Effect of the new coactivator steroid RNA Activator on the transcriptional activity of the estrogen receptor

Nuclear receptor coactivators are factors that enhance the transcriptional activity of the receptor. Most coactivators characterized to date work in a ligand-dependent manner by interacting with the activation function-2 (AF-2) of the receptor. A newly characterized coactivator termed steroid RNA activator (SRA) was cloned as an AF-1-dependent and ligand-independent coactivator. SRA was shown to enhance the transcriptional activity of the steroid receptors by interacting with their AF-1. Here, we describe the effect of SRA on the transcriptional activity of the estrogen receptor alpha (ERalpha) and beta (ERbeta). SRA coactivates ERalpha and ERbeta in a ligand-dependent manner and the transcriptional activity of ERalpha can be enhanced by SRA in a ligand-independent manner through the AF-1 domain of the receptor. The integrity of the serine residue at position 118 (S118) in ERalpha AF-1 is required for the complete coactivation of ERalpha by SRA. Activation of MAPK induces ligand-independent activation of ERalpha by SRA, a mechanism independent of the AF-2 activity of the receptor. Mutation of S118 to an alanine residue abolishes the MAPK-induced activation of ERalpha, suggesting that phosphorylation of S118 by MAPK may be important for the ligand-independent effect of SRA on ERalpha AF-1. Thus SRA may play an important role in the regulation of ER transcriptional activity