Georgetown University LogoGeorgetown University Library LogoDigitalGeorgetown Home
    • Login
    View Item 
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown College
    • Department of Biology
    • Graduate Theses and Dissertations - Biology
    • View Item
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown College
    • Department of Biology
    • Graduate Theses and Dissertations - Biology
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Inflammatory cytokines induce ubiquitination and loss of the prostate suppressor protein NKX3.1

    Cover for Inflammatory cytokines induce ubiquitination and loss of the prostate suppressor
      protein NKX3.1
    View/Open
    View/Open: markowskiMark.pdf (8.3MB) Bookview

    Creator
    Markowski, Mark Christopher.
    Description
    Thesis (Ph.D.)--Georgetown University, 2008.; Includes bibliographical references. Epithelial dysplasia in the prostate is seen adjacent to foci of inflammatory atrophy. How the inflammatory process leads to cellular dysplasia and transformation is not well understood. This thesis identifies a mechanism for inflammation to cause decreased expression of a key prostate tumor suppressor protein, NKX3.1. We have found that the inflammatory cytokine TNF-alpha induced rapid ubiquitination and proteasomal degradation of NKX3.1 in vitro. Inhibition of proteasomal degradation prevented the loss of NKX3.1 and resulted in the accumulation of ubiquitin-bound NKX3.1. The C-terminus of NKX3.1 is comprised of 51 amino acids distal to the homeodomain. Deletion of the C-terminal domain of NKX3.1 resulted in prolonged protein half-life and absence of TNF-alpha-induced ubiquitination. Site-directed mutation of either or both of the two lysines (193 and 201), possible sites for ubiquitin ligation, in the C-terminus did not affect ubiquitination or protein half-life. Sequential deletion of fragments of the C-terminus identified amino acids 185-199 as the peptide region affecting NKX3.1 stability. In the C-terminal region of NKX3.1, serines 185,195, and 196 were identified as potential phosphorylation sites. Mutation of serine 185 to alanine resulted in a significant increase in protein half-life, but retained susceptibility to TNF-alpha-induced ubiquitination. In contrast, steady-state NKX3.1 turnover was unaffected by a serine 196 to alanine substitution. However, mutation of serine 196 to alanine abrogated TNF-alpha-induced ubiquitination and degradation. Serine 195 was shown to have a modulating affect and attenuated TNF-alpha-induced ubiquitination. Phosphorylation of NKX3.1 was increased in the presence of TNF-alpha, but the role of serines 185, 195, 196 was not studied. Our data provides evidence that inflammatory cytokines can reduce NKX3.1 levels. Strategies to inhibit inflammation may result in a therapeutic intervention to maintain NKX3.1 levels and slow prostate cancer development and progression.
    Permanent Link
    http://hdl.handle.net/10822/552861
    Date Published
    2008
    Subject
    Cytokines; Tumor suppressor proteins; Prostate--Cancer
    Type
    thesis
    Publisher
    Georgetown University
    Collections
    • Graduate Theses and Dissertations - Biology
    Metadata
    Show full item record

    Related items

    Showing items related by title, author, creator and subject.

    • Thumbnail

      Invasion of the Prostate Snatchers: No More Unnecessary Biopsies, Radical Treatment or Loss of Sexual Potency 

      Blum, Ralph and Scholz, Mark (2010)
    Related Items in Google Scholar

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility
     

     

    Browse

    All of DigitalGeorgetownCommunities & CollectionsCreatorsTitlesBy Creation DateThis CollectionCreatorsTitlesBy Creation Date

    My Account

    Login

    Statistics

    View Usage Statistics

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility