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

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dc.contributor.advisorDillon, Glenn
dc.contributor.committeeMemberMallet, Robert T.
dc.contributor.committeeMemberShepard, Allan
dc.creatorEllis, Joel James
dc.date.accessioned2019-08-22T21:23:34Z
dc.date.available2019-08-22T21:23:34Z
dc.date.issued2006-05-01
dc.date.submitted2013-07-23T11:00:11-07:00
dc.description.abstractJoel 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.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29297
dc.language.isoen
dc.provenance.legacyDownloads0
dc.subjectBiochemistry
dc.subjectBiology
dc.subjectCardiology
dc.subjectCardiovascular Diseases
dc.subjectCardiovascular System
dc.subjectCell Biology
dc.subjectCells
dc.subjectCellular and Molecular Physiology
dc.subjectDevelopmental Biology
dc.subjectGenetic Phenomena
dc.subjectGenetics and Genomics
dc.subjectLife Sciences
dc.subjectMedical Cell Biology
dc.subjectMedicine and Health Sciences
dc.subjectMicrobiology
dc.subjectMolecular Biology
dc.subjectOther Cell and Developmental Biology
dc.subject14-3-3 inhibitor peptide
dc.subjectcardiomyocyte hypertrophic gene expression
dc.subjectmyocyte enhancer factor-2
dc.subjectphosphorylation
dc.subjectatrial natriuretic peptide transcriptional activity
dc.subjectheart disease
dc.titleThe Effects of a 14-3-3 inhibitor peptide on cardiomyocyte hypertrophic gene expression
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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