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J. Biol. Chem., Vol. 282, Issue 7, 4830-4840, February 16, 2007

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The Hormonal Response of Estrogen Receptor Is Decreased by the Phosphatidylinositol 3-Kinase/Akt Pathway via a Phosphorylation-dependent Release of CREB-binding Protein^*

Mélanie Sanchez, Karine Sauvé, Nathalie Picard, and André Tremblay¹

From the Research Center, Sainte-Justine Hospital, and the Departments of Biochemistry and Obstetrics and Gynecology, University of Montreal, Montréal H3T 1C5, Québec, Canada

The hormonal response of estrogen receptors (ER) and ER is controlled by a number of cofactors, including the general transcriptional coactivator CREB-binding protein (CBP). Growing evidence suggests that specific kinase signaling events also modulate the formation and activity of the ER coactivation complex. Here we show that ER activity and target gene expression are decreased upon activation of ErbB2/ErbB3 receptors despite the presence of CBP. This inhibition of ER involved activation of the phosphatidylinositol 3-kinase/Akt pathway, abrogating the potential of CBP to facilitate ER response to estrogen. Such reduced activity was associated with an impaired ability of ER to recruit CBP upon activation of Akt. Mutation of serine 255, an Akt consensus site contained in the hinge region of ER, prevented the release of CBP and rendered ER transcriptionally more responsive to CBP coactivation, suggesting that Ser-255 may serve as a regulatory site to restrain ER activity in Akt-activated cells. In contrast, we found that CBP intrinsic activity was increased by Akt through threonine 1872, a consensus site for Akt in the cysteine- and histidine-rich 3 domain of CBP, indicating that such enhanced transcriptional potential of CBP did not serve to activate ER. Interestingly, nuclear receptors sharing a conserved Akt consensus site with ER also exhibit a reduced ability to be coactivated by CBP, whereas others missing that site were able to benefit from the activation of CBP by Akt. These results therefore outline a regulatory mechanism by which the phosphatidylinositol 3-kinase/Akt pathway may discriminate nuclear receptor response through coactivator transcriptional competence.

Received for publication, August 17, 2006 , and in revised form, November 17, 2006.

^* This work was supported by the Canadian Institutes of Health Research, the Cancer Research Society Inc., and the Canadian Foundation for Innovation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ New Investigator of the Canadian Institutes of Health Research. To whom correspondence should be addressed: Research Center, Ste-Justine Hospital, 3175 Côte Ste-Catherine, Montréal, Québec H3T 1C5, Canada. Tel.: 514-345-4931, ex. 2830; Fax: 514-345-4988; E-mail: andre.tremblay{at}recherche-ste-justine.qc.ca.

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				N. Picard, C. Charbonneau, M. Sanchez, A. Licznar, M. Busson, G. Lazennec, and A. Tremblay Phosphorylation of Activation Function-1 Regulates Proteasome-Dependent Nuclear Mobility and E6-Associated Protein Ubiquitin Ligase Recruitment to the Estrogen Receptor {beta} Mol. Endocrinol., February 1, 2008; 22(2): 317 - 330. [Abstract] [Full Text] [PDF]

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