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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostacyclin (PGI(2)) is a key mediator of pulmonary vasodilation during perinatal cardiopulmonary transition, at a time when fetal plasma estrogen levels are rising. We have previously shown that estradiol-17beta (E(2)) rapidly stimulates nitric oxide production by ovine fetal pulmonary artery endothelial cells (PAEC), and that this occurs through nongenomic mechanisms which are calcium- and tyrosine kinase-mitogen-activated protein (MAP) kinase-dependent. In the present study, we determined if E(2) acutely activates PGI(2) production in PAEC. E(2) (10(-8) M for 15 min) caused a 52% increase in PGI(2), the threshold concentration was 10(-10) M E(2), the effect occurred within 5 min, and it was not related to changes in cyclooxygenase type 1 (COX-1) or COX-2 abundance. Estrogen receptor (ER) alpha and ER beta proteins and mRNAs were found to be constitutively expressed in PAEC, and PGI(2) stimulation with E(2) was fully blocked by both ER antagonism with ICI 182,780, which is not selective for either ER isoform, and the ER beta-specific antagonist RR-tetrahydrochrysene. The rapid response to E(2) was also inhibited by calcium chelation, whereas genistein- or PD98059-induced inhibition of tyrosine kinase and MAP kinase kinase, respectively, had no effect. Thus, E(2) causes rapid stimulation of PGI(2) synthesis in fetal PAEC, this process is mediated by ER beta, and it is calcium-dependent and tyrosine kinase-MAP kinase-independent. These mechanisms may play a role in pulmonary vasodilation in the perinatal period.
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PMID:Estrogen acutely activates prostacyclin synthesis in ovine fetal pulmonary artery endothelium. 1197 Sep 14

We showed previously in neocortical explants, derived from developing wild-type and estrogen receptor (ER)-alpha gene-disrupted (ERKO) mice, that both 17alpha- and 17beta-estradiol elicit the rapid and sustained phosphorylation and activation of the mitogen-activated protein kinase (MAPK) isoforms, the extracellular signal-regulated kinases ERK1 and ERK2. We proposed that the ER mediating activation of the MAPK cascade, a signaling pathway important for cell division, neuronal differentiation, and neuronal survival in the developing brain, is neither ER-alpha nor ER-beta but a novel, plasma membrane-associated, putative ER with unique properties. The data presented here provide further evidence that points strongly to the existence of a high-affinity, saturable, 3H-estradiol binding site (K(d), approximately 1.6 nm) in the plasma membrane. Unlike neocortical ER-alpha, which is intranuclear and developmentally regulated, and neocortical ER-beta, which is intranuclear and expressed throughout life, this functional, plasma membrane-associated ER, which we have designated "ER-X," is enriched in caveolar-like microdomains (CLMs) of postnatal, but not adult, wild-type and ERKO neocortical and uterine plasma membranes. We show further that ER-X is functionally distinct from ER-alpha and ER-beta, and that, like ER-alpha, it is re-expressed in the adult brain, after ischemic stroke injury. We also confirmed in a cell-free system that ER-alpha is an inhibitory regulator of ERK activation, as we showed previously in neocortical cultures. Association with CLM complexes positions ER-X uniquely to interact rapidly with kinases of the MAPK cascade and other signaling pathways, providing a novel mechanism for mediation of the influences of estrogen on neuronal differentiation, survival, and plasticity.
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PMID:ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. 1235 13

