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)

This is the first report on estrogen-dependent growth of human-derived colon carcinoma cells. Under selected conditions, growth of subconfluent Caco-2 cells is triggered by estradiol. Cell growth is estradiol concentration dependent, with maximal effect occurring at about 0.4 nM. Growth is prevented by two different antiestrogens: the partial agonist, OH-Tamoxifen, and the pore antagonist, ICI 182,780. The growth effect is specific for estradiol since other hormonal steroids tested do not affect cell growth. The amount of estradiol receptor in subconfluent Caco-2 cells, detected by blot with monoclonal antibodies directed against the receptor as well as estradiol binding assays, is similar to that of the classical estradiol-responsive, human mammary cancer-derived MCF-7 cells. Estradiol treatment of subconfluent Caco-2 cells rapidly and reversibly stimulates four important intermediates in a signal transduction pathway that is known to trigger cell proliferation: two members of the large family of c-src-related tyrosine kinases, c-src and c-yes, and two serine/threonine kinases, the mitogen-activated protein (MAP) kinases, erk-1 and erk-2. Tyrosine kinases activated by estradiol are up-stream MAP kinases and Caco-2 cell proliferation. In fact, genistein, a specific tyrosine kinase inhibitor, abolishes the estradiol stimulatory effect on both erk-2 activity and cell proliferation. Our findings show that in subconfluent Caco-2 cells, the estradiol-receptor complex activates the c-src, c-yes/MAP kinase pathway and activates growth. This could have important implications for the understanding of human intestinal carcinogenesis.
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PMID:Estradiol activation of human colon carcinoma-derived Caco-2 cell growth. 881 50

We have shown that estrogen elicits a selective enhancement of the growth and differentiation of axons and dendrites (neurites) in the developing CNS. We subsequently demonstrated widespread colocalization of estrogen and neurotrophin receptors (trk) within developing forebrain neurons and reciprocal transcriptional regulation of these receptors by their ligands. Using organotypic explants of the cerebral cortex, we tested the hypothesis that estrogen/neurotrophin receptor coexpression also may result in convergence or cross-coupling of their signaling pathways. Estradiol elicited rapid (within 5-15 min) tyrosine phosphorylation/activation of the mitogen-activated protein (MAP) kinases, ERK1 and ERK2, that persisted for at least 2 hr. This extracellular signal-regulated protein kinase (ERK) activation was inhibited successfully by the MEK1 inhibitor PD98059, but not by the estrogen receptor (ER) antagonist ICI 182,780, and did not appear to result from estradiol-induced activation of trk. Furthermore, we also found that estradiol elicited an increase in B-Raf kinase activity. The latter and subsequent downstream events leading to ERK activation may be a consequence of our documentation of a multimeric complex consisting of, at least, the ER, hsp90, and B-Raf. These novel findings provide an alternative mechanism for some of the estrogen actions in the developing CNS and 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.
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PMID:Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. 995 96

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

The protein synthesis inhibitor anisomycin activates stress-related mitogen-activated protein kinases (MAPKs), namely, c-jun NH(2)-terminal kinase (p46/54(JNK)) and p38(MAPK) in mammalian cells. In this paper, we show that although exposure to anisomycin resulted in rapid and strong activation of p46/54(JNK) and p38(MAPK), with a delayed low level dual-phosphorylation of mitogen/extracellular protein kinase (p42/44(MAPK)), low density lipoprotein (LDL) receptor induction depends solely on the mild activation of p42/44(MAPK) signaling cascade in HepG2 cells. Unlike hepatocyte growth factor (HGF) which caused LDL receptor induction via rapid, strong, and Ras-dependent p42/44(MAPK) activation, anisomycin-induced p42/44(MAPK) activity and increased LDL receptor expression in a Ras-independent manner. Finally, we examined the role of the p42/44(MAPK) signaling cascade in LDL receptor induction by activating this kinase independently of anisomycin or HGF. By using estrogen-dependent human Raf-1 protein kinase in transient transfection assays, we show that the exclusive activation of the Raf-1/MEK-1/p42/44(MAPK) signaling cascade with antiestrogen ICI 182, 780 caused induction of LDL receptor expression to the same level as observed with either HGF or anisomycin. Consistent with the role of p42/44(MAPK), induction was strongly inhibited by pretreatment with the MEK-1/2 inhibitor PD98059. Our observation that anisomycin can use p42/44(MAPK) signaling cascade is a departure from established thinking, and the results presented shows that activation of the p42/44(MAPK) alone is sufficient to fully induce LDL receptor transcription.
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PMID:Critical role of p42/44(MAPK) activation in anisomycin and hepatocyte growth factor-induced LDL receptor expression: activation of Raf-1/Mek-1/p42/44(MAPK) cascade alone is sufficient to induce LDL receptor expression. 1050 11

