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)

Estrogen affects proliferation and migration of different skin components, thus influencing wound healing processes. The human keratinocyte cell line NCTC 2544 has been used to examine the effects of estrogen, dissect its mechanism of action and characterize receptor subtypes involved. Western blot and immunocytochemical analyses confirmed the expression of estrogen receptors (ERs) alpha and beta, with prevalence in the nuclear and extranuclear compartment, for ER alpha and ER beta respectively. Treatment with 10 nM 17beta-estradiol (17beta-E(2)) and the ER alpha and ER beta selective agonists, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT; 100 nM), and diarylpropionitrile (DPN; 1 nM) produced a slight but significant increase in cell proliferation, as by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and bromodeoxyuridine incorporation assays, only after a long-term treatment (96 h). Analysis of cell migration by a scratch wound assay showed that 17beta-E(2) (10 nM) accelerated migration between 5 and 24 h after scratching, an effect confirmed by the transwell migration assay. PPT and DPN elicited similar effects. Pre-treatment with the mitogen-activated protein kinase inhibitor, U0126 (1 microM), abolished the ability of 17beta-E(2) and DPN, but not of PPT, to accelerate wound closure. TGF-beta1 (10 ng/ml) produced a similar positive effect on wound closure and the TGF-beta1 receptor antagonist, SB431542 (10 microM), reduced the ability of 17beta-E(2) and PPT to accelerate cell migration, but did not modify DPN effect. It is suggested that estrogen positively affects in vitro wound healing by stimulating cell proliferation after long-term exposure but mainly by accelerating cell migration within a few hours from treatment. Selective activation of ER beta may result in favorable stimulation of wound healing without any increase of transforming growth factor-beta1 production.
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PMID:Differential involvement of estrogen receptor alpha and estrogen receptor beta in the healing promoting effect of estrogen in human keratinocytes. 1900 31

Heat shock protein 90 (HSP90) is a ubiquitously expressed chaperone that is involved in the posttranslational folding and stability of proteins. Inhibition at the NH(2)-terminal ATP-binding site leads to the degradation of client proteins by the ubiquitin proteasome pathway. Inhibition of HSP90 leads to the degradation of known oncogenes, such as ERB-B2, BRAF, and BCR-ABL, leading to the combinatorial blockade of multiple signal transduction pathways, such as the RAS-RAF-mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase and phosphatidylinositol 3-kinase pathways. Multiple structurally diverse HSP90 inhibitors are undergoing early clinical evaluation. The clinical focus of these drugs should be solid tumors, such as breast, prostate, and lung cancers, along with malignant melanoma, in addition to hematologic malignancies, such as chronic myeloid leukemia and multiple myeloma. HSP90 inhibitors can be used as single agents or in combination with other targeted treatments or conventional forms of treatment such as chemotherapy and radiotherapy. Clinical trials evaluating efficacy of these agents should include innovative designs to capture cytostasis evidenced by clinical nonprogression and enrichment of patient populations by molecular characterization. The results of clinical trials evaluating the efficacy of drugs targeting this exciting target are awaited.
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PMID:Heat shock protein 90 as a drug target: some like it hot. 1911 27

Females have a lower incidence of heart failure and improved survival after myocardial ischemia-reperfusion (I/R) compared with males. Although estrogen-suppressed cardiomyocyte apoptosis may be mediated through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, it is unclear whether this action is mediated via estrogen receptor beta (ERbeta). Therefore, we hypothesized that ERbeta mediates estrogen-induced cardioprotection through PI3K/Akt and antiapoptotic signaling in females but not in males. Isolated male and female hearts from ERbeta knockout (ERbetaKO) and wild-type (WT) mice (n = 5 mice/group) were subjected to 20-min ischemia followed by 60-min reperfusion (Langendorff). Ablation of ERbeta significantly decreased postischemic recovery of left ventricular developed pressure in female, but not male, hearts. Reduced activation of PI3K and Akt was noted in female ERbetaKO hearts, which was associated with increased expression of caspase-3 and -8, as well as decreased Bcl-2 levels compared with WT. However, myocardial STAT3, SOCS3 (suppressor of cytokine signaling 3), VEGF, and TNF receptors 1 and 2 levels did not change in ERbetaKO of either sex following I/R. Furthermore, deficiency of ERbeta increased myocardial JNK activation in females but increased ERK1/2 activity in males during acute I/R. We conclude that ERbeta mediates myocardial protection via upregulation of PI3K/Akt activation, decreased caspase-3 and -8, and increased Bcl-2 in female hearts following I/R. These findings provide evidence of ERbeta-mediated PI3K/Akt and antiapoptotic signaling in the myocardium and may lend insight into the mechanistic pathways behind the observed variation in clinical outcomes between males and females after myocardial infarction.
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PMID:Estrogen receptor beta mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia. 1921 25

