Date of Award

2023-12-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Marc B. Cox

Second Advisor

Sourav Roy

Abstract

Aberrant signaling mechanisms by the Androgen Receptor (AR) are attributed as the main culprits for the initiation and progression of prostate cancer (PCa). Due to its dependence on androgens, research efforts have focused on developing strategies to directly target androgen-mediated receptor activity. However, given the recurrence and treatment resistance of PCa despite androgen targeted therapies, recent efforts have shifted to find novel targets against the disease. These efforts include further revealing the molecular components and their mechanisms underlying AR signaling in both normal and disease physiological settings. Hence, our lab's work is focused on characterizing and targeting molecular chaperones that are critical for folding, activation, and translocation of AR. In this study, we aimed to discover auxiliary proteins influencing AR activity through known co-chaperones, FKBP51 and FKBP52, in PCa cells. To address this goal, I implemented tandem affinity purifications and a proteomic analysis. Among the top protein interactors, our results revealed associations by FKBP51 and FKBP52 with peroxiredoxins, a family of antioxidant proteins. Peroxiredoxins have been linked to AR signaling under normal physiological conditions, as well as to the progression of various types of cancer. Based on these reports and peroxiredoxinsâ?? ability to protect cells from oxidative stress, we hypothesize there is a cooperative interaction between members of the peroxiredoxin family and FKBP51 or FKBP52 that promote survival of cells in a prostate cancer setting. Identified proteins were then validated for their direct interaction using purified protein pull-downs or or indirect interaction by Co-Immunoprecipitation. Although further analyses are necessary to understand the role these protein interactions play in oxidative stress response under normal and PCa signaling, this dataset contributes to the growing list of functionally diverse protein-protein interactions that modulate AR transcriptional activity in PCa. Given that our research efforts mainly focus on FKBP52 as a druggable target against PCa, this interactome will also provide insight into the cellular functions impacted by FKBP52 inhibition. In a broader context of AR signaling, future studies are required to characterize the mechanisms by which FKBP51 and FKBP52 and their interactors revealed in this study differentially regulate hormone-dependent signaling pathways.

Language

en

Provenance

Recieved from ProQuest

File Size

147 p.

File Format

application/pdf

Rights Holder

Olga Soto

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Biology Commons

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