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)

Mitogen-activated protein kinase (MAP kinase) cascades transmit and amplify signals involved in cell proliferation as well as cell death. These signal transduction pathways serve as an indicators of the intensity of trafficking induced by various growth factor, steroid hormone, and G protein receptor mediated ligands. Three major MAP kinase pathways exist in human tissues, but the one involving ERK-1 and -2 is most relevant to breast cancer. Peptide growth factors acting through tyrosine kinase containing receptors are the major regulators of ERK-1 and -2. Estradiol, progesterone, and testosterone can act non-genomically via membrane associated receptors to activate MAP kinase as can various other ligands acting through heterotrimeric G protein receptors. Recent studies demonstrate that breast cancers frequently contain an increased proportion of cells with the activated form of MAP kinase. In estrogen receptor positive breast tumors, MAP kinase pathways can exert "cross talk" effects at the level of ER induced transcription as well as at the level of the cell cycle. Estradiol stimulates cell proliferation by mechanisms which involve activation of MAP kinase, either through rapid, non-transcription effects or by increasing growth factor production and consequently MAP kinase. Progesterone and androgens also stimulate MAP kinase through both of these two mechanisms. Strategies used to treat hormone dependent breast cancer appear to result in upregulation of MAP kinase activation. Direct experimental data demonstrate that the pressure of estradiol deprivation results in the upregulation of MAP kinase in breast cancer cells growing in tissue culture and as xenografts. A number of investigators have now studied the expression of activated MAP kinase in human breast cancer tissues by enzymatic assay and by immunohistochemical techniques. Approximately half of breast tumors express more activated MAP kinase than does the surrounding benign tissue. Studies show a trend toward higher MAP kinase activity in primary tumors of node positive than in node negative patients. However, larger numbers of patients must be studied for these results to achieve statistical significance. The up-regulation of MAP kinase activity does not represent mutations of Ras, but appears to result from enhancement of growth factor pathway activation. No data are yet available on the relationship between MAP kinase activation and apoptosis. Additional studies are now needed to determine the precise relationship between MAP kinase activation and tumor proliferation, apoptosis, and degree of invasiveness as well as on disease free and overall survival.
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PMID:The role of mitogen-activated protein (MAP) kinase in breast cancer. 1189 7

Gender-related differences in the unstimulated and estrogen-induced activation of the mitogen-activated protein kinases (MAPKs) ERK1 and ERK2, cell proliferation, and cell death were examined using rat cortical astrocytes in culture. Females have higher unstimulated levels of phosphorylated ERK1 and ERK2 than males. 17beta-Estradiol (E(2)) decreases activation of ERK1 and ERK2, with females showing a greater response than males. Further, E(2) results in more inhibition of DNA synthesis and greater increase in cell death in females than in males. The inhibitory effects of E(2) on DNA synthesis are mimicked and enhanced by a specific MAPK kinase (MEK) inhibitor, PD98059. Finally, the inhibitory effects of E(2) are blocked by the estrogen receptor antagonist tamoxifen in astrocytes from females but not males, with ER-alpha (estrogen receptor alpha) present in the former but not the latter. Taken together, these results suggest that the sex differences in unstimulated and estrogen-modulated activation of MAPKs may result in differential regulation of cell proliferation and death in astrocytes and possibly contribute to sexual dimorphisms in brain development.
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PMID:Sex-related differences in MAPKs activation in rat astrocytes: effects of estrogen on cell death. 1210 87

Estradiol and insulin-like growth factor-I (IGF-I) interact in the hypothalamus to regulate neuronal function, synaptic plasticity and neuroendocrine events. However, the molecular mechanisms involved in these interactions are still unknown. In the present study, the effect of estradiol on the signaling pathways of IGF-I receptor has been assessed in the hypothalamus of young adult ovariectomized rats, using specific antibodies for the phosphorylated forms of extracellular-signal regulated kinase (ERK) 1 and ERK2 and Akt/protein kinase B (Akt/PKB). Estradiol treatment resulted, between 6 and 24 h after systemic administration, in dose-dependent effects on the phosphorylation of ERK and Akt/PKB. Estradiol did not modify the level of ERK phosphorylation induced by intracerebroventricular administration of IGF-I. However, both hormones had a synergistic effect on the phosphorylation of Akt/PKB. These findings suggest that estrogen effects in the hypothalamus may be mediated in part by the activation of the signaling pathways of the IGF-I receptor.
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PMID:Synergistic interaction of estradiol and insulin-like growth factor-I in the activation of PI3K/Akt signaling in the adult rat hypothalamus. 1241 26

