Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and experimental studies have suggested that estrogens, the archetype of female hormones, participate in the control of male germ cell proliferation and that fetal exposure to environmental estrogens may contribute to hypofertility and/or to testicular germ cell cancer. However, the underlying mechanisms remain to be elucidated. 17beta-Estradiol (E2) conjugated to BSA was able to stimulate human testicular seminoma cell proliferation by triggering a rapid, nongenomic, membrane-mediated activation of ERK1/2 and cAMP-dependent protein kinase A (PKA). Both ERK1/2 and PKA participated in this promoting effect. This activation was associated with phosphorylation of the transcription factor cAMP response element-binding protein and the nuclear factor retinoblastoma protein. Enhanced proliferation together with ERK activation could be reversed by pertussis toxin, a G protein inhibitor. Estrogen receptors (ERs) in JKT-1 were characterized by immunofluorescence, subcellular fractioning, and Western blot. JKT-1 cells did not express ERalpha but ERbeta, which localized to the mitochondria and the nucleus but not to the membrane. Moreover, neither ICI-182,780, a classical ER antagonist, nor tamoxifen, a selective ER modulator, could reverse the 17beta-estradiol-BSA-induced promoting effect. Estrogens contribute to human testicular germ cell cancer proliferation by rapid activation of ERK1/2 and PKA through a membrane nonclassical ER. This nongenomic effect represents a new basis for understanding the estrogenic control of spermatogenesis and evaluating the role of fetal exposure to xenoestrogens during malignant transformation of testicular germ stem cells.
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PMID:Estrogens promote human testicular germ cell cancer through a membrane-mediated activation of extracellular regulated kinase and protein kinase A. 1803 75

Estrogen has direct and indirect effects on mitochondrial activity, but the mechanisms mediating these effects remain unclear. Others reported that long-term estradiol (E(2)) treatment increased nuclear respiratory factor-1 (NRF-1) protein in cerebral blood vessels of ovariectomized rats. NRF-1 is a transcription factor that regulates the expression of nuclear-encoded mitochondrial genes, e.g. mitochondrial transcription factor A (TFAM), that control transcription of the mitochondrial genome. Here we tested the hypothesis that E(2) increases NRF-1 transcription resulting in a coordinate increase in the expression of nuclear- and mitochondrial- encoded genes and mitochondrial respiratory activity. We show that E(2) increased NRF-1 mRNA and protein in MCF-7 breast and H1793 lung adenocarcinoma cells in a time-dependent manner. E(2)-induced NRF-1 expression was inhibited by the estrogen receptor (ER) antagonist ICI 182,780 and actinomycin D but not by phosphoinositide-3 kinase and MAPK inhibitors, indicating a genomic mechanism of E(2) regulation of NRF-1 transcription. An estrogen response element (ERE) in the NRF-1 promoter bound ER alpha and ER beta in vitro, and E(2) induced ER alpha and ER beta recruitment to this ERE in chromatin immunoprecipitation assays in MCF-7 cells. The NRF-1 ERE activated reporter gene expression in transfected cells. Small interfering RNA to ER alpha and ER beta revealed that ER alpha mediates E(2)-induced NRF-1 transcription. The E(2)-induced increase in NRF-1 was followed by increased TFAM and the transcription of Tfam-regulated mitochondrial DNA-encoded COI and NDI genes and increased mitochondrial biogenesis. Knockdown of NRF-1 blocked E(2) stimulation of mitochondrial biogenesis and activity, indicating a mechanism by which estrogens regulate mitochondrial function by increasing NRF-1 expression.
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PMID:Estradiol stimulates transcription of nuclear respiratory factor-1 and increases mitochondrial biogenesis. 1804 42

Estrogen receptors (ERalpha and ERbeta) are estrogen-regulated transcription factors that play important roles in the development and progression of breast cancer. The biological function of ERs has been shown to be modulated by ER-interacting proteins. However, the ER-interacting proteins that not only activate MAPK and AKT, two important growth regulatory protein kinases, but also increase growth related estrogen-responsive gene expression remain unknown. Here, we report that hematopoietic PBX-interacting protein (HPIP) interacts both with ERalpha and with ERbeta, and increases ERalpha target gene expression through activation of MAPK and AKT and enhanced ERalpha phosphorylation. ERbeta inhibits ERalpha target gene expression, possibly by competition of ERbeta with ERalpha for binding to HPIP, and by a decrease in available ERalpha for HPIP binding through the interaction of ERbeta with ERalpha. Furthermore, HPIP increases breast cancer cell growth. These data suggest that HPIP may be an important regulator in ER signaling and that the relative ratio of ERbeta to ERalpha may be important for HPIP function.
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PMID:The estrogen receptor-interacting protein HPIP increases estrogen-responsive gene expression through activation of MAPK and AKT. 1830 41