Most types of prostate cancer (PCa) are usually initially responsive to androgenic regulation and, therefore, to androgen ablation therapy. However, in several patients tumors may progress to androgen resistance and be poorly responsive to any therapy. Many factors may account for this progression to androgen independence, including increased responsiveness to estrogens and peptide growth factors. The role of estrogens in androgen independence has been suggested by the observation that both primary and metastatic PCa express the estrogen receptor (ER-beta), a recently discovered ER subtype. On the other hand, peptide growth factors, like IGF-1, IGF-2, and the insulin-like growth factor receptor (IGF-1R), may play a role in regulating growth, survival, and invasion of PCa cells. Here, we show that both androgens and estrogens markedly upregulate the IGF-1R expression in PCa cells by activating a nongenotropic pathway and sensitizing cells to the biological effects of IGF-1. This effect is specific for IGF-1R because it does not involve the highly homologous insulin receptor. IGF-1R upregulation is caused by increased mRNA transcription. However, it does not require steroid receptor binding to DNA, but involves AR and ER binding to c-Src and subsequent activation of ERK1/2 and other cytoplasmatic kinases, which eventually stimulate IGF-1R promoter activity. In conclusion, our data indicate that both androgens and estrogens contribute to IGF system deregulation in PCa and may play a role in tumor progression to androgen independence. Inhibition of the IGF-1R or the Src-ERK pathway should be considered, therefore, as an adjuvant therapy in PCa.
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PMID:Sex steroids upregulate the IGF-1R in prostate cancer cells through a nongenotropic pathway. 1925 Feb 14

Women in the reproductive age are more vulnerable to develop affective disorders than men. This difference may attribute to anatomical differences, hormonal influences and environmental factors such as stress. However, the higher prevalence in women normalizes once menopause is established, suggesting that ovarian hormones may play an important role in the development of depression in women. Ovarian hormones such as estrogen can pass the brain-blood barrier and bind to cytoplasmatic estrogen receptor (ER)-alpha and ER-beta in different areas of the limbic system. During stress, estrogen can modulate the behavioral and neurobiological response depending on the concentrations of estrogen. In this review we present evidence for disparate effects of chronic stress on neuroplasticity and brain activity in male and female rats. Furthermore, we will demonstrate that effects of social support on coping with stress can be mimicked by social housing of rats and that this model can be used for identification of underlying neurobiological mechanisms, including behavior, phosphorylation of CREB and ERK1/2, and brain activity changes as measured with fos expression. Using cyclic administration of estrogen in ovariectomized female rats we could specifically address effects of different plasma estrogen levels and antidepressants on stress-induced neuroplasticity and activity changes. In this model we also studied effects of estrogen on recovery after chronic stress. We conclude that the female brain has a different innate strategy to handle stress than the male brain and that female animal models are necessary for studying the underlying mechanisms and options for treatment.
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PMID:Sex differences in stress responses: focus on ovarian hormones. 1927 10

