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)

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

In this study, we show that 17beta-Estradiol (E2) induced the proliferation of T84 colonic carcinoma cells. We, further, investigated the mechanisms underlying this proliferation and show that E2 induced c-fos protooncogene expression in T84 cells in a timescale consistent with a rapid non-genomic action of the hormone. Furthermore, E2 rapidly phosphorylated both CREB and ELK1, transcription factors that bind to the c-fos promoter and stimulate transcription. Pretreatment with PD98059 and H89, mitogen-activated protein kinase (MAPK) pathway and protein kinase A (PKA) inhibitors, respectively showed that phosphorylation of CREB and ELK1 and subsequent c-fos induction was mediated by the MAPK pathway only. Finally, the estrogen receptor (ER) antagonist, ICI 182,780, blocked the activation of MAPK pathway, subsequent CREB and ELK1 phosphorylation and c-fos induction in T84 cells suggesting an ER dependent mechanism. Consistent with this finding, ICI 182,780 caused a substantial reduction in the proliferative effects of E2 on T84 cells.
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PMID:17beta-Estradiol rapidly stimulates c-fos expression via the MAPK pathway in T84 cells. 1560 27

It is now well known that 17beta-estradiol has an endothelium-independent, non-genomic vasorelaxant effect. We hypothesized that 17beta-estradiol has its non-genomic effect on calcium-independent contraction in de-endothelialized rat aortic rings. Rat aortic ring preparations were mounted in organ baths and exposed to contractile agents. 17beta-Estradiol (8, 20 or 50 microM), but not 17alpha-estradiol, concentration-dependently decreased the tension induced by 1.0 microM phenylephrine (PE) in the presence, but not in the absence, of calcium in the solution. Pretreatment with 17beta-estradiol concentration-dependently inhibited vascular contractions induced by cumulative addition of PE or calcium and almost completely abolished those induced by cumulative addition of Bay K8644, a calcium channel opener. Furthermore, 17beta-estradiol also concentration-dependently decreased the tension induced by 0.3 microM phorbol 12,13-dibutyrate (PDBu), a protein kinase C activator, in the presence of calcium in the solution, but not in the absence of calcium in the solution. Pretreatment with 17beta-estradiol had little effect on vascular contractions induced by PDBu or PE or on PE-induced mitogen-activated protein kinase (MAPK) activation in calcium-free Krebs solution. These results suggest that 17beta-estradiol inhibits calcium-dependent, but not calcium-independent, vascular contraction.
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PMID:17beta-Estradiol inhibits calcium-dependent, but not calcium-independent, contraction in isolated rat aorta. 1569 18

Transcription of the prolactin gene is dynamically controlled by positive and negative hormone signals that target the regulatory promoter region. Based on the inducibility of prolactin gene expression by inhibitors of histone deacetylases (HDACs), we examined the role of histone acetylation at the genomic prolactin promoter as a late step in transcriptional regulation. Chromatin immunoprecipitation analysis of GH4 cells revealed elevated levels of acetylated histones in the promoter and enhancer regions of the gene, compared with downstream intron sequences. 17beta-Estradiol stimulated histone H4 acetylation in the promoter region by 2- to 3-fold within 30 min. Dopamine inhibited histone H4 acetylation by 2-fold in 30 min, an effect mimicked by the MAPK kinase (MEK1) inhibitor U0126. In contrast, the synthetic glucocorticoid dexamethasone, which inhibits prolactin transcription, failed to alter histone acetylation over the same time frame. Association of transcription activator Pit-1 with the prolactin promoter was unchanged by hormone treatment. However, in response to dopamine, histone deacetylase HDAC2 and corepressor mSin3A were rapidly recruited to the prolactin promoter, and association was sustained above basal levels over a 1-h period. Consistent with this corepressor function, depletion of endogenous mSin3A by small interfering RNA was sufficient to enhance prolactin gene expression by 70%, comparable to the induction by the HDAC inhibitor, trichostatin A. These studies demonstrate that dopamine D2 receptor activation and inhibition of MAPK (ERK1/2) signaling lead to rapid deacetylation of histones at the genomic prolactin promoter. Recruitment of specific HDAC/ corepressor complexes may be an important mechanism for repression of target gene transcription by Gi/o-coupled receptors.
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PMID:Epigenetic mechanisms in the dopamine D2 receptor-dependent inhibition of the prolactin gene. 1573 Nov 70

