Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The classical estrogen receptor ERalpha mediates many of the known cardiovascular effects of estrogen and is expressed in male and female vascular cells. Estrogen-independent activation of ERalpha is known to occur in cells from reproductive tissues, but has not been investigated previously in vascular cells. In this study, transient transfection assays in human saphenous vein smooth muscle cells (HSVSMC) and pulmonary vein endothelial cells (PVEC) demonstrated ERalpha-dependent activation of estrogen response element-based, and vascular endothelial growth factor-based reporter plasmids by both estrogen-deficient FBS (ED-FBS) and EGF. In nonvascular cells, ERalpha-mediated gene expression can be activated via mitogen-activated protein (MAP) kinase- induced phosphorylation of serine 118 of ERalpha. However, in vascular cells, we found that pharmacologic inhibition of MAP kinase did not alter EGF-mediated ERalpha activation. In addition, a mutant ER containing an alanine-for-serine substitution at position 118 was activated to the same degree as the wild-type receptor by ED-FBS and EGF in both HSVSMC and PVEC. Furthermore, constitutively active MAP kinase kinase (MAPKK) activated ERalpha in Cos1 cells as expected, but MAPKK inhibited ER activation in PVEC. We conclude that growth factors also stimulate ERalpha-mediated gene expression in vascular cells, but find that this occurs via a MAP kinase-independent pathway distinct from that reported previously in nonvascular cells.
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PMID:Growth factor activation of the estrogen receptor in vascular cells occurs via a mitogen-activated protein kinase-independent pathway. 963 19

Estrogen is an important vasoprotective molecule that causes the rapid dilation of blood vessels by activating endothelial nitric oxide synthase (eNOS) through an unknown mechanism. In studies of intact ovine endothelial cells, 17beta-estradiol (E2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists. Overexpression of the known transcription factor ERalpha led to marked enhancement of the acute response to E2, and this was blocked by ER antagonists, was specific to E2, and required the ERalpha hormone-binding domain. In addition, the acute response of eNOS to E2 was reconstituted in COS-7 cells cotransfected with wild-type ERalpha and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E2, and E2 caused rapid ER-dependent activation of MAP kinase. These findings demonstrate that the short-term effects of estrogen central to cardiovascular physiology are mediated by ERalpha functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms.
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PMID:Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. 992 1

Estrogen elicits a selective enhancement of the growth and differentiation of axons and dendrites (neurites) in the developing brain. Widespread colocalization of estrogen and neurotrophin receptors (trk) within estrogen and neurotrophin targets, including neurons of the cerebral cortex, sensory ganglia, and PC12 cells, has been shown to result in differential and reciprocal transcriptional regulation of these receptors by their ligands. In addition, estrogen and neurotrophin receptor coexpression leads to convergence or cross-coupling of their signaling pathways, particularly at the level of the mitogen-activated protein (MAP) kinase cascade. 17beta-Estradiol elicits rapid (within 5-15 min) and sustained (at least 2 h) tyrosine phosphorylation and activation of the MAP kinases, extracellular-signal regulated kinase (ERK)1, and ERK2, which is successfully inhibited by the MAP kinase/ERK kinase 1 inhibitor PD98059, but not by the estrogen receptor (ER) antagonist ICI 182,780 and also does not appear to result from estradiol-induced activation of trk. Furthermore, the ability of estradiol to phosphorylate ERK persists even in ER-alpha knockout mice, implicating other estrogen receptors such as ER-beta in these actions of estradiol. The existence of an estrogen receptor-containing, multimeric complex consisting of hsp90, src, and B-Raf also suggests a direct link between the estrogen receptor and the MAP kinase signaling cascade. Collectively, these novel findings, coupled with our growing understanding of additional signaling substrates utilized by estrogen, provide alternative mechanisms for estrogen action in the developing brain which could explain not only some of the very rapid effects of estrogen, but also the ability of estrogen and neurotrophins to regulate the same broad array of cytoskeletal and growth-associated genes involved in neurite growth and differentiation. This review expands the usually restrictive view of estrogen action in the brain beyond the confines of sexual differentiation and reproductive neuroendocrine function. It considers the much broader question of estrogen as a neural growth factor with important influences on the development, survival, plasticity, regeneration, and aging of the mammalian brain and supports the view that the estrogen receptor is not only a ligand-induced transcriptional enhancer but also a mediator of rapid, nongenomic events.
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PMID:Novel mechanisms of estrogen action in the brain: new players in an old story. 1032 86

Estrogen has a variety of effects on the vascular wall including rapid vasodilation due to the stimulation of endothelial nitric oxide synthase (eNOS). Studies in cultured endothelium indicate that the hormone cause acute, direct activation of eNOS that is unaffected by actinomycin D but fully inhibited by estrogen receptor (ER) antagonism. Overexpression of ERalpha leads to marked enhancement of the acute response to estrogen, and this process is blocked by ER antagonism and requires the ERalpha hormone binding domain. The acute response of eNOS to estrogen can also be reconstituted in COS-7 cells cotransfected with ERalpha and eNOS, but not by transfection with eNOS alone. The inhibition of calcium influx, or tyrosine kinases or mitogen-activated protein (MAP) kinase prevents eNOS stimulation by estrogen, and estrogen causes rapid ER-dependent activation of MAP kinase. Thus, the acute effect of estrogen on eNOS is mediated by ERalpha functioning in a novel, nongenomic manner to activate the enzyme via calcium-dependent, MAP kinase-dependent mechanisms.
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PMID:Novel role of estrogen receptors in vascular endothelium. 1070 64

