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    Tumor Angiogenesis and the role of RUNX2 transcription factor in endothelial cell function: regulation by glucose levels and oxidative stress

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    Author
    Kommineni, Sravya
    Advisor
    Passaniti, Antonino
    Date
    2011
    Type
    dissertation
    
    Metadata
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    Abstract
    The RUNX2 DNA-binding transcription factor is an important regulator of tumor angiogenesis. Its transcriptional activity is dependent on interaction with a cofactor, CBF?, which does not bind DNA, but enhances RUNX2 DNA binding. Recently, we discovered that RUNX2 DNA binding activity is regulated by glucose and the redox status of the cell. Euglycemic levels of glucose initiate a series of events leading to RUNX2 phosphorylation and DNA binding. In the presence of elevated levels of glucose (hyperglycemia), RUNX2 oxidation may reduce its ability to bind DNA. Therefore, we propose the hypothesis that the RUNX2 transcription factor regulates endothelial cell (EC) proliferation through its glucose response and redox status. To test this hypothesis, in specific aim 1, we will examine the ability of RUNX2 to associate with a target gene that regulates cell cycle progression and proliferation, the p21Cip1 promoter. This DNA interaction will be examined by chromatin immunoprecipitation assays and by DNA-binding assays. In specific aim 2, we will examine the effect of mutations in critical cysteine and methionine residues within RUNX2 that regulate DNA binding. The effect of these mutations on DNA binding will be examined using electrophoretic mobility shift assays. Two mutant proteins will be used: a GFP.tagged RUNT DNA binding domain fusion protein in which a methionine is converted to a valine (RUNT.M106V) and a cysteine to serine substitution in full-length RUNX2 at position 118 (RUNX2.C118S). These studies will help define the mechanisms through which nutrients and cellular redox status regulate RUNX2 activity and will provide opportunities for new therapeutic approaches.
    Description
    University of Maryland in Baltimore. Molecular Medicine. M.S. 2011
    Keyword
    Angiogenesis Inhibitors
    Neoplasms
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/770
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    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

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