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    Mechanistic Study of USP15-Dependent Deubiquitination and Characterization of Natural Compounds that Modulate the Nrf2-Keap1 Antioxidant Response

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    Author
    Villeneuve, Nicole Frances
    Issue Date
    2011
    Keywords
    cinnamic aldehyde
    Keap1
    Nrf2
    oridonin
    ubiquitination
    USP15
    Advisor
    Zhang, Donna D.
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Embargo: Release after 10/7/2011
    Abstract
    Nrf2 (NF-E2-related factor 2) is a transcription factor that regulates a battery of downstream genes that contain an antioxidant response element (ARE) in their promoters, including intracellular redox-balancing proteins, phase II detoxifying enzymes, and transporters. These Nrf2-dependent proteins work in collaboration to protect against many diseases where oxidative stress plays an essential role in disease onset and progression. Consequently, it is imperative to understand the basic molecular mechanisms of how Nrf2 is regulated so we can target this pathway for disease prevention and treatment.Nrf2 is mainly regulated at the protein level by the ubiquitin proteasome system. Under basal conditions Nrf2 is constantly ubiquitinated by the Keap1-Cul3-E3 ubiquitin ligase complex and subsequently degraded by the 26S proteasome. Currently, regulation of the Nrf2-Keap1 pathway by ubiquitination is largely understood. However, the mechanism responsible for removal of ubiquitin conjugated to Nrf2 or Keap1 remains unknown. In this dissertation, we identified two molecular mechanisms that are important in understanding how the Nrf2-Keap1 pathway is regulated: (i) USP15 negatively regulates the Nrf2-Keap1 pathway by deubiquitinating Keap1 and (ii) deubiquitinated-Keap1 binds in the Cul3-Keap1-E3 ligase complex more tightly than ubiquitinated-Keap1. Additionally, (iii) we demonstrated the importance of the Nrf2-Keap1 pathway in USP15-dependent paclitaxel-chemoresistance.Under oxidative stressed or induced conditions the ability of the E3-ligase to target Nrf2 for degradation becomes impaired. As a result, Nrf2 is stabilized and free Nrf2 translocates to the nucleus and initiates transcription of ARE-bearing genes. Activation of this pathway is advantageous for chemoprevention. In Chapters 4 and 5, we identified and characterized two activators of the Nrf2 cytoprotective pathway, oridonin and cinnamic aldehyde. These compounds inhibit Cul3-Keap1-dependent degradation of Nrf2, stabilize Nrf2 protein levels, and activate the antioxidant response. Furthermore, both compounds are able to protect against cytotoxic and genotoxic stress-induced cell death. Moreover, our study on USP15 has elucidated an additional mechanism that allows small molecules, such as oridonin, to activate Nrf2 by causing a switch in ubiquitination from Nrf2 to Keap1. Taken together, these findings further our understanding of how the Nrf2-Keap1 pathway is regulated, which is imperative in targeting this pathway for chemoprevention or chemotherapy.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Pharmacology & Toxicology
    Degree Grantor
    University of Arizona
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