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Genes & Dev. 24 (7): 708-719

Copyright © 2010 by Cold Spring Harbor Laboratory Press.

CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor {alpha} by cAMP

Sophie Carascossa1, Peter Dudek1, Bruno Cenni2, Pierre-André Briand,, and Didier Picard3

Département de Biologie Cellulaire, Université de Genève, Sciences III, CH-1211 Genève 4, Switzerland

Abstract: The estrogen receptor {alpha} (ER{alpha}) is activated as a transcription factor by both estrogen and a large variety of other extracellular signals. The mechanisms of this ligand-independent activation, notably by cAMP signaling, are still largely unknown. We now close the gap in the signaling pathway between cAMP and ER{alpha}. Whereas the direct phosphorylation of ER{alpha} by the cAMP-activated protein kinase A (PKA) is dispensable, the phosphorylation of the coactivator-associated arginine methyltransferase 1 (CARM1) by PKA at a single serine is necessary and sufficient for direct binding to the unliganded hormone-binding domain (HBD) of ER{alpha}, and the interaction is necessary for cAMP activation of ER{alpha}. Sustained PKA activity promoting a constitutive interaction may contribute to tamoxifen resistance of breast tumors. Binding and activation involve a novel regulatory groove of the ER{alpha} HBD. As a result, depending on the activating signal, ER{alpha} recruits different coactivator complexes to regulate alternate sets of target genes.

Key Words: Steroid receptor • signaling • coactivator • protein kinase A • breast cancer • endocrine resistance

Received for publication November 18, 2009. Accepted for publication February 15, 2010.

1 These authors contributed equally to this work.

2 Present address: Novartis Institutes for BioMedical Research, WSJ-386.9.09, 4002 Basel, Switzerland.

3 Corresponding author.

E-MAIL didier.picard{at}unige.ch; FAX 41-22-379-6928.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.568410.

Supplemental material is available at http://www.genesdev.org.

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