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    Rab-Vesicle Trafficking is Required for Ras-Mediated Proliferation

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    Genre
    Thesis/Dissertation
    Date
    2015
    Author
    Gaisford, Esme Ann
    Advisor
    Goldfinger, Lawrence
    Committee member
    Thomas, Gareth
    Haines, Dale
    Sirover, Michael A.
    Department
    Biomedical Sciences
    Subject
    Biology
    Biochemistry
    Cellular Biology
    Cancer
    Rab
    Ras
    Trafficking
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/2890
    
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    DOI
    http://dx.doi.org/10.34944/dspace/2872
    Abstract
    The Ras superfamily consists of over 150 members including the well-known: H-Ras, K-Ras and N-Ras. We propose to target Ras related proliferation in cancer cells by inhibiting Rab vesicle formation. H-Ras, K-Ras and N-Ras are carcinogenic; activating mutations in Ras signaling are generally associated with increased proliferation and survival in cancer cells. Ras is mutated in up to 30% of all human cancers and represents an early survival mutation in cancer cells. Vesicle-bound Ras is trafficked to the plasma membrane, which facilitates interaction between Raf, and effector proteins. Previously, farnsesylation inhibitors, (FTIs) and GTP binding agonists of Ras have been tested as potential pharmacological inhibitors of Ras signaling. However, both drug types have proven ineffective in-vivo. Therefore, there are currently no effective pharmacological treatments to target Ras signaling. However, unpublished data from our lab has identified co-localization of Ras and Rab proteins, in vesicles. Rab proteins are associated with vesicle budding, and endosome development. Rab activity is driven by GTP binding and geranylgeranylation. Non-geranylgeranylated Rab is cytosolic, and does not facilitate endosome formation or vesicle trafficking. We propose that by targeting the Rab specific geranylgeranylation via Rab-specific geranylgeranyl transferase II, we will inhibit Ras associated proliferation. We will pursue this hypothesis by testing three objectives. First, we will produce and test Rab-geranylgeranyl transferase (RGGT)-shRNA to target Rab specific geranylgeranyl transferase. Second, we will illustrate the effect of RGGT knockdown on a downstream signaling target of Ras, specifically pERK levels. Finally, we will measure the direct effect of RGGT knockdown on Ras mediated cellular proliferation. Our results conclude that RGGT-shRNA is a potential target of Ras mediated tumor proliferation.
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