Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BACKGROUND: Ligand-bound estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) modulate AP-1-dependent transcription via protein-protein interactions on DNA, in a manner that depends on the type of cells and the subtype of ER. We present here evidence for an additional mechanism by which ERs modulate the transcriptional activity of AP-1. RESULTS: We show that ERs located in the cytoplasm efficiently activate transcription at AP-1 sites in response to 17beta-estradiol, while ERs present in the nucleus repress transcription under the same conditions. 17beta-estradiol-induced activation of the coll-73-luc reporter correlated with cytoplasmic localization of various ERalpha and ERbeta mutant receptors, and was inhibited in the presence of the full estrogen antagonist ICI 182,780 and the MAP-kinase inhibitor UO126. We also show that the selective estrogen receptor modulator (SERM) tamoxifen is as potent as 17beta-estradiol in inducing activation of AP-1 when ERalpha is present in the cytoplasm. CONCLUSIONS: These results suggest that non-genomic signalling is involved in the mechanism by which ERalpha and ERbeta influence AP-1-dependent transcription. We have previously shown that Stat3 and Stat5 are targeted by non-genomic actions of ERs, and the results presented here allow us to conclude that ERs bound to 17beta-estradiol mediate the transcriptional activation of promoters regulated by AP-1 and by Stat proteins via different combinations of signal transduction pathways. Our observations thereby provide new insights into the mechanisms by which ERs act at alternate response elements, and suggest a mechanism by which tamoxifen exerts its action as a tissue-selective agonist.
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PMID:Estrogen receptor-dependent activation of AP-1 via non-genomic signalling. 1519 29

Prompted by reports about strong estrogenic effects of cadmium, attempts were made to reproduce these observations using the yeast estrogen screen (YES) and the E-Screen assays. For the first time, possible activation of the Src/MAPK pathway was also investigated. In the YES, only a slight activation (10% of a maximal effect) of the estrogen receptor alpha (ERalpha) was observed at cadmium concentrations between 5 x 10(-7) M and 5 x 10(-6) M. In the E-Screen assay, carried out by two laboratories, the heavy metal was without observable cell proliferative effects when tested in the range between 6 x 10(-11) M and 1 x 10(-5) M. However, in both assays, cadmium led to a reduction of the effects of 17beta-estradiol (E2). Treatment of MCF-7 human breast cancer cells with 1 x 10(-7) M cadmium failed to induce phosphorylation of Src and the MAP kinases Erk1 and Erk2-effects shown to occur with E2 and epidermal growth factor (EGF). In summary, we were unable to confirm the strong estrogenicity of cadmium reported recently by a number of laboratories. This apparent absence of effects in our hands is not due to a lack of uptake of the metal or to effective protection against cadmium by high levels of glutathione or metallothionein, since toxicity and an antagonism of E2 responses were observed both in the YES and the E-Screen.
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PMID:Lack of activity of cadmium in in vitro estrogenicity assays. 1671 72

Multiple steroid receptors (SR) have been proposed to localize to the plasma membrane. Some structural elements for membrane translocation of the estrogen receptor alpha (ER alpha) have been described, but the mechanisms relevant to other steroid receptors are entirely unknown. Here, we identify a highly conserved 9 amino acid motif in the ligand binding domains (E domains) of human/mouse ER alpha and ER beta, progesterone receptors A and B, and the androgen receptor. Mutation of the phenylalanine or tyrosine at position-2, cysteine at position 0, and hydrophobic isoleucine/leucine or leucine/leucine combinations at positions +5/6, relative to cysteine, significantly reduced membrane localization, MAP and PI 3-kinase activation, thymidine incorporation into DNA, and cell viability, stimulated by specific SR ligands. The localization sequence mediated palmitoylation of each SR, which facilitated caveolin-1 association, subsequent membrane localization, and steroid signaling. Palmitoylation within the E domain is therefore a crucial modification for membrane translocation and function of classical sex steroid receptors.
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PMID:A conserved mechanism for steroid receptor translocation to the plasma membrane. 1753 99