Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dehyroepiandrosterone (DHEA), an adrenal-derived steroid, has been clinically implicated in protection against coronary artery disease and experimentally in inhibition of atherosclerosis and plaque progression. Because DHEA is enzymatically metabolized to androgens or estrogens, it is not clear whether DHEA exerts effects directly or after conversion to these hormones, both of which are associated with well-characterized pathways of action. We therefore examined the effects of DHEA on proliferation of human vascular smooth muscle cells (VSMCs) in culture in the presence or absence of the ER antagonist ICI 182,780 and the AR antagonist flutamide and compared them with the effects of 17beta-estradiol, androstenedione, and T. We also determined the affinity of DHEA for ERs and ARs in VSMC and its specific binding in intact cells. To explore a possible mechanism for DHEA action in these cells, we measured the phosphorylation of ERK-1, c-jun N-terminal protein kinase, and p38 (three members of the MAPK superfamily). Both DHEA and 17beta-estradiol significantly inhibited platelet derived growth factor (PDGF)-BB-induced increases in VSMC proliferation, whereas androstenedione and T increased proliferation. Although E2-induced inhibition of the PDGF effect was abolished by ICI 182,780 and T-induced stimulation was abolished by flutamide, neither receptor antagonist altered the inhibitory effect of DHEA. Binding studies confirmed the presence of both ERs and ARs; DHEA showed minimal affinity for either receptor but bound specifically and with high affinity to putative receptors in intact cells. Following 4-h incubation with DHEA (1-100 nM), ERK1 phosphorylation was significantly reduced in a dose-dependent manner, whereas neither c-jun N-terminal protein kinase nor p38 kinase activity was altered by either PDGF-BB or DHEA. DHEA inhibits human VSMC proliferation by a mechanism independent of either ARs or ERs, presumably via a DHEA-specific receptor that involves ERK1 signaling pathways.
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PMID:Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ARs and ERs. 1178 44

Glucose homeostasis in blood is mainly maintained by insulin released from beta-cells and glucagon released from alpha-cells, both integrated within the pancreatic islet of Langerhans. The secretory processes in both types of cells are triggered by a rise in intracellular calcium concentration ([Ca2+](i)). In this study, rapid effects of the natural hormone E2 on [Ca2+](i) were studied in both types of cells within intact islets using laser scanning confocal microscopy. alpha- And beta-cells showed opposite [Ca2+](i) responses when stimulated with physiological concentrations of 17beta-E2. Although the estrogen produced an increase in the frequency of glucose-induced [Ca2+](i) oscillations in insulin-releasing beta-cells, it prevented the low glucose-induced [Ca2+](i) oscillations in glucagon-releasing alpha-cells. The effects of 17beta-E2 on alpha-cells were mimicked by the cGMP permeable analog 8bromo-cGMP and blocked by the cGMP-dependent protein kinase (PKG) inhibitor KT5823. Evidence indicated that these were membrane actions mediated by a nonclassical ER. Both effects were rapid in onset and were reproduced by 17beta-E2 linked to horseradish peroxidase, a cell-impermeable molecule. Furthermore, these actions were not blocked by the specific ER blocker ICI 182,780. Competition studies performed with 17beta-E2 linked to horseradish peroxidase binding in alpha-cells supported the idea that the membrane receptor involved is neither ERalpha nor ERbeta. Additionally, the binding site was shared by the neurotransmitters epinephrine, norepinephrine, and dopamine and had the same pharmacological profile as the receptor previously described for beta-cells. Therefore, rapid estrogen actions in islet cells are initiated by a nonclassical estrogen membrane receptor.
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PMID:A nonclassical estrogen membrane receptor triggers rapid differential actions in the endocrine pancreas. 1187 8

