BAG-1L protein enhances androgen receptor function

BAG-1 is a regulator of heat shock protein (Hsp) 70/ Hsc70 family proteins that interacts with steroid hormone receptors, The recently identified BAG-1 long (BAG-1L) protein, an isoform of BAG-1 that arises from translation initiation at a noncanonical CUG codon, was co-immunoprecipitated with androgen receptors (AR) from LNCaP prostate cancer cells and other cell lysates, whereas the shorter originally identified BAG-1 and BAG-1M (RAP 46) proteins were not. BAG-IL, but not BAG-1 or BAG-1M (RAP46), also markedly enhanced the ability of AR to transactivate reporter gene plasmids containing an androgen response element (ARE) in PC3 prostate cancer and other cell lines. A C-terminal region deletion mutant of BAG-IL failed to co-immunoprecipitate with AR and functioned as a trans-dominant inhibitor of BAG-IL, impairing AR-induced transactivation of ARE-containing reporter plasmids, In addition, BAG-IL significantly reduced the concentrations of 5 alpha-dihydrotestosterone (DHT) required for AR activity but did not induce Ligand-independent transactivation, BAG-IL also markedly improved the ability of AR to transactivate reporter genes when cells were cultured with DHT in combination with the anti-androgen cyproterone acetate. The effects of BAG-IL on AR could not be explained by detectable alterations in the DHT-induced translocation of AR from cytosol to nucleus, nor by BAG-1L-induced increases in the amounts of AR protein. These findings implicate BAG-IL in the regulation of AR function and may have relevance to mechanisms of prostate cancer resistance to hormone-ablative and anti-androgen therapy.