Estradiol (E2) rapidly stimulates signal transduction from plasma membrane estrogen receptors (ER) that are G protein-coupled. This is reported to occur through the transactivation of the epidermal growth factor receptor (EGFR) or insulin-like growth factor-1 receptor, similar to other G protein-coupled receptors. Here, we define the signaling events that result in EGFR and ERK activation. E2-stimulated ERK required ER in breast cancer and endothelial cells and was substantially prevented by expression of a dominant negative EGFR or by tyrphostin AG1478, a specific inhibitor for EGFR tyrosine kinase activity. Transactivation/phosphorylation of EGFR by E2 was dependent on the rapid liberation of heparin-binding EGF (HB-EGF) from cultured MCF-7 cells and was blocked by antibodies to this ligand for EGFR. Expression of dominant negative mini-genes for Galpha(q) and Galpha(i) blocked E2-induced, EGFR-dependent ERK activation, and Gbetagamma also contributed. G protein activation led to activation of matrix metalloproteinases (MMP)-2 and -9. This resulted from Src-induced MMP activation, implicated using PP2 (Src family kinase inhibitor) or the expression of a dominant negative Src protein. Antisense oligonucleotides to MMP-2 and MMP-9 or ICI 182780 (ER antagonist) each prevented E2-induced HB-EGF liberation and ERK activation. E2 also induced AKT up-regulation in MCF-7 cells and p38beta MAP kinase activity in endothelial cells, blocked by an MMP inhibitor, GM6001, and tyrphostin AG1478. Targeting of only the E domain of ERalpha to the plasma membrane resulted in MMP activation and EGFR transactivation. Thus, specific G proteins mediate the ability of E2 to activate MMP-2 and MMP-9 via Src. This leads to HB-EGF transactivation of EGFR and signaling to multiple kinase cascades in several target cells for E2. The E domain is sufficient to enact these events, defining additional details of the important cross-talk between membrane ER and EGFR in breast cancer.
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PMID:Proximal events in signaling by plasma membrane estrogen receptors. 1242 25

We examined the hypothesis whether rapid non-genomic effects of oestradiol (E2) on [Ca(2+)](i) are mediated via a membrane-located oestrogen receptor (ER) and further elucidated the signalling pathways involved in rapid non-genomic effects of E2 on [Ca(2+)](i) in distal colonic crypts. Basal [Ca(2+)](i) was significantly increased, within minutes, in response to physiological concentrations of E2. Oestradiol linked to bovine serum albumin (E2-BSA), which renders the E2 membrane impermeable, rapidly increased [Ca(2+)](i) suggesting mediation by a membrane surface receptor. A classical ER is not involved however, as no inhibition of either the E2 or E2-BSA [Ca(2+)](i) response was seen in the presence of the classical ER antagonist ICI 182,780. Treatment with the Galphas inhibitor cholera toxin abolished both E2 and E2-BSA induced Ca(2+) increases. In contrast, treatment with pertussis toxin, an inhibitor of Galphai and Galphao, had no inhibitory effect. Following subsequent additions of E2 and E2-BSA, no further increases in [Ca(2+)](i) were observed, indicating receptor desensitisation. The E2-induced increase in [Ca(2+)](i) was completely abolished by the PKCdelta-specific inhibitor rottlerin, whereas Go6976, an inhibitor of Ca(2+)-sensitive PKC isoforms, was without inhibitory effect. The phospholipase A2 antagonist, quinacrine, and the COX1 inhibitor, indomethacin, abolished the E2-induced increase in [Ca(2+)](i). MAP kinase activation is not involved in rapid stimulatory effects of E2 on [Ca(2+)](i) as the specific inhibitor PD98059 did not inhibit the E2 response. These results demonstrate that rapid E2-induced stimulation of [Ca(2+)](i), in femal rat distal colonic crypts, occurs via a CTx-sensitive Galphas-coupled membrane receptor distinct from the classical ER. PKCdelta and fatty acids are involved in the E2 signalling pathway. In contrast, PKCalpha and MAP kinase are not required.
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PMID:A Galphas protein-coupled membrane receptor, distinct from the classical oestrogen receptor, transduces rapid effects of oestradiol on [Ca2+]i in female rat distal colon. 1258 82

In the brain, as in other tissues, estradiol interacts with growth factors. One of the growth factors that is involved in the neural actions of estradiol is insulin-like growth factor-I (IGF-I). Estradiol and IGF-I cooperate in the central nervous system to regulate neuronal development, neural plasticity, neuroendocrine events and the response of neural tissue to injury. The precise molecular mechanisms involved in these interactions are still not well understood. In the central nervous system there is abundant co-expression of estrogen receptors (ERs) and IGF-I receptors (IGF-IRs) in the same cells. Furthermore, the expression of estrogen receptors and IGF-I receptors in the brain is cross-regulated. In addition, using specific antibodies for the phosphorylated forms of extracellular-signal regulated kinase (ERK) 1 and ERK2 and Akt/protein kinase B (Akt/PKB) it has been shown that estradiol affects IGF-I signaling pathways in the brain. Estradiol treatment results in a dose-dependent increase in the phosphorylation of ERK and Akt/PKB in the brain of adult ovariectomized rats. In addition, estradiol and IGF-I have a synergistic effects on the activation of Akt/PKB in the adult rat brain. These findings suggest that estrogen effects in the brain may be mediated in part by the activation of the signaling pathways of the IGF-I receptor.
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PMID:Interactions of estrogen and insulin-like growth factor-I in the brain: molecular mechanisms and functional implications. 1265 Jul 18