Estrogen receptors can activate transcription in the nucleus, and activate rapid signal transduction cascades in the cytosol. Multiple reports identify estrogen receptors at the plasma membrane, while others document the dynamic responses of estrogen receptor to ligand binding. However, the function and identity of membrane estrogen receptors remain controversial. We have used confocal microscopy and cell fractionation on the murine hippocampus-derived HT22 cell line and rat primary cortical neurons transfected with estrogen receptor-green fluorescent protein constructs to address the membrane localization of these receptors. We observe translocation of estrogen receptor beta (beta) to the plasma membrane 5 min after exposure to 17beta-estradiol, whereas estrogen receptor alpha (alpha) localization remains unchanged. Membrane localization of estrogen receptor beta is transient, selective for 17beta-estradiol, and is not blocked by ICI182,780. Inhibition of the mitogen-activated protein kinase pathway does not block estrogen-mediated estrogen receptor beta membrane translocation, and in fact prolongs membrane localization. These data suggest that while both estrogen receptor alpha and estrogen receptor beta can be present at the neuronal membrane, their presence is differentially regulated.
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PMID:Estrogen induces rapid translocation of estrogen receptor beta, but not estrogen receptor alpha, to the neuronal plasma membrane. 1840 37

The function of pancreatic beta-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ER alpha and ER beta, are important molecules involved in glucose metabolism, yet their role in pancreatic beta-cell physiology is still greatly unknown. In this report we show that both ER alpha and ER beta are present in pancreatic beta-cells. Long term exposure to physiological concentrations of 17beta-estradiol (E2) increased beta-cell insulin content, insulin gene expression and insulin release, yet pancreatic beta-cell mass was unaltered. The up-regulation of pancreatic beta-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA). The use of ER alpha and ER beta agonists as well as ER alphaKO and ER betaKO mice suggests that the estrogen receptor involved is ER alpha. The up-regulation of pancreatic insulin content by ER alpha activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.
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PMID:Pancreatic insulin content regulation by the estrogen receptor ER alpha. 1844 33

Estrogen and its receptors influence growth and differentiation by stimulating the production and secretion of growth factors. Our previous studies indicate an increased expression of estrogen receptor (ER)-alpha and decreased growth factor synthesis in the olfactory bulb of reproductive senescent female rats as compared with young animals. The present study tests the hypothesis that abnormal overexpression of ERalpha contributes to decreased growth factor synthesis. We developed the HeLa-Tet-On cell line stably transfected with ERalpha (HTERalpha) that expresses increasing amounts of ERalpha with increasing doses of doxycycline (Dox). Increasing doses of Dox had no effect on vascular endothelial growth factor (VEGF) secretion in HTERalpha cells. However, in the presence of 40 nm 17beta-estradiol, VEGF secretion increased in low-dose Dox-exposed HTERalpha cultures, which was attenuated by the ERalpha antagonist, 1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]1H-pyrazole dihydrochloride. However, at high-dose Dox and, consequently, high ERalpha levels, estradiol failed to increase VEGF. In the HeLa X6 cell line in which the Tet-On construct is upstream of an unrelated gene (Pitx2A), estradiol failed to induce VEGF at any Dox dose. Furthermore, in the HTERalpha cell line, estradiol selectively down-regulates phospho-ERK2 and phospho-Akt at high ERalpha expression. This study clearly demonstrates that the dose of receptor critically mediates estradiol's ability to regulate growth factors and survival kinases. The present data also support the hypothesis that 17beta-estradiol treatment to an ERalpha overexpressing system, such as the senescent brain, could reverse the normally observed beneficial effect of estrogen.
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PMID:Estrogen receptor-alpha overexpression suppresses 17beta-estradiol-mediated vascular endothelial growth factor expression and activation of survival kinases. 1845 Sep 51

Estrogen controls multiple biological functions through binding to estrogen receptors (ERs). Traditionally, ERs have been regarded as transcription factors regulating the expression of target genes. However, growing evidence of rapid estrogen's actions in a number of tissues has been accumulating and alternative mechanisms of signal transduction have been proposed. These so called "extra-nuclear actions" do not require gene expression or protein synthesis and are independent of the nuclear localization of ERs. Indeed, some of these actions are elicited by ERs residing at or near the plasma membrane. Membrane-associated molecules such as ion channels, G proteins, the tyrosine kinase c-Src as well as growth factor receptors are modulated by liganded ERs within the membrane, leading to the activation of downstream cascades such as mitogen-activated protein kinase, phosphatidylinositol 3-OH kinase, protein kinase A, and protein kinase C. These cascades mediate some important rapid actions of estrogen, such as the activation of nitric oxide synthesis or the remodeling of actin cytoskeleton. In addition, these pathways are critical for the regulation of the expression of a number of target proteins implicated in cell proliferation, apoptosis, differentiation, movement, and homeostasis. In this manner, the extra-nuclear pathways are tightly integrated with the genomic pathways to orchestrate the full spectrum of estrogen's biological functions. The recent advancements in the characterization of the molecular basis of the extra-nuclear signaling of estrogen helps to understand the role of estrogen on human cells, and may in future turn out to be of relevance for clinical purposes.
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PMID:Extra-nuclear signaling of estrogen receptors. 1861 86