The ability of estrogen to rapidly initiate a variety of signal transduction cascades is increasingly recognized as playing an important role in a number of tissue-specific transcriptional actions of the hormone. In vivo, estrogen rapidly elicits phosphorylation of cAMP response element-binding protein (CREB). We have previously shown that both ER alpha and ER beta are capable of activating the MAPK pathway in response to a low dose of 17beta-estradiol. In the present study, the ability of estrogen to act through both ER alpha and ER beta to increase CREB phosphorylation was evaluated in an immortalized hippocampal cell line stably expressing either receptor. Estrogen treatment promoted rapid CREB phosphorylation, reaching a maximum by 15 min. This activation is completely blocked by the antiestrogen ICI 182,780, suggesting an estrogen receptor-dependent mechanism. The addition of the mitogen/ERK kinase-1 inhibitor, PD98059, also blocked the ability of estrogen to signal to CREB phosphorylation. Estrogen also caused an increase in p90Rsk activity, a critical mediator of MAPK effects. Surprisingly, blockade of the protein kinase A pathway in cells treated with estrogen did not affect estrogen-mediated CREB phosphorylation. Thus, MAPK and p90Rsk appear to be the primary mediators of estrogen-induced gene transcription through ER alpha and ER beta.
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PMID:Estrogen activation of cyclic adenosine 5'-monophosphate response element-mediated transcription requires the extracellularly regulated kinase/mitogen-activated protein kinase pathway. 1258 59

Aromatase plays a critical role in breast cancer development by converting androgen to estrogen. In this report, results are presented to demonstrate that estrogen, the product of aromatase, can up-regulate its expression. Estrogen receptor (ER) transient transfection experiments were performed using the SK-BR-3 breast cancer cell line, which is ER negative and expresses aromatase. When SK-BR-3 cells were transfected with the expression plasmid pCI-ER alpha, but not pCI-ER beta, aromatase activity was elevated by 17beta-estradiol (E(2)) in a dose-dependent manner. The E(2) induction could be enhanced by cotransfection with the coactivator GRIP1 and suppressed by antiestrogens such as tamoxifen and ICI 182,780. The aromatase activity in the ER alpha-transfected SK-BR-3 cells could also be induced by environmental chemicals that were known to have an estrogen-like activity. Using aromatase gene exon Is-specific reverse transcription-PCR, the level of promoter I.1-driven transcripts was found to be elevated in E(2)-treated ER alpha-transfected cells. This suggested that E(2) induced aromatase expression through the up-regulation of promoter I.1. Using DNA deletion analysis of the 5'-flanking region of promoter I.1, the section between -300 and -280 bp upstream from exon I.1 was identified to be important for mediating E(2) induction. However, a direct binding of ER alpha to this 20-bp region could not be demonstrated. It was found that E(2) induction could be suppressed by the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor, PD98059, and the epidermal growth factor receptor tyrosine kinase inhibitor, PD153035 hydrochloride. A significant induction of aromatase expression was also detected in ER-positive MCF-7 breast cancer cells after transfection with pCI-ER alpha and E(2) treatment. Furthermore, after ER alpha transfection and E(2) treatment, the aromatase activity in Her-2-overexpressing MCF-7 cells was drastically higher than that of the wild-type MCF-7 cells. In addition, aromatase induction in MCF-7 cells could also be suppressed by PD153035 hydrochloride. These results suggest that E(2) up-regulates aromatase expression by a nongenomic action of ER alpha via cross-talk with growth factor-mediated pathways.
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PMID:Induction of aromatase (CYP19) expression in breast cancer cells through a nongenomic action of estrogen receptor alpha. 1283 40

Mammary gland development involves complex cycles of proliferation, differentiation, and morphogenesis, regulated by hormones including estrogens, prolactin (PRL), and epidermal growth factor (EGF). The mouse mammary epithelial cell line HC11 has been shown to be valuable for investigations of differentiation of mammary gland. In this study, we show that HC11 cells express estrogen receptor (ER)alpha and ER beta proteins at all developmental stages. We have established two different stable HC11 cell lines; H-estrogen response element (ERE) containing an ERE-reporter and H-Bc containing a beta-casein reporter. Transcription of the ERE-reporter was activated only in proliferating cells in the presence of EGF. When the cells entered the differentiation program, in the absence of EGF, estradiol-induced transcription of the ERE reporter was repressed, and similar results were obtained when MAPK signaling was inhibited in proliferating cells. We propose that these findings are related to changes in ER corepressor levels, regulated by EGF. We also report that the beta-casein reporter was activated in terminally differentiated cells and that this induction was effectively repressed by estradiol treatment. Finally, we show a physical interaction between endogenous ER alpha and signal transducer and activator of transcription 5 in differentiated HC11 cells. In summary, our results show that ER functional activity changes during differentiation of HC11 cells.
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PMID:Estrogen receptor functional activity changes during differentiation of mammary epithelial cells. 1460 98