Estrogen and insulin-like-growth factor 1 (IGF-1) are potent mitogenic stimuli that share important properties in the control of cellular proliferation. However, the coupling between the signaling cascades of estrogen receptors alpha and beta and the IGF-1 receptor (IGF-1R) is poorly understood. Therefore, we selectively transfected estrogen receptor alpha or beta in COS7 and HEK293 cells, which contain IGF-1R. In presence of estrogen receptor alpha but not beta, 17beta-estradiol (E2) rapidly induces phosphorylation of the IGF-1R and the extracellular signal-regulated kinases 1/2. Furthermore, upon stimulation with E2, estrogen receptor alpha but not beta bound rapidly to the IGF-1R in COS7 as well as L6 cells, which express all investigated receptors endogenously. Control experiments in the IGF-1R-deficient fibroblast cell line R(-) showed that after stimulation with E2 only estrogen receptor alpha bound to the transfected IGF-1R. Overexpression of dominant negative mitogen-activated protein kinases kinase inhibited this effect. Finally, estrogen receptor alpha but not beta is required to induce the activation of the estrogen receptor-responsive reporter ERE-LUC in IGF-1-stimulated cells. Taken together, these data demonstrate that ligand bound estrogen receptor alpha is required for rapid activation of the IGF-1R signaling cascade.
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PMID:Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway. 1074 89

Estrogen rapidly activates the mitogen-activated protein kinases, Erk-1 and Erk-2, via an as yet unknown mechanism. Here, evidence is provided that estrogen-induced Erk-1/-2 activation occurs independently of known estrogen receptors, but requires the expression of the G protein-coupled receptor homolog, GPR30. We show that 17beta-estradiol activates Erk-1/-2 not only in MCF-7 cells, which express both estrogen receptor alpha (ER alpha) and ER beta, but also in SKBR3 breast cancer cells, which fail to express either receptor. Immunoblot analysis using GPR30 peptide antibodies showed that this estrogen response was associated with the presence of GPR30 protein in these cells. MDA-MB-231 breast cancer cells (ER alpha-, ER beta+) are GPR30 deficient and insensitive to Erk-1/-2 activation by 17beta-estradiol. Transfection of MDA-MB-231 cells with a GPR30 complementary DNA resulted in overexpression of GPR30 protein and conversion to an estrogen-responsive phenotype. In addition, GPR30-dependent Erk-1/-2 activation was triggered by ER antagonists, including ICI 182,780, yet not by 17alpha-estradiol or progesterone. Consistent with acting through a G protein-coupled receptor, estradiol signaling to Erk-1/-2 occurred via a Gbetagamma-dependent, pertussis toxin-sensitive pathway that required Src-related tyrosine kinase activity and tyrosine phosphorylation of tyrosine 317 of the Shc adapter protein. Reinforcing this idea, estradiol signaling to Erk-1/-2 was dependent upon trans-activation of the epidermal growth factor (EGF) receptor via release of heparan-bound EGF (HB-EGF). Estradiol signaling to Erk-1/-2 could be blocked by: 1) inhibiting EGF-receptor tyrosine kinase activity, 2) neutralizing HB-EGF with antibodies, or 3) down-modulating HB-EGF from the cell surface with the diphtheria toxin mutant, CRM-197. Our data imply that ER-negative breast tumors that continue to express GPR30 may use estrogen to drive growth factor-dependent cellular responses.
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PMID:Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. 1104 79

Estrogen (E2) palys critical roles in the development of tumors in female reproductive organs. Development of most breast cancers is dependent on E&sub2; in most cases. Most E&sub2; actions are considered to be exerted through two subtypes of Estrogen receptors (ERs), ERalpha and ERbeta. ERs belong to the nuclear receptor superfamily, and act as ligand-inducible transcription factors to activate transcription of a particular set of the target genes. Ligand-bound ER recruits at least two distinct classes of coactivator complexes. In estrogen-dependent breast cancer, growth factors are shown to often act synergisticaly with E&sub2;, and the breast cancer often become resistant to treatment of estogen antagonists. However, the molecular basis of this coupled regulation of growth factor and ER-mediated signaling and hormone-resistance are largely unknown. We have previously shown that MAP (mitogen-activated protein) kinase (MAPK) activated by growth factors phosphorylates and potentiates the N-terminal transactivation function (AF-1), indicating a possible molecular mechanism of a novel cross-talk between two signalings (Kato et al, 1995). Furthermore, we have identified a coactivator that specifically interacts with ER alpha AF-1 (Endoh et al, 1999). In this review, this cross-talk is discussed in terms of the transactivation function of ERs and their coactivators.
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PMID:Estrogen receptor-mediated cross-talk with growth factor signaling pathways. 1118 Jul 60

