Date of Award
2024-05-01
Degree Name
Doctor of Philosophy
Department
Biosciences
Advisor(s)
Marc B. Cox
Abstract
Prostate Cancer (PCa) is one of the most common life-threatening malignancies diagnosed among American men. Initiation and progression of PCa are dependent upon androgen receptor (AR) regulated genes. Functional receptor conformation is influenced by the cooperation of chaperone and cochaperone proteins including the 52 and 51 kDa FK506 binding proteins (FKBP52 and FKBP51). FKBP52 is known for being a positive regulator of AR, PR (progesterone receptor), and GR (glucocorticoid receptor) activity, whereas FKBP51 negatively regulates steroid hormone receptor activity. As a result, these two proteins have become highly promising therapeutic targets for the disruption of mechanisms important in several endocrine-related diseases such as prostate cancer. Previous studies have identified the BF3 surface as an AR-specific regulatory site for FKBP52, and it is likely that there is another common FKBP regulatory surface among all the regulated receptors, like the H1-H3 loop. GR is known to be more hypersensitive to FKBP52 regulation, and mutations within the GR H1-H3 loop affect FKBP-mediated receptor activities. Thus, we conducted site-directed mutagenesis to identify the residues within the human AR H1-H3 loop that are critical for FKBP co-chaperone regulation. Taking advantage of the distinct GR hypersensitivity to FKBP52, two classes of functional mutants were generated to make the human AR H1-H3 loop more like human GR or guinea pig GR. In addition, yeast-based reporter assays were performed to assess the role and relevance of those mutations in receptor activity. Similarly, mammalian reporter assays were conducted to corroborate our findings in a higher vertebrate model system. Our current data shows that, mechanistically, the H1-H3 loop is a relevant FKBP regulatory surface for the steroid hormone receptors AR and GR, and suggests that the H1- H3 loop may represent a novel target surface for the simultaneous inhibition of AR, GR, and PR.
Language
en
Provenance
Received from ProQuest
Copyright Date
2024-05
File Size
81 p.
File Format
application/pdf
Rights Holder
Isela Rodriguez
Recommended Citation
Rodriguez, Isela, "Characterization Of The Androgen Receptor H1-H3 Loop As A Putative Fkbp Regulatory Surface" (2024). Open Access Theses & Dissertations. 4142.
https://scholarworks.utep.edu/open_etd/4142