incorporation in MCF-7 only; E(2)-BSA had no effect. Tamoxifen did not alter E(2)-dependent increases in MCF-7 cells, whereas ICI 182780 reduced DNA synthesis in control and E(2)-treated cultures. PKC activity was positively correlated with tumor severity in 133 breast cancer specimens and was greater in ER(-) tumors. Tamoxifen treatment reduced recurrence, and recurrent tumors had higher PKC activity. This indicates that E(2) rapidly increases PKC activity via membrane pathways not involving ER alpha or ER beta and suggests that tamoxifen works by reducing PKC activity through non-ER alpha/ER beta-dependent mechanisms.
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PMID:Estrogen-dependent rapid activation of protein kinase C in estrogen receptor-positive MCF-7 breast cancer cells and estrogen receptor-negative HCC38 cells is membrane-mediated and inhibited by tamoxifen. 1269 87

Estrogen receptor-alpha (ER) is down-regulated in the presence of its cognate ligand, estradiol (E2), as well as in the presence of antiestrogens, through the ubiquitin proteasome pathway. Here, we show that, at pharmacological concentrations, the degradation rate of pure antagonist/endogenous ER complexes from human breast cancer MCF-7 cells is 10 times faster than that of ER-E2 complexes, while 4-hydroxy-tamoxifen (4-OH-T)-ER complexes are stable. Whereas pure antagonist-ER complexes are firmly bound to a nuclear compartment from which they are not extractable, the 4-OH-T-ER accumulates in a soluble cell compartment. No difference was observed in the fate of ER whether bound to pure antiestrogens ICI 182,780 or RU 58668. Cycloheximide experiments showed that, while the proteasome-mediated destruction of E2-ER (unlike that of RU 58668- and ICI 182,780-ER) complexes could implicate (or not) a protein synthesis-dependent process, both MAPKs (p38 and ERKs p44 and p42) are activated. By using a panel of kinase inhibitors/activators to study the impact of phosphorylation pathways on ER degradation, we found that protein kinase C is an enhancer of proteasome-mediated degradation of both ligand-free and ER bound to either E2, 4-OH-T, and pure antagonists. On the contrary, protein kinase A, MAPKs, and phosphatidyl-inositol-3 kinase all impede proteasome-mediated destruction of ligand free and E2-bound ER while only MAPKs inhibit the degradation of pure antiestrogens/ER species. In addition, no correlation was found between the capacity of kinase inhibitors to affect ER stability and the basal or E2-induced transcription. These results suggest that, in MCF-7 breast cancer cells, ER turnover, localization, and activity are maintained by an equilibrium between various phosphorylation pathways, which are differently modulated by ER ligands and protein kinases.
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PMID:Various phosphorylation pathways, depending on agonist and antagonist binding to endogenous estrogen receptor alpha (ERalpha), differentially affect ERalpha extractability, proteasome-mediated stability, and transcriptional activity in human breast cancer cells. 1285 46


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