Estrogens have been associated with risk for epithelial ovarian cancer (OVCA). Both IL-6 and IL-8 are also likely involved in the progression of OVCA. In order to discover the underline molecular mechanism, we investigated the modulation of estrogen and two cytokines in the growth and progression of epithelial OVCA. In these studies, the effect of 17beta-estradiol (E(2)) on the expression levels of IL-6, IL-8 and their receptors was investigated. The effect of IL-6 and IL-8 on activation of estrogen-responsive promoter as well as estrogen receptor (ER)alpha and ER beta expression was also analyzed. Gene expression profile analysis revealed that CAOV-3 and OVCAR-3 cells, which express ER, IL-6 and IL-8 receptors, are suitable model for this study. We found that E(2) not only enhanced IL-6 and IL-8 production via NF-kappaB signaling pathway, but also modulated their respective receptor expression. Tamoxifen (Txf), an ER antagonist, completely abolished E(2)-stimulated cell growth and the expression of IL-6 and IL-8. IL-6/IL-8-induced cell proliferation was completely blocked by their specific neutralizing antibodies, which partially inhibited E(2)-induced cell growth. In the absence of estrogen, both cytokines activated estrogen-responsive promoter, which was completely blocked by Txf, and caused a dose-dependent ER alpha increase and ER beta decrease. Pretreatment of OVCAR-3 with p38 MAPK, MEK1/2 or ErbB2 MAPK inhibitors, respectively, blocked IL-6-mediated induction of estrogen-responsive promoter while Src inhibitor blocked IL-8-induced activation of estrogen-responsive promoter. These results provide a novel mechanism that estrogens, IL-6 and IL-8 may form a common amplifying signaling cascade to modulate OVCA growth and progression. Estrogen-induced OVCA proliferation is partially occurring via enhanced IL-6 and IL-8 production and modulated their receptors, and IL-6/IL-8 could also promote OVCA growth through an ER alpha pathway.
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PMID:Reciprocal regulation of 17beta-estradiol, interleukin-6 and interleukin-8 during growth and progression of epithelial ovarian cancer. 1940 Dec 70

In non-small cell lung cancer (NSCLC) cells, 17beta-estradiol increases transcription, activates MAPK, and stimulates proliferation. We hypothesize that estrogen receptor beta (ERbeta) mediates these responses because it, but not ERalpha, is detected in our NSCLC cell lines. To test this, we determined the effects of the ERbeta-selective agonists genistein (GEN) and 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) and the ERalpha-selective agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) in 201T cells. The cells were transfected with either an ERalpha or an ERbeta expression vector and an estrogen response element (ERE)-tk-luciferase reporter construct. PPT increased luciferase activity in cells expressing ERalpha but not ERbeta. GEN and DPN selectively increased luciferase activity in ERbeta-transfected cells at concentrations < or =10 nM. Fulvestrant blocked the GEN- and DPN-mediated increases, indicating that transcription was ER-dependent. GEN but not PPT mediated a significant 1.5-fold increase in reporter activity upon transfection with ERE-tk-luciferase alone, demonstrating that endogenous ERbeta activates transcription. PPT and DPN increased MAPK phosphorylation (2.5-fold and 3.7-fold, respectively). However, only DPN stimulated 201T growth in vitro (p=0.008) and in vivo (p=0.05). We conclude that ERbeta mediates genomic and non-genomic responses to estrogen in 201T cells and that activation of both pathways may be necessary for increased proliferation of these cells.
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PMID:Estrogen receptor beta (ERbeta) subtype-specific ligands increase transcription, p44/p42 mitogen activated protein kinase (MAPK) activation and growth in human non-small cell lung cancer cells. 1946 Apr 33

