Development of a yeast-based assay for the functional characterization of FKBP52/ β-catenin interactions with the androgen receptor
Prostate cancer development is uniquely dependent on the androgen receptor’s (AR’s) transcriptional regulation in response to hormone binding. Current therapies directly target AR acting as an antagonist at androgen binding sites. However, once androgen-dependence is lost, meaning the patient has progressed into a late-stage hormone resistant phenotype, all current treatments are essentially ineffective. Utilizing the yeast strain Saccharomyces cerevisiae we are capable of creating a model system that allows for the exogenous expression of AR while still retaining the chaperone components needed for this steroid receptor complex. The 52kDa FK506 binding protein (FKBP52) has been shown to be an important positive regulator of AR receptor function. Additional analysis has also identified a synergistic interaction occurring between FKBP52 and the cadherin-associated protein known as β-catenin. Data gleaned from yeast-reporter assays determined that within S. cerevisiae this synergism is essentially lost. Previous research shows that the Inhibitor of β-catenin and T-cell factor (ICAT) protein is capable of modulating AR activity within mammalian cells. Introduction of this protein within yeast, interestingly, resulted in a significant increase of AR activity while in the presence of only FKBP52. His tagged pull-down assays determined that there is no direct protein-protein interaction between the two. Instead, it is likely that FKBP52 and ICAT are capable of modulating AR activity directly on the receptor surface or can induce a positive conformational change. This information can help us understand the multi-protein complex that regulates AR activity for novel CRPC therapeutic sites.
Rodriguez, Theresa Anne, "Development of a yeast-based assay for the functional characterization of FKBP52/ β-catenin interactions with the androgen receptor" (2015). ETD Collection for University of Texas, El Paso. AAI1600346.