RNA, proteins and hormone action: tales from down under
The discovery of coregulators, such as SRC-1, that augment nuclear receptor activity revolutionized our understanding of hormone action, and provided a new avenue of potential therapeutic targets for a variety of human diseases. Numerous coregulators (comprising coactivators and corepressors) have been identified in the past few years. Remarkably, one of these coregulators (SRA, Steroid receptor RNA Activator) functions as an RNA coactivator of classical nuclear receptors (eg. ER, AR, GR), and is aberrantly expressed in BCa suggesting a possible role in pathogenesis. During our efforts to define the role of SRA in the modulation of estrogen action, we have identified several novel SRA-binding proteins that contain well-described RNA-binding domains from two structurally distinct families. Each of these proteins binds SRA in vitro and in vivo and modifies SRA-mediated coregulation of estrogen action. For example, SLIRP, which is a novel RNA Recognition Motif (RRM)-containing SRA-binding protein, represses ER activity. Interestingly, the majority of SLIRP resides in the mitochondrion, suggesting that it shuttles to the nucleus to participate in ER-mediated transcription. ChIP assays indicate that each of these new SRA-binding proteins is recruited to the DNA of estrogen-regulated genes in BCa cells. Antagonist studies show that some of the SRA-binding proteins accentuate the inhibitory effect of anti-estrogens whereas over-expression of others, particularly in combination with SRA, can remove inhibition of estrogen signaling by these drugs. Taken together, these results emphasize the important contribution of SRA-protein interactions to nuclear receptor transcription, support a key physiological role for each of these SRA-binding proteins in estrogen signaling in BCa and suggest a mechanism in which over-expression could lead to anti-estrogen resistance and tumor progression.