The proto-oncogene c-myc is up-regulated by estrogen stimulation of hormone-dependent breast cancer cells and is frequently overexpressed in breast and other cancers. Therapeutic interventions that inhibit c-Myc expression have been extensively investigated, including antisense oligonucleotides that have high specificity and potential clinical application. This investigation compared antiestrogen-mediated growth arrest with the molecular events after repression of c-Myc expression in MCF-7 breast cancer cells using an antisense oligonucleotide. We show that the decreased cellular proliferation of MCF-7 cells after direct inhibition of c-Myc is a consequence of inhibition of cyclin D1 expression, subsequent redistribution of p21(WAF1/CIP1) from cyclin D1-Cdk4 to cyclin E-Cdk2 complexes, and a decline in cyclin E-Cdk2 enzymatic activity. Simultaneous repression of p21(WAF1/CIP1) can attenuate the growth-inhibitory effects of reduced c-Myc expression emphasizing the importance of this cyclin-dependent kinase (CDK) inhibitor in growth arrest. These molecular events are similar to the initial changes in cyclin gene expression, CDK complex formation and CDK activity seen after antiestrogen (ICI 182780)-mediated growth inhibition of MCF-7 cells, which suggests that the down-regulation of c-Myc by ICI 182780 is a primary event that culminates in cell cycle arrest.
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PMID:Mechanisms of growth arrest by c-myc antisense oligonucleotides in MCF-7 breast cancer cells: implications for the antiproliferative effects of antiestrogens. 1203 24

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

Estrogen receptor alpha (ERalpha) is a transcription factor that regulates expression of target genes in a ligand-dependent manner. Activation of gene expression is mediated by two transcription activation functions AF-1 and AF-2, which act in a promoter- and cell-specific manner. Whilst AF-2 activity is regulated by estrogen (E2) binding, the activity of AF-1 is additionally modulated by phosphorylation at several sites. One of these phosphorylation sites, serine 118 (S118) is of particular interest as its mutation significantly reduces ERalpha activity. Previous studies have shown that S118 can be phosphorylated by the ERK1/2 mitogen activated protein kinases (MAPK) and by the cyclin-dependent protein kinase Cdk7. In this study we use antisera that specifically recognize ERalpha phosphorylated at S118 to demonstrate that MAPK phosphorylates S118 in a ligand-independent manner, whereas Cdk7 mediates E2-induced phosphorylation of S118. E2 stimulation of S118 phosphorylation was observed within 10 min of its addition and was maximal at 10(-7) M E2. S118 phosphorylation was maximal at 30 min but then declined, such that by 180 min following E2 addition little S118 phosphorylation was evident. S118 phosphorylation was also induced by the partial estrogen antagonist 4-hydroxytamoxifen, but not by the complete antagonist ICI 182, 780. S118 phosphorylation upon addition of the MAPK inducers EGF or PMA followed the expected time courses. Finally, we show that ERalpha is phosphorylated at S118 in vivo using immunoblotting of extracts prepared from a series of ERalpha-positive breast tumours.
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PMID:Phosphorylation of human estrogen receptor alpha at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera. 1211 71

Estrogens stimulate the differentiation of neurons and neural networks in the CNS. The concordance of the cellular responses of estrogens and growth factors suggests that both factors may interact on the cellular level to ensure their developmental role. We have put forward this hypothesis and analyzed the effect of estrogens on the expression of glial cell line-derived neutrotrophic factor (GDNF) in developing hypothalamic cells. Using Western blotting and competitive RTPCR, we have demonstrated that 17beta-estradiol (E2) increases the expression of GDNF in hypothalamic cell cultures. E2-induced GDNF expression was seen in neurons but not astrocytes. GDNF induction by E2 appeared to be transmitted through nonclassical estrogen action, since the application of the nuclear estrogen receptor antagonists ICI 182, 780 did not abolish this effect. Only inhibitors of intracellular Ca(2+) and cAMP/protein kinase A signaling were effective in preventing E2 effects. We conclude that E2 is capable of influencing GDNF expression in the developing hypothalamus. Thus, it is conceivable that developmental E2 effects in the hypothalamus are partially mediated through the regulation of other important developmental signals such as growth factors.
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PMID:Estradiol stimulates GDNF expression in developing hypothalamic neurons. 1213 May 84

