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Estrogen Activation of Cyclic Adenosine 5'-Monophosphate Response Element-Mediated Transcription Requires the Extracellularly Regulated Kinase/Mitogen-Activated Protein Kinase Pathway

Department of Pharmacology (C.B.W.), University of Washington, Seattle, Washington 98195; and Department of Physiology and Pharmacology (D.M.D.), Oregon Health and Science University, Portland, Oregon 97201

Address all correspondence and requests for reprints to: Daniel M. Dorsa, Ph.D., Vice-President for Research, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mail Code: L335, Portland, Oregon 97201-3098. E-mail: dorsad{at}ohsu.edu.

The ability of estrogen to rapidly initiate a variety of signal transduction cascades is increasingly recognized as playing an important role in a number of tissue-specific transcriptional actions of the hormone. In vivo, estrogen rapidly elicits phosphorylation of cAMP response element-binding protein (CREB). We have previously shown that both ER and ERß are capable of activating the MAPK pathway in response to a low dose of 17ß-estradiol. In the present study, the ability of estrogen to act through both ER and ERß to increase CREB phosphorylation was evaluated in an immortalized hippocampal cell line stably expressing either receptor. Estrogen treatment promoted rapid CREB phosphorylation, reaching a maximum by 15 min. This activation is completely blocked by the antiestrogen ICI 182,780, suggesting an estrogen receptor-dependent mechanism. The addition of the mitogen/ERK kinase-1 inhibitor, PD98059, also blocked the ability of estrogen to signal to CREB phosphorylation. Estrogen also caused an increase in p90Rsk activity, a critical mediator of MAPK effects. Surprisingly, blockade of the protein kinase A pathway in cells treated with estrogen did not affect estrogen-mediated CREB phosphorylation. Thus, MAPK and p90Rsk appear to be the primary mediators of estrogen-induced gene transcription through ER and ERß.

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