In premature infants, oxygen free radicals generated following neonatal resuscitation are associated with subsequent diseases such as retinopathy of prematurity and bronchopulmonary dysplasia. Recent studies in brain tissue samples have shown that nonphysiologic oxygen levels play a key role in induction of apoptosis in the developing brain. Estrogen is a well-established agent in neuroprotection and, therefore, is thought to be neuroprotective even in the premature brain. Astrocytes appear to have a critical role in protection and survival of neurons in the brain. As one of the glial cell types, they have a great potential for possible involvement in the mediation of estrogen neuroprotective effects. The aim of our study was to analyze whether astrocytes in cell cultures are damaged by hyperoxia and whether 17beta-estradiol (E2) can protect them against apoptosis. Additionally, we investigated the mechanism of the protection by E2, hypothesizing that it is mediated through extracellular signal-regulated kinase (ERK1/2). Cells underwent eightfold more apoptosis when cultivated in hyperoxia compared with normoxia. Addition of E2 reduced apoptosis in hyperoxia by more than 50%. Levels of ERK1/2 and phosphorylated ERK1/2 were increased after hyperoxia compared with normoxia. Preincubation with E2 prior to exposure to hyperoxia resulted in decreased levels of ERK1/2 and pERK1/2. Hyperoxia induces apoptosis in C8-D1A cells, and E2 seems to be a protecting factor for astrocytes in hyperoxia. This effect is not mediated through up-regulation of pERK1/2.
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PMID:17beta-estradiol attenuates hyperoxia-induced apoptosis in mouse C8-D1A cell line. 1861 75

Estrogen plays a role in restoring homeostatic balance during the stress response by altering hypothalamic function and NO production in the brain. While we know that estrogen acts on the hypothalamus to stimulate the NO system through an ERbeta-dependent mechanism in neurons, the molecular mechanisms responsible for these effects are unknown. Because phosphorylation of nNOS at Ser(1412) increases nNOS activity which leads to increased NO production, we investigated the effects of ERbeta activation on nNOS phosphorylation at Ser(1412) and NO production in primary hypothalamic neurons. Using the selective ERbeta agonist, DPN (10nM), we show that activation of ERbeta rapidly increases phosphorylation levels of nNOS at Ser(1412) and NO production. We also show that the PI3K pathway, but not the MAPK pathway, mediates the increases in levels of Ser(1412) phosphorylation and NO production induced by ERbeta activation, as the selective PI3K inhibitor, LY294002 (10microM), blocked the effects of ERbeta activation. Finally, we demonstrate that Src kinase acts upstream of the PI3K/Akt pathway based on our finding that the selective Src inhibitor, PP2 (10microM), blocked the increases in nNOS phosphorylation levels, NO production, and PI3K/Akt activity induced by ERbeta activation. Together, our results show that Src kinase mediates ERbeta-induced increases in phosphorylation levels of nNOS at Ser(1412) and NO production by activating the PI3K/Akt pathway. These findings provide novel insight into the signaling mechanisms through which E2 stimulates the NO system in hypothalamic neurons.
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PMID:Activation of ERbeta increases levels of phosphorylated nNOS and NO production through a Src/PI3K/Akt-dependent pathway in hypothalamic neurons. 1865 36

Estrogen receptors are historically perceived as nuclear ligand activated transcription factors. An estrogen receptor has now been found localized to the plasma membrane of human myeloblastic leukemia cells (HL-60). Its expression occurs throughout the cell cycle, progressively increasing as cells mature from G(1) to S to G(2)/M. To ascertain that the receptor functioned, the effect of ligands, including a non-internalizable estradiol-BSA conjugate and tamoxifen, an antagonist of nuclear estrogen receptor function, were tested. The ligands caused activation of the ERK MAPK pathway. They also modulated the effect of retinoic acid, an inducer of MAPK dependent terminal differentiation along the myeloid lineage in these cells. In particular the ligands inhibited retinoic acid-induced inducible oxidative metabolism, a functional marker of terminal myeloid cell differentiation. To a lesser degree they also diminished retinoic acid-induced earlier markers of cell differentiation, namely CD38 and CD11b. However, they did not regulate retinoic acid-induced G(0) cell cycle arrest. There is thus a membrane localized estrogen receptor in HL-60 myeloblastic leukemia cells that can cause ERK activation and modulates the response of these cells to retinoic acid, indicating crosstalk between the membrane estrogen and retinoic acid evoked pathways relevant to propulsion of cell differentiation.
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PMID:Human myeloblastic leukemia cells (HL-60) express a membrane receptor for estrogen that signals and modulates retinoic acid-induced cell differentiation. 1869 45


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