Estradiol-17beta (E2) and some phytoestrogens induce a biphasic effect on DNA synthesis in cultured human vascular smooth muscle cells (VSMC), i.e., stimulation at low concentrations and inhibition at high concentrations. These compounds also increase the specific activity of creatine kinase (CK) as well as intracellular Ca2+ concentration in both VSMC and human female-derived cultured bone cells (OBs), and stimulate ERK1/2 phosphorylation in VSMC. At least some of these effects are exerted via membranal binding sites (mER), as would appear from observations that protein-bound, membrane impermeant estrogenic complexes can mimic the effect of E2 on DNA synthesis, intracellular Ca2+ concentration and MAPK, but not on CK activity. We now extend these studies by examining the effects of a novel carboxy-derivative of biochanin A, 6-carboxy-biochanin A (cBA) in VSMC and human osteoblasts in culture. cBA increased DNA synthesis in VSMC in a dose-dependent manner and was able to maintain this effect when linked to a cell membrane impermeable protein. In VSMC both cBA and estradiol, in their free or protein-bound forms induced a steep and immediate rise in intracellular calcium. Both the free and protein-bound conjugates of cBA and estradiol increased net MAPK-kinase activity. Neither the stimulatory effect of cBA nor the inhibitory effect of estradiol on DNA synthesis in VSMC could be shown in the presence of the MAPK-kinase inhibitor UO126. The presence of membrane binding sites for both estradiol and cBA was supported by direct visualization, using fluorescence labeling of their respective protein conjugates, E2-BSA and cBA-ovalbumin. Furthermore, these presumed membrane ER for estradiol and cBA were co-localized. In cultured human osteoblasts, cBA stimulated CK activity in a dose related fashion, which paralleled the increase in CK induced by estradiol per se, confirming the estrogenic properties of cBA in human bone cells. Both the free and protein-bound forms of cBA elicited immediate and substantial increments in intracellular Ca2+, similar to, but usually larger than the responses elicited by estradiol per se. cBA also increased ERalpha and suppressed ERbeta mRNA expression in human osteoblasts. Cultured human osteoblasts also harbor membrane binding sites for protein-bound form of cG, which are co-localized with the binding sites for protein-bound estradiol. The extent to which these properties of the novel synthetic phytoestrogen derivatives may be utilized to avert human vascular and/or bone disease requires further study.
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PMID:Membranal effects of phytoestrogens and carboxy derivatives of phytoestrogens on human vascular and bone cells: new insights based on studies with carboxy-biochanin A. 1586 Feb 73

Physiological doses of 17-beta Estradiol (E2) rapidly induce mitogen-activated protein kinase (MAPK) phosphorylation in a variety of cell culture and tissue explant preparations. Rapid MAPK phosphorylation has been implicated as a critical step in estrogen's effects on neuronal activity, gene transcription and neuroprotection. The present series of in vivo experiments were designed to determine whether acute administration of estrogen rapidly increased extracellular signal-regulated protein kinase (ERK) 2 phosphorylation. Brains were harvested 20 min after a single i.p. injection of 15 microg/kg of 17-beta or 17-alpha estradiol. Twelve brain structures were micro-dissected, homogenized and processed for Western blotting. E2-treated rats exhibited a statistically significant increase in ERK2 phosphorylation in the diagonal band of Broca, rostral nucleus accumbens, paraventricular nucleus, arcuate nucleus and anteromedial visual cortex. Administration of the same dose of 17-alpha estradiol did not enhance ERK phosphorylation in any of the brain regions examined. The in vivo data presented here extend previously published in vitro data indicating that E2 rapidly activates MAPK in primary neuronal cultures, explants and cell lines. These data also indicate that MAPK activation is a potential mediator of estrogens effects in some but not all estrogen receptor containing regions of the brain.
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PMID:17-Beta estradiol rapidly enhances extracellular signal-regulated kinase 2 phosphorylation in the rat brain. 1589 55

Females live longer than males. Oestrogens protect females against aging by up-regulating the expression of antioxidant, longevity-related genes such as glutathione peroxidase (GPx) and Mn-superoxide dismutase (Mn-SOD). The mechanism through which oestrogens up-regulate those enzymes remains unidentified, but may have implications for gender differences in lifespan. We show that physiological concentrations of oestradiol act through oestrogen receptors to reduce peroxide levels in MCF-7 cells (a mammary gland tumour cell line). Oestradiol increases MAP kinase (MAPK) activation as indicated by ERK1 and ERK2 phosphorylation in MCF-7 cells, which in turn activates the nuclear factor kappa B (NFkappaB) signalling pathways as indicated by an increase in the p50 subunit of NFkappaB in nuclear extracts. Blockade of MAPK and NFkappaB signalling reduces the antioxidant effect of oestradiol. Finally, we show that activation of MAPK and NFkappaB by oestrogens drives the expression of the antioxidant enzymes Mn-SOD and GPx. We conclude that oestradiol sequentially activates MAPK and NFkappaB following receptor activation to up-regulate the expression of antioxidant enzymes, providing a cogent explanation for the antioxidant properties of oestrogen and its effects on longevity-related genes.
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PMID:17beta-oestradiol up-regulates longevity-related, antioxidant enzyme expression via the ERK1 and ERK2[MAPK]/NFkappaB cascade. 1592 67

