In this article we summarize the birth of the field of nuclear receptors, the discovery of untransformed and transformed isoforms of ligand-binding macromolecules, the discovery of the three-domain structure of the receptors, and the properties of the Hsp90-based heterocomplex responsible for the overall structure of the oligomeric receptor and many aspects of the biological effects. The discovery and properties of the subfamily of receptors called orphan receptors is also outlined. Novel molecular aspects of the mechanism of action of nuclear receptors and challenges to resolve in the near future are discussed.

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Coordinated cochaperone interactions with Hsp90 and associated client proteins are crucial for a multitude of signaling pathways in normal physiology, as well as in disease settings. Research on the molecular mechanisms regulated by the Hsp90 multiprotein complexes has demonstrated increasingly diverse roles for cochaperones throughout Hsp90‐regulated signaling pathways. Thus, the Hsp90‐associated cochaperones have emerged as attractive therapeutic targets in a wide variety of disease settings. The tetratricopeptide repeat (TPR)‐domain immunophilins FKBP51 and FKBP52 are of special interest among the Hsp90‐associated cochaperones given their Hsp90 client protein specificity, ubiquitous expression across tissues, and their increasingly important roles in neuronal signaling, intracellular calcium release, peptide bond isomerization, viral replication, steroid hormone receptor function, and cell proliferation to name a few. This review summarizes the current knowledge of the structure and molecular functions of TPR‐domain immunophilins FKBP51 and FKBP52, recent findings implicating these immunophilins in disease, and the therapeutic potential of targeting FKBP51 and FKBP52 for the treatment of disease.

Background: Prostate cancer (PCa) is the most common non-cutaneous cancer afflicting men, both in the United States and worldwide. Aberrant molecular signaling mechanisms mediated by the Androgen Receptor (AR) are attributed as the main culprits for the initiation and progression of PCa, and research efforts have focused on developing strategies to directly target the AR. In an alternative approach, molecular chaperones that are critical for the maturation and signaling of the AR have emerged as potential therapeutic targets. Our lab has demonstrated the potential of inhibitors that target AR cochaperones, FKBP51 and FKBP52, in PCa cells. Previously, FKBP51 and FKBP52 have been shown to play a role in cell proliferation and survival, steroid hormone receptor maturation, and other mechanisms highly implicated in prostate carcinogenesis. Therefore, it is imperative to understand the protein-protein interactions that regulate FKBP51 and FKBP52-mediated AR function in PCa. We hypothesize that unknown interactors cooperate with FKBP51 and FKBP52 to promote PCa progression via the AR signaling pathways. Here, we performed a series of experiments aimed to identify and characterize auxiliary proteins influencing FKBP51- and FKBP52-mediated AR activity. Ultimately, our goal is to define novel protein interactions involved in AR-mediated PCa progression for therapeutic intervention. Methods: We implemented tandem affinity purification followed by mass spectrometry analysis in 22RV1 PCa cells using FKBP51 and FKBP52 as bait. The spectral counts of proteins identified were then used to analyze protein-protein interactions through the IDEP workflow software. Gene Ontology (GO) term enrichment analysis was used to generate a STRING interaction network. Protein interactions of interest were then validated via reciprocal immunoprecipitations. Results: This interactome analysis resulted in 353 IDs for FKBP51 and FKBP52 interactors. Heatmaps representing top 100 interactors were generated for both bait proteins. Members of the peroxiredoxin family, implicated in development of PCa and resistance to treatment, are among the top candidates of interest resulting from this interactome. Conclusion: This analysis aims to provide important insights into the androgen signaling milieu, which can be applied in the development of novel treatments targeting AR interacting partners in PCa progression. This study contributes to the growing list of functionally diverse proteins that help modulate AR transcriptional activity, and supports the idea that AR signaling is dynamic with numerous molecules involved in the aberrant activation of AR in prostate-tumor cells Citation Format: Olga B. Soto, Abhijeet R. Patil, Sourav Roy, Marc B. Cox. Identification of androgen receptor co-chaperone interactors implicated in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB038.

In casual conversation with non-medical individuals, it is common for them to ask: why do we not have a cure for cancer or vaccinations for all diseases? It seems somewhat logical to assume that after so many years of research that cures should be readily available, diseases in general should simply require a pill or jab and that somehow, if scientists are not deliberately hiding these cures, then they must be asleep at the wheel. A typical response to such questions focuses on the complexity of the different cancers/diseases and that there will be no “one cure fits all”. When it comes to vaccinations, there is absolutely no doubt that many vaccines are extremely effective and a multitude of publications can attest to this and cite how many lives have been saved because of our vaccination programs; indeed, vaccinations typically pop up on a list of reasons why humans today are living substantially longer than at any previous time in history.1-3 Nevertheless, there is always an overriding and to some extent embarrassing realization that despite the relative success of vaccines we still do not, for the most part, know how to make consistently effective vaccines and that often it boils down to a trial and error procedure to establish the best vaccine for a given target