Neutral antagonists and inverse agonists can produce different cellular responses in some systems. The effects of chronic (14-day) infusion of three ligands, ICI-118,551, carvedilol, and alprenolol were examined in cardiac tissue from wild-type and transgenic mice with cardiac-specific overexpression of the human beta2-adrenoceptor. These ligands vary in their negative efficacy at the human beta2-adrenoceptor, with two (ICI-118,551 and carvedilol) behaving as inverse agonists and one (alprenolol) behaving as a neutral antagonist. Cardiac tissue from the transgenic mice exhibited elevated levels of protein kinase A activity and G protein receptor kinase-2. Fourteen-day infusions of the three ligands lowered the elevated levels of protein kinase A activity of the transgenic hearts to control levels. Alprenolol and carvedilol also decreased G protein receptor kinase-2 amounts to control levels. The left atria from transgenic mice exhibited an impaired inotropic response to histamine relative to responses of wild-type mice atria. Infusions of the inverse agonists and a neutral antagonist at the beta2-adrenoceptor significantly restored the impaired histamine response. Restoration of protein kinase A activity and the impaired histamine responses in the atria from transgenic mice can be observed following 14-day infusions of both a neutral antagonist and inverse agonists. The reversal of the effects of the transgene by both inverse agonists and a neutral antagonist suggests that agonist occupancy, and not spontaneous activity, of the beta2-adrenoceptor is producing the elevated protein kinase A activity and the impaired histamine response.
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PMID:Chronic infusion of beta-adrenoceptor antagonist and inverse agonists decreases elevated protein kinase A activity in transgenic mice with cardiac-specific overexpression of human beta 2-adrenoceptor. 1219 31

Molecular genetics experiments using gene targeting and transgenic technology demonstrated the importance of alpha-calcium-calmodulin-dependent protein kinase II (alphaCaMKII) in long-term potentiation (LTP) and memory. Little information is available though on how CaMKII activity may be regulated in vivo. We show that estradiol benzoate activates CaMKII in a dose and time-dependent manner in mouse hippocampus after 30 min stimulation. The effect of estrogen is via a very rapid nongenomic mechanism that is blocked in vitro in hippocampal primary neurons by the pure estrogen receptor antagonist, ICI 182,780. These results suggest that estrogen action in the hippocampus is linked to CaMKII activation.
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PMID:Estrogen induces a rapid increase of calcium-calmodulin-dependent protein kinase II activity in the hippocampus. 1223 Dec 58

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

Cyclin D1 and cyclin E are overexpressed in approximately 45% and 30% of breast cancers, respectively, and adverse associations with patient outcome have been reported. The potential roles of cyclin D1 and cyclin E expression as markers of therapeutic responsiveness to the pure steroidal antiestrogen ICI 182780 were investigated using T-47D breast cancer cell lines constitutively overexpressing cyclin D1 or cyclin E. Measurement of S phase fraction, phosphorylation states of the retinoblastoma protein, and cyclin E-cyclin-dependent kinase (Cdk) 2 activity demonstrated that overexpression of cyclin D1 decreased sensitivity to antiestrogen inhibition at 24 and 48 h. Overexpression of cyclin E produced a less pronounced early cell cycle effect indicating only partial resistance to antiestrogen inhibition in the short-term. In ICI 182780-treated cyclin D1-overexpressing cells, sufficient Cdk activity was retained to allow retinoblastoma protein phosphorylation and cell proliferation, despite an increase in the association of p21 and p27 with cyclin D1-Cdk4/6 and cyclin E-Cdk2 complexes. After longer-term (>7 days) treatment, antiestrogens inhibited colony growth in cyclin D1- or cyclin E-overexpressing breast cancer cells, but with an approximately 2-2.5-fold decrease in dose sensitivity. This was associated with a fall in cyclin D1 levels, a reduction in the half-life of cyclin D1 protein and a decline in cyclin E-Cdk2 activity in cyclin D1-overexpressing cells, and the maintenance of cyclin E-p27 association in the cyclin E-overexpressing cells. These data confirm that cyclin D1 expression and cyclin E-p27 association play important roles in antiestrogen action, and suggest that cyclin D1 or cyclin E overexpression has subtle effects on antiestrogen sensitivity. Additional studies to elucidate the contribution of alterations in cyclin D1 stability to antiestrogen action and to assess the relationship between antiestrogen sensitivity and expression of cyclin D1, cyclin E, or p27 in a clinical setting are required.
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PMID:Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells. 1246 Sep 7


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