Human and animal models have evidenced how estrogen insufficiency is associated with abnormal spermatogenesis and male infertility. We previously demonstrated that estradiol is able to influence both capacitation and acrosome reaction in human ejaculated spermatozoa. It remains to be elucidated whether the biochemical changes induced by estradiol, in a rapid nongenomic way, are mediated by a single estrogen receptor (ER) or by the two ER subtypes, ER alpha and ER beta. In the present study, we have first demonstrated the concomitant expression of ER beta and ER alpha in human ejaculated spermatozoa. By RT-PCR and Southern blot, transcripts of both ERs were detected. Western blot analysis showed ER alpha and ER beta proteins at the same size as the "classical" ERs. The localization of ER alpha and ER beta with the immunocytochemistry shows a differential distribution of the two ER subtypes, the former being prevalently located in the midpiece, but the latter being in the tail. Estradiol has been associated with sperm longevity; however, the mechanism through which estradiol acts in sperm survival was never investigated. Upon estradiol exposure, we observed an enhanced phosphorylation of the proteins involved in the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway like PDK1, Akt, GSK-3, Bcl-2, together with ERK1/2, which was also involved in cell survival signals. Moreover, such phosphorylations were reduced in the presence of ICI 182, 780, addressing the role of estradiol and ERs in sperm survival. For instance we have provided, for the first time, a different interaction of the two ERs with the PI3K/Akt pathway, because ER alpha interacts with the p55 regulatory subunit of PI3K, whereas ER beta interacts with Akt1. However, it still remains to be elucidated whether the functional role of each of the ER subtypes in sperm survival signaling is redundant or distinct.
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PMID:Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway. 1500 46

The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces tumours of the breast, colon and prostate in rats. Here we show that in addition to its well-established genotoxicity, which can be detected at concentrations >10(-6) M, PhIP is also oestrogenic. In COS-1 cells transiently transfected with an oestrogen-responsive reporter gene, PhIP (10(-10)-10(-6) M) mediated transcription through oestrogen receptor (ER) alpha, but not ER-beta, and inhibition by the pure ER antagonist ICI 182 780 demonstrated a requirement for a functional ER. In contrast, the structurally related food-derived carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) failed to induce reporter gene transcription. Additionally, we show that in a hormonally responsive breast cancer cell line (MCF-7 cells), PhIP induced transcriptional activation using endogenously expressed ER. Examination of the genotoxic potential of PhIP using a model mammalian cell mutation assay (hprt(-) locus) demonstrated that the genetic toxicology of PhIP was readily detectable, but separate, in terms of effective concentration, from its oestrogenic activity. To determine whether the oestrogenicity of PhIP could mediate oestrogen-dependent responses such as cell growth, we examined the growth of hormonally responsive cells (MCF-7 cells). We show that PhIP can stimulate cell proliferation and, again, this was dependent upon a functional ER. Using ligand blotting, we further show that PhIP can stimulate the expression of progesterone receptor (PR-A and PR-B) and c-MYC and activate the MAPK signal transduction pathway. These responses were similar to that produced by oestradiol, in terms of temporal aspects, potency and a requirement for a functional ER. Each of these dose-dependent mitogenic responses occurred at concentrations of PhIP ( approximately 10(-9)-10(-11)M) that are likely to be equivalent to systemic human exposure via consumption of cooked meat. Thus PhIP can induce cellular responses that encompass altered gene expression and mitogenesis. We suggest that the combination of genetic toxicology and oestrogen-like promotion of genomic and cellular events provide a mechanism for the tissue-specific tumorigenicity of this compound.
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PMID:The cooked food derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine is a potent oestrogen: a mechanistic basis for its tissue-specific carcinogenicity. 1531 1

