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Sci. Signal., 13 April 2010
Vol. 3, Issue 117, p. ec112
[DOI: 10.1126/scisignal.3117ec112]

EDITORS' CHOICE

Cell Biology Ligand-Independent ER Activation

Annalisa M. VanHook

Science Signaling, AAAS, Washington, DC 20005, USA

Ligand binding to estrogen receptor (ER) causes a conformational change that allows binding of various cofactors that mediate context-specific transcriptional regulatory effects. Activation of the receptor by different ligands and by ligand-independent mechanisms involves the recruitment of different sets of cofactors. The {alpha} isoform of the ER (ER{alpha}) may be activated by growth factor or adenosine 3',5'-monophosphate (cAMP) signaling in the absence of ligand. Although the mechanism by which growth factors trigger ligand-independent activation of ER{alpha} has been described, the mechanism by which cAMP elicits ligand-independent ER{alpha} responses has not. Carascossa et al. report that protein kinase A (PKA), which is activated by cAMP and was required for cAMP-induced activity of ER{alpha} in MCF7 breast cancer cells, did indeed phosphorylate ER{alpha}, but this phosphorylation was not required for cAMP-induced ER{alpha} activation, as assayed by expression of an ER{alpha}-responsive luciferase reporter. Instead, PKA-mediated phosphorylation of coactivator-associated arginine methyltransferase 1 (CARM1) was required for cAMP-induced ER{alpha} activation. Overexpression of a transgene encoding wild-type or catalytically inactive CARM1 enhanced cAMP-induced ER{alpha} transcriptional activation of both the luciferase reporter and an endogenous ER{alpha} target gene, and reducing CARM1 abundance by RNA interference reduced the cAMP-induced activity of ER{alpha}. Immunoprecipitation studies using MCF7 cell extracts indicated that endogenous CARM1 associated with endogenous ER{alpha} in a cAMP-dependent manner. Mutation of the PKA phosphorylation site in CARM1 prevented its interaction with ER{alpha} and abrogated cAMP-induced activation of the ER{alpha}-responsive luciferase reporter. A mutation that mimicked constitutive phosphorylation at this site elicited constitutive interaction of CARM1 with ER{alpha} and activation of the ER{alpha}-responsive luciferase reporter. Finally, the authors demonstrated that endogenous CARM1 was constitutively associated with ER{alpha} in LCC2 cells, which are resistant to inhibition by the ER antagonist tamoxifen, and this interaction was abolished by treating the cells with the PKA inhibitor H89. This mode of ER{alpha} activation even in the presence of antagonist offers a plausible explanation for the observation that PKA can induce resistance to tamoxifen in cultured cells. The CARM1-ER{alpha} interaction may thus be a potential route for combating tamoxifen resistance in human breast cancers.

S. Carascossa, P. Dudek, B. Cenni, P.-A. Briand, D. Picard, CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor {alpha} by cAMP. Genes Dev. 24, 708–719 (2010). [Abstract] [Full Text]

Citation: A. M. VanHook, Ligand-Independent ER Activation. Sci. Signal. 3, ec112 (2010).



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