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-1L, 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-1L failed to co-immunoprecipitate with AR and functioned as a trans-dominant inhibitor of BAG-1L, impairing AR-induced transactivation of ARE-containing reporter plasmids. In addition, BAG-1L significantly reduced the concentrations of 5alpha-dihydrotestosterone (DHT) required for AR activity but did not induce ligand-independent transactivation. BAG-1L 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-1L 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-1L in the regulation of AR function and may have relevance to mechanisms of prostate cancer resistance to hormone-ablative and anti-androgen therapy.
Froesch
B A
BA
Burnham Institute, La Jolla, California 92037, USA.
Takayama
S
S
Reed
J C
JC
D017398:Alternative Splicing; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006801:Humans; D011485:Protein Binding; D011944:Receptors, Androgen / Q000502:physiology*; D017384:Sequence Deletion; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D011944:Receptors, Androgen; D014157:Transcription Factors