Estrogen-Induced Activation of Mitogen-Activated Protein Kinase Requires Mobilization of Intracellular Calcium

• Published in: Proceedings of the National Academy of Sciences - PNAS 1999-04, Vol.96 (8), p.4686-4691
• Main Authors: Improta-Brears, Teresa, Whorton, A. Richard, Codazzi, Franca, York, John D., Meyer, Tobias, McDonnell, Donald P.
• Format: Article
• Language: English
• Subjects: Antibodies; Biological Sciences; Breast cancer; Breast Neoplasms; Calcimycin - pharmacology; Calcium; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell lines; Cell Nucleus - enzymology; Cellular immunity; Cytoplasm - enzymology; Egtazic Acid - pharmacology; Enzyme Activation - drug effects; Enzymes; Epidermal Growth Factor - pharmacology; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estradiol - physiology; Estrogen Antagonists - pharmacology; Estrogen receptors; Estrogens; Female; Fulvestrant; HeLa Cells; Humans; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Pharmacology; Receptors; Recombinant Proteins - pharmacology; Second messengers; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.8.4686

Estrogens and growth factors such as epidermal growth factor (EGF) act as mitogens promoting cellular proliferation in the breast and in the reproductive tract. Although it was considered originally that these agents manifested their mitogenic actions through separate pathways, there is a growing body of evidence suggesting that the EGF and estrogen-mediated signaling pathways are intertwined. Indeed, it has been demonstrated recently that 17β -estradiol (E2) can induce a rapid activation of mitogenactivated protein kinase (MAPK) in mammalian cells, an event that is independent of both transcription and protein synthesis. In this study, we have used a pharmacological approach to dissect this novel pathway in MCF-7 breast cancer cells and have determined that in the presence of endogenous estrogen receptor, activation of MAPK by E2 is preceded by a rapid increase in cytosolic calcium. The involvement of intracellular calcium in this process was supported by the finding that the presence of EGTA and Ca2+-free medium did not affect the activation of MAPK by E2 and, additionally, that this response was blocked by the addition of the intracellular calcium chelator$\text{1,2-bis(2-aminophenoxy)ethane-}N,N,N^{\prime},N^{\prime}\text {-tetraacetate}$. Cumulatively, these data indicate that the estrogen receptor, in addition to functioning as a transcription factor, is also involved, through a nongenomic mechanism, in the regulation of both intracellular calcium homeostasis and MAPK-signaling pathways. Although nongenomic actions of estrogens have been suggested by numerous studies in the past, the ability to link estradiol and the estrogen receptor to a well defined signaling pathway strongly supports a physiological role for this activity.