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    The Effects of a 14-3-3 inhibitor peptide on cardiomyocyte hypertrophic gene expression

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    Date
    2006-05-01
    Author
    Ellis, Joel James
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    Abstract
    Joel James Ellis, The Effects of a 14-3-3 inhibitor peptide on cardiomyocyte hypertrophic gene expression. Doctor of Philosophy (Biomedical Sciences), May 2006, 164 pp, 2 tables, 29 illustrations, references, 117 titles. The myocyte enhancer factor-2 (MEF2) family of transcription factors regulates transcription of muscle-dependent genes in skeletal, smooth and cardiac muscle types. MEF2 is activated by calcium/calmodulin (CaM)-dependent protein kinases I and IV and silenced by CaM kinase IlδC. MEF2 is held inactive in the nucleus by class I histone deacetylases (HDAC4&5) until phosphorylated by either CaM kinase I or IV. This phosphorylation results in HDAC transport out of the nucleus via a 14-3-3-dependent mechanism, thereby freeing MEF2 to drive transcription. 14-3-3 proteins exist as homodimers, which are modulated by the phosphorylation of serines 60 and 65 in the dimerization region. In this study, a HIV TAT protein transduction domain (PTD) fused 14-3-3 peptide inhibitor was generated that is designed to prevent the dimerization of 14-3-3 proteins. The data presented demonstrates that the 14-3-3 inhibitor peptide freely enters cardiomyocytes and is not cytotoxic under culture conditions. The presence of this 14-3-3 inhibitor promotes nuclear localization of class II HDACs in the presence of hypertrophic stimuli. Moreover, the 14-3-3 inhibitor prevented dimerization of wild type 14-3-3β in ventricular cardiomyocytes. Finally, increased MEF2-dependent transcriptional activity, due to CaMKI, CaMKIV and PE, was effectively silenced by this 14-3-3 inhibitor in cardiomyocytes. Atrial natriuretic peptide (ANP) transcriptional activity was also pressed in the presence of the 14-3-3 inhibitor under these same conditions. Taken together, these data suggest that the 14-3-3 inhibitor peptide is able to affect dimerization of 14-3-3, revealing a key regulatory point in the signaling of cardiac hypertrophy. Information from these results may provide a promising point of therapeutic intervention in the progression of heart disease due to cardiomyocyte hypertrophy.
    Subject
    Biochemistry
    Biology
    Cardiology
    Cardiovascular Diseases
    Cardiovascular System
    Cell Biology
    Cells
    Cellular and Molecular Physiology
    Developmental Biology
    Genetic Phenomena
    Genetics and Genomics
    Life Sciences
    Medical Cell Biology
    Medicine and Health Sciences
    Microbiology
    Molecular Biology
    Other Cell and Developmental Biology
    14-3-3 inhibitor peptide
    cardiomyocyte hypertrophic gene expression
    myocyte enhancer factor-2
    phosphorylation
    atrial natriuretic peptide transcriptional activity
    heart disease
    URI
    https://hdl.handle.net/20.500.12503/29297
    Collections
    • School of Biomedical Sciences
    • Theses and Dissertations

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