• Login as Editor
    View Item 
    •   Yeshiva Academic Institutional Repository
    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
    • View Item
    •   Yeshiva Academic Institutional Repository
    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Identification and characterization of a nuclear export signal in INI1/hSNF5, a component of the human SWI /SNF chromatin remodeling complex

    Thumbnail

    Date
    2001
    Author
    Craig, Errol Andrew
    Metadata
    Show full item record
    Share
    Abstract
    INI1 (Integrase Interactor 1)/hSNF5 is a component of the mammalian SWI/SNF complex which acts to remodel chromatin. It was originally identified through its binding interaction with HIV-1 integrase, and has been shown to stimulate integration in-vitro. The exact role of INI1/hSNF5 in the HIV-1 life cycle is, however, at this point unclear. In this thesis, we identify and characterize a nuclear export signal (NES) in INI1/hSNF5.;While full length INI1/hSNF5 is predominantly in the nucleus, INI1/hSNF5 C-terminal truncations aberrantly localize to the cytoplasm. Cytoplasmic localization of these deletions appears to be due to the presence of a NES within the highly conserved hydrophobic repeat 2 region of INI1/hSNF5. Leptomycin B, a fungal compound that specifically binds to and inactivates the nuclear export receptor hCRM1/exportin1, inhibits the observed nuclear export of INI1/hSNF5 C-terminal deletions. Mutation of INI1/hSNF5 NES residues to alanine abrogates its nuclear export capability, whereas mutation of nearby hydrophobic residues that are not part of the NES do not disrupt this export. INI1/hSNF5 specifically and directly interacts with hCRM1/exportin1 in-vitro, and the two proteins can co-immunoprecipitate in vivo. In addition, data is provided suggesting that this NES is important for changes in subcellular localization of INI1/hSNF5 seen after HIV-1 infection.;Recently INI1/hSNF5 has been implicated as being a tumor suppressor. Several malignant rhabdoid tumor samples have been demonstrated to contain inactivating truncating mutations in the C-terminus of INI1/hSNF5. Since deletion of the C-terminus of INI1/hSNF5 results in the nuclear export of the protein, we surmised that several of the identified malignant rhabdoid tumors could contain mislocalized INI1/hSNF5. To test this hypothesis we reconstructed one of the INI1/hSNF5 mutants found in a malignant rhabdoid tumor as a GFP fusion [termed GFP INI1(1-319delG950)] and examined its subcellular localization. As predicted, GFP-INI1(1-319delG950) mislocalized to the cytoplasm. While GFP-INI1 causes flat cell formation when reintroduced into an INI1/hSNF5 deficient cell line (indicative of growth arrest), GFP-INI1(1-319delG950) does not. These results suggest that the growth suppressive properties of INI1/hSNF5 are linked to its action in the nucleus, and cytoplasmic mislocalization of INI1/hSNF5 may be one of the mechanisms of tumorigenesis in malignant rhabdoid tumors.
    Permanent Link(s)
    https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3027415
    https://hdl.handle.net/20.500.12202/539
    Citation
    Source: Dissertation Abstracts International, Volume: 62-09, Section: B, page: 3876.;Advisors: Ganjam V. Kalpana.
    *This is constructed from limited available data and may be imprecise.
    Collections
    • Albert Einstein College of Medicine: Doctoral Dissertations [1674]

    Yeshiva University Libraries copyright © 2021  DuraSpace
    YAIR Self-Deposit | YAIR User's Guide | Take Down Policy | Contact Us
    Yeshiva University
     

     

    Browse

    AllCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    Login as Editor

    Statistics

    View Usage Statistics

    Yeshiva University Libraries copyright © 2021  DuraSpace
    YAIR Self-Deposit | YAIR User's Guide | Take Down Policy | Contact Us
    Yeshiva University