We have shown previously in the developing cerebral cortex that estrogen elicits the rapid and sustained activation of multiple signaling proteins within the mitogen-activated protein (MAP) kinase cascade, including B-Raf and extracellular signal-regulated kinase (ERK). Using estrogen receptor (ER)-alpha gene-disrupted (ERKO) mice, we addressed the role of ER-alpha in mediating this action of estrogen in the brain. 17beta-Estradiol increased B-Raf activity and MEK (MAP kinase/ERK kinase)-dependent ERK phosphorylation in cerebral cortical explants derived from both ERKO and their wild-type littermates. The ERK response was stronger in ERKO-derived cultures but, unlike that of wild-type cultures, was not blocked by the estrogen receptor antagonist ICI 182,780. Surprisingly, both the ER-alpha selective ligand 16alpha-iodo-17beta-estradiol and the ER-beta selective ligand genistein failed to elicit ERK phosphorylation, suggesting that a different mechanism or receptor may mediate estrogen-induced ERK phosphorylation in the cerebral cortex. Interestingly, the transcriptionally inactive stereoisomer 17alpha-estradiol did elicit a strong induction of ERK phosphorylation, which, together with the inability of the ER-alpha- and ER-beta-selective ligands to elicit ERK phosphorylation, and of ICI 182,780 to block the actions of estradiol in ERKO cultures, supports the hypothesis that a novel, estradiol-sensitive and ICI-insensitive estrogen receptor may mediate 17beta-estradiol-induced activation of ERK in the brain.
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PMID:Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-alpha knock-out mice. 1068 71

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

Thyroid tumors are about 3 times more frequent in females than in males. Epidemiological studies suggest that the use of estrogens may contribute to the pathogenesis of thyroid tumors. In a very recent study a direct growth stimulatory effect of 17beta-estradiol was demonstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors alpha and beta in thyroid cells derived from human goiter nodules and in human thyroid carcinoma cell line HTC-TSHr was demonstrated. There was no difference between the expression levels of estrogen receptor alpha in males and females, but there was a significant increase in expression levels in response to 17beta-estradiol. Stimulation of benign and malignant thyroid cells with 17beta-estradiol resulted in an increased proliferation rate and an enhanced expression of cyclin D1 protein, which plays a key role in the regulation of G(1)/S transition in the cell cycle. In malignant tumor cells maximal cyclin D1 expression was observed after 3 h, whereas in benign cells the effect of 17beta-estradiol was delayed. ICI 182780, a pure estrogen antagonist, prevented the effects of 17beta-estradiol. In addition, 17beta-estradiol was found to modulate activation of mitogen-activated protein (MAP) kinase, whose activity is mainly regulated by growth factors in thyroid carcinoma cells. In response to 17beta-estradiol, both MAP kinase isozymes, extracellular signal-regulated protein kinases 1 and 2, were strongly phosphorylated in benign and malignant thyroid cells. Treatment of the cells with 17beta-estradiol and MAP kinase kinase 1 inhibitor, PD 098059, prevented the accumulation of cyclin D1 and estrogen-mediated mitogenesis. Our data indicate that 17beta-estradiol is a potent mitogen for benign and malignant thyroid tumor cells and that it exerts a growth-promoting effect not only by binding to nuclear estrogen receptors, but also by activation of the MAP kinase pathway.
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PMID:Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms. 1123 88

Prostacyclin (PGI(2)) is a key mediator of pulmonary vasodilation during perinatal cardiopulmonary transition, at a time when fetal plasma estrogen levels are rising. We have previously shown that estradiol-17beta (E(2)) rapidly stimulates nitric oxide production by ovine fetal pulmonary artery endothelial cells (PAEC), and that this occurs through nongenomic mechanisms which are calcium- and tyrosine kinase-mitogen-activated protein (MAP) kinase-dependent. In the present study, we determined if E(2) acutely activates PGI(2) production in PAEC. E(2) (10(-8) M for 15 min) caused a 52% increase in PGI(2), the threshold concentration was 10(-10) M E(2), the effect occurred within 5 min, and it was not related to changes in cyclooxygenase type 1 (COX-1) or COX-2 abundance. Estrogen receptor (ER) alpha and ER beta proteins and mRNAs were found to be constitutively expressed in PAEC, and PGI(2) stimulation with E(2) was fully blocked by both ER antagonism with ICI 182,780, which is not selective for either ER isoform, and the ER beta-specific antagonist RR-tetrahydrochrysene. The rapid response to E(2) was also inhibited by calcium chelation, whereas genistein- or PD98059-induced inhibition of tyrosine kinase and MAP kinase kinase, respectively, had no effect. Thus, E(2) causes rapid stimulation of PGI(2) synthesis in fetal PAEC, this process is mediated by ER beta, and it is calcium-dependent and tyrosine kinase-MAP kinase-independent. These mechanisms may play a role in pulmonary vasodilation in the perinatal period.
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PMID:Estrogen acutely activates prostacyclin synthesis in ovine fetal pulmonary artery endothelium. 1197 Sep 14