Estradiol (E2) stimulates proliferation of hormone-dependent breast cancer and exerts downstream effects on growth factors and their receptors. Key among the pathways' mediating growth factor action is the MAP kinase signaling cascade and the PI-3 kinase pathway with its downstream effector mTOR. We postulated that farnesylthiosalicylic acid (FTS), a novel anti-Ras drug, could effectively inhibit hormone-dependent breast cancer because Ras activates both the MAP kinase and the PI3 kinase pathways. Wild-type MCF-7 cells and a long-term estrogen-deprived subline (LTED) were used to examine the effect of FTS on cell growth and on several biochemical parameters. FTS inhibited growth of both cell lines by reducing proliferation and inducing apoptosis. These effects correlated best with blockade of phosphorylation of PHAS-I and p70 S6 kinase, 2 downstream effectors of mTOR. We observed only minimal inhibition of Akt, an effector upstream of mTOR. Taken together, these findings demonstrate a novel effect of FTS to inhibit mTOR signaling and also suggest that mTOR has a key role in breast cancer cell proliferation. Unexpectedly, only minimal inhibition of MAP kinase occurred in response to FTS at concentrations that markedly reduced cell growth. These later data provide support for the concept that FTS exerts its effects predominantly by blocking mTOR and to a lesser effect by inhibition of MAP kinase in breast cancer cells.
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PMID:Farnesylthiosalicylic acid blocks mammalian target of rapamycin signaling in breast cancer cells. 1595 61

Breast tumors in women can adapt to endocrine deprivation therapy by developing hypersensitivity to estradiol. For this reason, aromatase inhibitors can be effective in women relapsing after treatment with tamoxifen or following oophorectomy. To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term estradiol deprivation (LTED) causes "adaptive hypersensitivity". The primary mechanisms responsible involve up-regulation of ER alpha as well as the MAP kinase, PI-3 kinase, and mTOR growth factor pathways. ER alpha is 4-10-fold up-regulated and co-opts a classical growth factor pathway using Shc, Grb2, and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. Estradiol binds to cell membrane associated ER alpha, physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb2 and Sos which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk activation and by morphologic changes in cell membranes. Additional effects include activation of PI-3 kinase and mTOR pathways through estradiol induced binding of ER alpha to the IGF-1 and EGF receptors. Further proof of the non-genomic effects of estradiol involved use of "designer" cells which selectively express ER alpha in nucleus, cytosol, and cell membrane. We have used a new downstream inhibitor of these pathways, farnesyl-thio-salicylic acid (FTS), to block proliferation in hypersensitive cells as a model for a potentially effective strategy for treatment of patients.
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PMID:Adaptive hypersensitivity to estrogen: mechanisms and clinical relevance to aromatase inhibitor therapy in breast cancer treatment. 1602 45

Estradiol (E2) and the naturally occurring polyamines (putrescine, spermidine, and spermine) play important roles in breast cancer cell growth and differentiation. We examined the effects of E2 and spermine on the phosphorylation and DNA binding of activating transcription factor-2 (ATF-2) in MCF-7 breast cancer cells. ATF-2 is a transcription factor involved in estrogenic regulation of cyclin D1 gene, and thereby cell cycle progression. DNA affinity immunoblot assays showed a six- to eightfold increase in the binding of ATF-2 to a 74-mer ATF/CRE oligonucleotide (ODN1) from cyclin D1 promoter in the presence of 4 nM E2 and 0.5 mM spermine, compared to untreated control. Individual treatments with E2 or spermine caused a twofold or lower increase in ATF-2 binding to ODN1. Immunoblotting with phospho-ATF-2 antibody showed that increased DNA binding of ATF-2 was associated with its phosphorylation. A p38 MAP kinase inhibitor, PD169316, inhibited ATF-2 phosphorylation. In contrast, the MEK-ERK1/2 inhibitor, PD98059, or the JNK inhibitor, SP600125, had no significant effect on DNA binding of ATF-2. Cyclin D1 promoter (-1745CD1) activity increased by approximately 12-fold (above control) in the presence of E2 and spermine, compared to a sixfold increase in the presence of E2 alone and a twofold increase with spermine. Cells transfected with a dominant negative mutant of ATF-2 showed decreased transactivation of cyclin D1 promoter in response to E2 and spermine. These results indicate that spermine can enhance E2-induced cell signaling and cyclin D1 transcription by activation of the p38 MAP kinase and phosphorylation of ATF-2, contributing to breast cancer cell proliferation.
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PMID:Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: a mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. 1605 Jan 33


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