We reported previously in HepG2 cells that estradiol induces cell cycle progression throughout the G1-S transition by the parallel stimulation of both PKC-alpha and ERK signaling molecules. The analysis of the cyclin D1 gene expression showed that only the MAP kinase pathway was involved. Here, the presence of rapid/nongenomic, estradiol-regulated, PI3K/AKT signal transduction pathway, its modulation by the levels of the tumor suppressor PTEN, its cross-talk with the ERK pathway, and its involvement in DNA synthesis and cyclin D1 gene promoter activity have all been studied in HepG2 cells. 17beta-Estradiol induced the rapid and biphasic phosphorylation of AKT. These phosphorylations were independent of each other, being the first wave of activation independent of the estrogen receptor (ER), whereas the second was dependent on ER. Both activations were dependent on PI3K activity; furthermore, the ERK pathway modulated AKT phosphorylation by acting on the PTEN levels. The results showed that the PI3K pathway, as well as ER, were strongly involved in both G1-S progression and cyclin D1 promoter activity by acting on its proximal region (-254 base pairs). These data indicate that in HepG2 cells, different rapid/nongenomic estradiol-induced signal transduction pathways modulate the multiple steps of G1-S phase transition.
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PMID:Biphasic estradiol-induced AKT phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells. 1280 53

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

Epilepsy is the most common neurologic disorder in young humans. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects by unknown mechanisms. We tested whether common AEDs cause neurodegeneration in the developing rat brain. Rats aged 3-30 days received phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, or valproic acid. Histologic examination of the brains revealed that these drugs cause widespread and dose-dependent apoptotic neurodegeneration in the developing rat brain during the brain growth spurt period. Apoptotic neurodegeneration was triggered at plasma drug levels relevant for seizure control in humans. Antiepileptic drugs lead to reduced expression of neurotrophins and decreased concentrations of the active forms of ERK1/2, RAF, and AKT. beta-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorated AEDs-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with pre- or postnatal exposure of humans to antiepileptic therapy.
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PMID:Antiepileptic drugs and apoptosis in the developing brain. 1285 1

The cyclin-dependent kinase (CDK) inhibitor p27Kip1 plays a key role in growth and development of the mammary epithelium and in breast cancer. p27Kip1 levels are regulated through ubiquitin/proteasome-mediated proteolysis, promoted by CDK2 and the F box protein Skp2 at the G1/S transition, and independent of Skp2 in mid-G1. We investigated the respective roles of Skp2 and subcellular localization of p27Kip1 in down-regulation of p27Kip1 induced in MCF-7 cells by estrogens. 17beta-Estradiol treatment increased Skp2 expression in MCF-7 cells; however, this increase was prevented by G1 blockade mediated by p16Ink4a or the CDK inhibitor roscovitine, whereas down-regulation of p27Kip1 was maintained. Exogenous Skp2 prevented growth arrest of MCF-7 cells by antiestrogen, coinciding with decreased p27Kip1 expression. Under conditions of G1 blockade, p27Kip1 was stabilized by inhibition of CRM1-dependent nuclear export with leptomycin B or by mutation of p27Kip1 (Ser10 --> Ala; S10A) interfering with CRM1/p27Kip1 interaction. Antisense Skp2 oligonucleotides and a dominant-interfering Cul-1(1-452) mutant prevented down-regulation of p27Kip1S10A, whereas Skp2 overexpression elicited its destruction in mitogen-deprived cells. Active mediators of the extracellular signal-regulated kinase (ERK) pathway including Raf-1caax induced cytoplasmic localization of p27Kip1 in antiestrogen-treated cells and prevented accumulation of p27Kip1 in these cells independent of Skp2 expression and coinciding with ERK activation. Genetic or chemical blockade of the ERK pathway prevented down-regulation and cytoplasmic localization of p27Kip1 in response to estrogen. Our studies indicate that estrogens elicit down-regulation of p27Kip1 in MCF-7 cells through Skp2-dependent and -independent mechanisms that depend upon subcellular localization of p27Kip1 and require the participation of mediators of the Ras/Raf-1/ERK signaling pathway.
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PMID:Estrogens down-regulate p27Kip1 in breast cancer cells through Skp2 and through nuclear export mediated by the ERK pathway. 1290 6


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