The capability of 17beta-estradiol (E2) to induce the non-genomic activities of its receptors (ER alpha and ER beta) and to evoke different signaling pathways committed to the regulation of cell proliferation has been analyzed in different cell cancer lines containing transfected (HeLa) or endogenous (HepG2, DLD1) ER alpha or ER beta. In these cell lines, E2 induced different effects on cell growth/apoptosis in dependence of ER isoforms present. The E2-ER alpha complex rapidly activated multiple signal transduction pathways (i.e., ERK/MAPK, PI3K/AKT) committed to both cell cycle progression and apoptotic cascade prevention. On the other hand, the E2-ER beta complex induced the rapid and persistent phosphorylation of p38/MAPK which, in turn, was involved in caspase-3 activation and cleavage of poly(ADP-ribose)polymerase, driving cells into the apoptotic cycle. In addition, the E2-ER beta complex did not activate any of the E2-ER alpha-activated signal molecules involved in cell growth. Taken together, these results demonstrate the ability of ER beta isoform to activate specific signal transduction pathways starting from plasma membrane that may justify the effect of E2 in inducing cell proliferation or apoptosis in cancer cells. In particular this hormone promotes cell survival through ER alpha non-genomic signaling and cell death through ER beta non-genomic signaling.
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PMID:Survival versus apoptotic 17beta-estradiol effect: role of ER alpha and ER beta activated non-genomic signaling. 1538 27

CHO-K1, COS-7, and Rat2 fibroblast cell lines are generally believed to be devoid of estrogen receptors (ERs) and have been widely used to study the functions of ER-alpha and ER-beta after transfection of their cDNAs. Numerous studies have demonstrated that transfected ER-alpha or ER-beta mediates estradiol-induced activation of multiple signaling pathways, including the MAPK/ERK pathways. We report here for the first time that both 17alpha-estradiol and 17beta-estradiol elicit activation of MAPK/ERK in native, nontransfected CHO-K1, COS-7, and Rat2 fibroblast cell lines. We further report that, contrary to the generally held belief, these cell lines are not unresponsive to estradiol in their native, nontransfected state, and that this estrogen responsiveness is associated with estrogen binding. Using multiple ER antibodies, we failed to find ER-alpha or ER-beta isoforms or even ER-X. In view of these findings, researchers, using such cells as models to investigate mechanisms of estrogen action, must always take into account the existence of endogenous estrogen binding proteins other than ER-alpha, ER-beta, or ER-X.
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PMID:Estrogen activates mitogen-activated protein kinase in native, nontransfected CHO-K1, COS-7, and RAT2 fibroblast cell lines. 1551 82

17beta-Estradiol is a greatly under-appreciated neural growth and trophic factor for the mammalian brain of all ages. Like other growth factors, such as the neurotrophins, 17beta-estradiol influences neurogenesis, neuronal differentiation, and neuronal survival of its targets throughout life. Estrogen elicits developmentally regulated differentiative effects, which are not normally seen in the adult brain. However, re-expression of this developmental response occurs in the adult, following loss of trophic support, whether induced by estrogen deprivation or brain injury. In addition to the classical intranuclear estrogen receptors (ER) ER-alpha and ER-beta, we have recently identified a novel, plasma membrane-associated, putative ER that is neither ER-alpha nor ER-beta, which we have designated 'ER-X'. ER-X is a developmentally regulated estrogen-binding protein, present in wild-type, ER-alpha gene-disrupted (alphaERKO) and ER-alpha null mice, which is re-expressed following ischemic brain injury. The preferred ligand of ER-X is 17alpha-estradiol. Although ER-X shares some homology with the C-terminus of ER-alpha, it is not an alternative splicing variant and may be a new gene. While ER-X appears to mediate 17alpha- and 17beta-estradiol activation of the MAPK cascade, ER-alpha, in contrast, is inhibitory to its activation. Estradiol activation of MAPK/ERK may be particularly relevant for neuroprotection during aging and Alzheimer's disease.
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PMID:Estrogen and the brain: beyond ER-alpha and ER-beta. 1558 72


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