The role of estrogens in the increased risk of lung adenocarcinoma in women remains uncertain. We reported that lung adenocarcinoma cell lines from female, but not male, patients with non-small cell lung cancer respond proliferatively and transcriptionally to estradiol (E(2)), despite equal protein expression of estrogen receptors (ER) alpha and beta. To test the hypothesis that nuclear localization of ER alpha corresponds to genomic E(2) activity in lung adenocarcinoma cells from females, cell fractionation, immunoblot, and confocal immunohistochemical microscopy were performed. We report for the first time that E(2) increases phospho-serine-118-ER alpha (P-ser118-ER alpha) and cyclin D1 (CCND1) nuclear colocalization in H1793, but not A549 lung adenocarcinoma cells, derived from a female and male patient, respectively. ER beta was primarily in the cytoplasm and mitochondria, independent of E(2) treatment, and showed no difference between H1793 and A549 cells. E(2) induced higher transcription of endogenous ER alpha-regulated CCND1 in H1793 than in A549 cells. Likewise, higher rapid, non-genomic E(2)-induced extracellular signal-regulated kinase 1/2 activation was detected in H1793 compared with A549 cells, linking extracellular signal-regulated kinase activation to increased P-ser118-ER alpha. Furthermore, E(2) increased cyclin D1 and P-ser118-ER alpha nuclear localization in H1793, but not A549 cells. Together, our results indicate that nuclear localization of P-ser118-ER alpha provides one explanation for sex-dependent differences in E(2)-genomic responses in lung adenocarcinoma cell lines.
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PMID:Sex differences in estrogen receptor subcellular location and activity in lung adenocarcinoma cells. 1955 4

Estrogen modulates synaptic plasticity, an important mechanism of memory storage. Previously, we have reported that estrogen rapidly increases the expression of Arc (activity-regulated cytoskeleton associated protein), a key protein for synaptic plasticity, via non-genomic phosphoinositide-3 kinase (PI-3K)-, mitogen-activated protein kinase (MAPK)-, and estrogen receptor (ER)-dependent pathways in SH-SY5Y cells. The present study aimed to investigate the role of each ER subtype, alpha and beta, in synaptic plasticity in SH-SY5Y cells. The specific agonist of ER beta (DPN) markedly induced Arc expression that mimics treatment with estrogen, but not ER alpha (PTT). Determination of subcellular localization of ER beta using immunocytochemistry shows that ER beta was retained in the cytoplasm of the untreated cells. In estrogen-treated cells, the membrane and cytosolic ER beta gradually decreased, while nuclear ER beta progressively increased in time-dependent manner, suggesting estrogen-dependent nuclear translocation of ER beta. Nuclear accumulation of ER beta at 6-12h post-estrogen treatment, leads to increased PSD-95 and SYP mRNA expression, indicating the classical genomic estrogenic action on synaptic plasticity. However, the block of PI-3K signaling by Wortmannin partially suppressed estrogen (48 h)-induced PSD-95 and SYP expression, suggesting a crosstalk mechanism between genomic and non-genomic actions of estrogen on synaptic plasticity. Therefore, the estrogen-enhanced synaptic plasticity is ER beta-dependent and involves the crosstalk mechanism of non-genomic and genomic estrogenic actions.
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PMID:Genomic and non-genomic actions of estrogen on synaptic plasticity in SH-SY5Y cells. 2003 14

Aim of the present study was to investigate whether estrogens were able to directly activate rapid signaling pathways controlling spermatogenesis in rat pachytene spermatocytes (PS). Classically, estrogens act by binding to estrogen receptors (ERs) alpha and beta. Recently, it has been demonstrated that rapid estrogen action can also be activated through the G-protein-coupled receptor (GPR)-30. Herein, we demonstrated that rat PS express ER alpha, ER beta and GPR30. Treatment of PS with estradiol (E2), the selective GPR30 agonist G1 and the selective ER alpha agonist PPT determined activation of ERK1/2 which are part of GPR30 signaling cascade. ERK1/2 activation in response to E2 and G1 was correlated to an increased phosphorylation of c-Jun. All treatments failed to induce these responses in the presence of EGFR inhibitor AG1478, ERK inhibitor PD98059 and ER inhibitor ICI182780. mRNA expression of cell cycle regulators cyclin A1 and B1 was downregulated by E2 and G1 while an up-regulation of proapoptotic factor Bax was observed in the same conditions. These data demonstrate that E2, working through both ER alpha and/or GPR30, activates in PS the rapid EGFR/ERK/c-Jun pathway, modulating the expression of genes involved in the balance between cellular proliferation and apoptosis.
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PMID:17 beta-estradiol activates rapid signaling pathways involved in rat pachytene spermatocytes apoptosis through GPR30 and ER alpha. 2013 63


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