Regulation of estrogen receptor beta by the p23 co-chaperone
Description
Several steroid hormone receptors are known to exist in a heterocomplex containing the 90 kilodalton heat shock protein (Hsp90) and the co-chaperone p23. These proteins maintain the receptor in a conformation such that they are able to bind hormone and activate signaling. p23 confers stability to the Hsp90-receptor complex, enabling ligand to bind to the receptor with high affinity. Hsp90-receptor complexes are unstable and readily disassemble in the absence of p23, resulting in insensitivity to cognate ligands. Because of p23's role in the conversion of receptors to a high ligand affinity state, the level of p23 within a cell may be a determining factor in how the cell responds to hormones. A role for the Hsp90-p23 chaperone machinery in ERbeta signaling remained largely unexplored, so I chose to investigate this question. I developed a yeast model system in which to assess ERbeta signaling in strains that express different human and yeast Hsp90 proteins in the presence or absence of Sba1 (yeast p23 homolog) or human p23. I observed a positive effect on ERbeta transcriptional activity in strains expressing human Hsp90 proteins, however ERbeta function was unaffected by the presence of Sba1 or human p23. The Miller and Picard groups have generated transgenic mouse strains containing disrupted p23 gene. These murine strains may serve as a mammalian system in which to study ERbeta function in a p23 null background. The p23 null mice were not viable, but we were able to generate mouse embryonic fibroblast (MEF) lines from p23 null and p23 wild type embryos to evaluate ERbeta function. Experiments with these cells were complicated by the inability to detect ERbeta protein in transfected MEF lines with commercially available antibodies. I used HEK-293 cells as an alternative mammalian cell type in which to study ERbeta function in relation to the Hsp90-p23 chaperone complex and found that p23 over-expression enhanced ERbeta function at the level of transcriptional activation. The reason for enhanced ERbeta signaling in the presence of p23 was unclear after several attempts were made to assess possible mechanisms that included ligand binding, receptor stabilization, and protein interactions. I conclude that p23 is a positive regulator of ERbeta signaling, however, further studies are required in order to determine the mechanism through which p23 regulates ERbeta