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 isoform of the ER (ER) 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 has been described, the mechanism by which cAMP elicits ligand-independent ER 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 in MCF7 breast cancer cells, did indeed phosphorylate ER, but this phosphorylation was not required for cAMP-induced ER activation, as assayed by expression of an ER-responsive luciferase reporter. Instead, PKA-mediated phosphorylation of coactivator-associated arginine methyltransferase 1 (CARM1) was required for cAMP-induced ER activation. Overexpression of a transgene encoding wild-type or catalytically inactive CARM1 enhanced cAMP-induced ER transcriptional activation of both the luciferase reporter and an endogenous ER target gene, and reducing CARM1 abundance by RNA interference reduced the cAMP-induced activity of ER. Immunoprecipitation studies using MCF7 cell extracts indicated that endogenous CARM1 associated with endogenous ER in a cAMP-dependent manner. Mutation of the PKA phosphorylation site in CARM1 prevented its interaction with ER and abrogated cAMP-induced activation of the ER-responsive luciferase reporter. A mutation that mimicked constitutive phosphorylation at this site elicited constitutive interaction of CARM1 with ER and activation of the ER-responsive luciferase reporter. Finally, the authors demonstrated that endogenous CARM1 was constitutively associated with ER 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 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 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 by cAMP. Genes Dev. 24, 708–719 (2010). [Abstract] [Full Text]

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