Signal transducers and activators of transcription as downstream targets of nongenomic estrogen receptor actions.
17Beta-estradiol-activated estrogen receptor alpha (ERalpha) and beta (ERbeta) are able to induce transcriptional activation of signal transducer and activator of transcription (Stat)-regulated promoters via cytoplasmic signal transduction pathways. Stat5 and Stat3 are required for promoter induction, which correlates with cytoplasmic sublocalization of ERs and is independent of intact coactivator binding sites and DNA-binding domains. In endothelial cells, Stat5 and Stat3 are rapidly phosphorylated on both tyrosine and serine residues in response to 17beta-estradiol, and nuclear translocation is subsequently induced. 17Beta-estradiol-induced transactivation of a Stat-regulated promoter requires at least three different signal transduction pathways, including MAPK, Src-kinase, and phosphatidylinositol-3-kinase activities. In conclusion, this work identifies a novel pathway involving an agonist-bound ER-activated phosphorylation cascade, resulting in nuclear transcriptional activation of target transcription factors. These findings reveal novel targets for the development of drugs that modulate a nongenomic-to-genomic ER-dependent mechanism.
D000818:Animals; D019556:COS Cells; D002364:Caseins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D016678:Genome; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002364:Caseins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D004958:Estradiol; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011960:Receptors, Estrogen; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D012694:Serine; D015534:Trans-Activators; D014443:Tyrosine; D019061:src-Family Kinases