Estrogen influences the development and function of the nervous system through estrogen receptor-dependent changes in gene expression and by rapidly influencing diverse intracellular signaling pathways. We have investigated the influence of estradiol on developing neonatal rat cerebellar neurons in primary culture and found that low concentrations of 17beta-estradiol (17beta-E2), 17alpha-E2, 17beta-E2-BSA, and ICI182,780 stimulated phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) mitogen-activated protein kinases (MAPK). Neither testosterone nor progesterone increased ERK1/2 phosphorylation. The effects of the estrogens were specific to the ERK1/2 MAPK pathway and were blocked by U0126, an inhibitor of the ERK1/2 MAPK kinase (MEK1/2). Compared with control cultures, significant MAPK-dependent decreases in viable granule cell numbers were observed in dissociated explant cultures of developing cerebellar neurons 24-96 hr after pulse treatment with 10 pm 17beta-E2 or 10 nm ICI182,780. In contrast, continuous exposure to 10 pm 17beta-E2 significantly increased granule cell numbers. Analysis of bromodeoxyuridine incorporation revealed that a 15 min pulsed treatment with 10 pm 17beta-E2 increased mitogenesis, whereas continuous exposure to the same concentration of 17beta-E2 was anti-mitotic. Estradiol did not increase caspase activity; however, significant increases in cellular permeability and lysis were observed. Cell lysis and death were independent of the pan-caspase inhibitor zVAD-fmk but were blocked fully by the irreversible calpain inhibitor PD150606. These results indicate that rapid activation of the ERK1/2 MAPK pathway by low concentrations of 17beta-E2 induces oncotic/necrotic, but not apoptotic, programmed cell death in a subpopulation of developing granule cells and increased mitogenesis of the granule cell neuroblasts refractory to estrogen-induced neurotoxicity.
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PMID:Estrogens and ICI182,780 (Faslodex) modulate mitosis and cell death in immature cerebellar neurons via rapid activation of p44/p42 mitogen-activated protein kinase. 1283 21

Classically, estrogen acts on cells by directly activating gene transcription driven by ligand-bound nuclear estrogen receptors (ER). Accumulating evidence demonstrates that estrogen acts on neurons by utilizing diverse molecular mechanisms, including rapid signaling by proteins localized to the plasma membrane. Recent studies showing that ERalpha localizes to axons and dendrites of hippocampal neurons suggest that nonnuclear stores of the receptor may transduce estrogen signaling. Here, we have studied the subcellular localization, dynamic regulation, and function of ERalpha in mouse cortical neurons. Estrogen-stimulated mouse cortical neurons activate both estrogen response element (ERE) stimulated transcription and rapid activation of p44/42 mitogen-activated protein kinases (MAPK). We demonstrate that green fluorescent protein (GFP)-tagged ERalpha localizes to neurites in cultured cortical neurons and that the expression within neurites can be down-regulated by estrogen or up-regulated by antiestrogen administered during synthesis. Neurite ERalpha appears to be directed to neurites directly from its site of translation and not from nuclear stores. By using confocal microscopy, we show that ERalpha within neurites stimulates local activation of p44/42 MAP kinases in response to estrogen. We conclude that hormonal status alters subcellular ERalpha targeting in cortical neurons and that neurite-expressed ERalpha is important in the activation of local MAPK signaling.
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PMID:Neurite-localized estrogen receptor-alpha mediates rapid signaling by estrogen. 1313 May 1

The effects of hormone and growth factor signaling on gene expression contribute significantly to breast tumorigenesis and disease progression; however, the targets of signaling networks associated with deregulated growth are not well understood. We defined the dynamic transcriptional effects elicited in MCF7, T-47D, and MDA-MB-436 breast cancer cell lines by nine regulators of growth and differentiation (17beta-estradiol, antiestrogens fulvestrant and tamoxifen, progestin R5020, antiprogestin RU486, all-trans-retinoic acid, epidermal growth factor, mitogen-activated protein/extracellular signal-regulated kinase 1/2 inhibitor U0126 and phorbol ester 12-O-tetradecanoylphorbol-13-acetate) and compared the patterns of gene regulation to published tumor expression profiles. The complex pattern of response to these agents revealed unexpected relationships between their effects, including a profound overlap in genes regulated by both steroids and epidermal growth factor, and striking overlaps between fulvestrant and all-trans-retinoic acid. Estrogen-responsive genes could be divided into two major clusters, only one of which is associated with cell proliferation. Gene ontology analysis was used to highlight functionally distinct biological responses to different mitogens. Significant correlations were identified between several clusters of drug-responsive genes and genes that discriminate estrogen receptor status or disease outcome in patient samples. The majority of estrogen receptor status discriminators were not responsive in our dataset and are therefore likely to reflect underlying differences in histogenesis and disease progression rather than growth factor signaling. This article highlights the overall impact at the gene expression level of diverse regulators of breast cancer growth and links the behavior of breast cancer cells in culture to important clinical properties of human breast tumors.
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PMID:The gene expression response of breast cancer to growth regulators: patterns and correlation with tumor expression profiles. 1461 9


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