Phytochemicals bind to and regulate the human estrogen receptors (ERalpha and ERbeta), mimicking actions of the endogenous estrogen, 17beta-estradiol, and known antiestrogens such as ICI 182,780. Recently, however, some of these estrogenic phytochemicals have been shown to affect other signal transduction pathways, such as receptor tyrosine kinases and mitogen-activated protein kinases (MAPK). Previously, we found that certain phytochemicals, such as flavone, apigenin, kaempferide and chalcone, have potent antiestrogenic activity. However, the antiestrogenicity of these compounds does not correlate with their ER binding capacity, suggesting alternative signaling as a mechanism for their antagonistic effects. In this study, we examined the effects of these compounds on the transcription factor activator protein-1 (AP-1). Using AP-1-luciferase stable human endometrial adenocarcinoma Ishikawa and human embryonic kidney (HEK) 293 cells, chalcone, flavone and apigenin all stimulated AP-1 activity. Additionally, we determined the effects of the phytochemicals on transcription factors that are downstream targets of various MAPK pathways. To test this, we used HEK 293 cells stably cointegrated with GAL4 transcriptional activation systems of Elk-1, c-Jun or C/EBP homologous protein (CHOP). Chalcone was the only phytochemical that activated all three transcription factors [Elk-1, 2.7-fold (P < 0.001); c-Jun, 2.7-fold (P = 0.025); CHOP, 3.0-fold (P = 0.002)], whereas apigenin stimulated CHOP (3.9-fold; P < 0.001), but inhibited phorbol myristoyl acetate-induced c-Jun activity (71%;P = 0.006). This work suggests that phytochemicals affect multiple signaling pathways that converge at the level of transcriptional regulation. The ability of flavonoids to regulate MAPK-responsive pathways in a selective manner indicates a mechanism by which phytochemicals may influence human health and disease.
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PMID:Flavonoid phytochemicals regulate activator protein-1 signal transduction pathways in endometrial and kidney stable cell lines. 1209 58

Clinical observations suggest that human breast tumors can adapt in response to endocrine therapy by developing hypersensitivity to estradiol. To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided evidence that long-term deprivation of estradiol causes adaptive hypersensitivity. The enhanced responses to estradiol do not involve mechanisms acting at the level of transcription of estrogen regulated genes. We found no evidence of hypersensitivity when examining the effects of estradiol on regulation of c-myc, pS2, progesterone receptor, several ER reporter genes or c-myb in hypersensitive cells. On the other hand, deprivation of breast cells long term was found to up-regulate a separate pathway whereby the estrogen receptor co-opts a classical growth factor pathway and induces rapid non-genomic effects. Through this pathway, estradiol caused rapid activation of mitogen-activated protein (MAP) kinase. In exploring the mechanisms mediating this event, we found that estradiol binds to cell membrane associated estrogen receptors and causes phosphorylation of Shc, an adaptor protein usually involved in growth factor signaling pathways. ERalpha was found to complex with Shc under these conditions. In turn, Shc bound Grb-2 and Sos which resulted in the activation of MAP kinase. The pure antiestrogen, ICI 182,780, blocked several steps in the rapidly responding ER alpha, Shc, MAP kinase pathway. These non-genomic effects of estradiol produced biologic effects by activating Elk and by inducing morphologic changes in cell membranes. Using confocal microscopy, we demonstrated that estradiol caused a rapid alteration in membrane ruffling, the formation of pseudopodia and translocation of ER alpha to regions contiguous with the cell membrane. These morphologic effects could be blocked with a pure anti-estrogen. We conclude that long-term estradiol deprived cells utilize both genomic (transcriptional) and rapid, non-genomic estradiol induced pathways. We postulate that synergy between these two pathways acting at the level of the cell cycle is responsible for adaptive hypersensitivity.
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PMID:Adaptive mechanisms induced by long-term estrogen deprivation in breast cancer cells. 1216 Sep 99


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