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

Abstract

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 alpha and ER beta are capable of activating the MAPK pathway in response to a low dose of 17beta-estradiol. In the present study, the ability of estrogen to act through both ER alpha and ER beta 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 alpha and ER beta.

Sex differences in drug abuse

“…This organization of signaling molecules and receptors allows mERs to modulate a variety of signal transduction cascades in target cells. In fibroblasts and neurons in culture, estradiol activation of MAP kinase signaling systems has been found after transfection with ERα or ERß [115,129,130]. Taken as a whole, these results support the idea that the classical ERs (ERα and ERß) are acting at the membrane to confer rapid responses to estradiol in the brain, as has been demonstrated peripherally and in model systems.…”

Inositol triphosphate participates in an oestradiol nongenomic signalling pathway involved in accelerated oviductal transport in cycling rats

“…Nongenomic activation of MAPK by E 2 has been reported in several cell systems (Chaturvedi & Sarkar 2004, Sengupta et al 2004, Wade & Dorsa 2003. However, we found that E 2 did not activate MAPKp44/42 and that inhibition of MAPK activity by PD98059 did not block the effect of E 2 on egg transport.…”

Antisense Oligodeoxynucleotides for Estrogen Receptor-β and α Attenuate Estradiol's Modulation of Affective and Sexual Behavior, Respectively

“…Furthermore, examining the effects of ER AS-ODN treatment to vehicleadministered ovx rats would provide additional information about the importance of ER function for these behavioral effects. Indeed, the downstream effectors of ERs, which may be membrane-bound and/or have membrane actions that potentiate intracellular events, such as extracellular regulated kinase/mitogen-activated protein kinase, need to be elucidated (Wade and Dorsa, 2003;Bryant et al, 2005;Vasudevan et al, 2001Vasudevan et al, , 2005Mhyre and Dorsa, 2006). In the future, it would be important to address these points.…”