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Please use this identifier to cite or link to this item: http://hdl.handle.net/1993/3172

Title: Transcriptional regulation of the pro-apoptotic gene Bnip3 by P65 NF-κB, Histone Deacetylase 1, and E2F-1 in postnatal ventricular myocytes
Authors: Shaw, James Alexander
Supervisor: Kirshenbaum, Lorrie (Pharmacology; Physiology)
Examining Committee: Kardami, Elissavet (Human Anatomy & Cell Sci); Parkinson, Fiona (Pharmacology); Sitar, Daniel (Pharmacology); Hall, Jennifer (Lillehei Heart Institute, Department of Medicine; Developmental Biology Center, University of Minnesota, USA)
Graduation Date: October 2009
Keywords: Bnip3
E2F-1
Apoptosis
Hypoxia
Mitochondria
Myocyte
NF-κB
Cell Culture
HDAC1
Issue Date: 20-Aug-2009
Citation: Shaw J, Kirshenbaum LA. Molecular regulation of autophagy and apoptosis during ischemic and non-ischemic cardiomyopathy. Autophagy. 2008;4(4):427-34.
Shaw J, Zhang T, Rzeszutek M, Yurkova N, Baetz D, Davie JR, Kirshenbaum LA. Transcriptional silencing of the death gene BNIP3 by cooperative action of NF-kappaB and histone deacetylase 1 in ventricular myocytes. Circ Res. 2006;99(12):1347-54.
Yurkova N, Shaw J, Blackie K, Weidman D, Jayas R, Flynn B, Kirshenbaum LA. The cell cycle factor E2F-1 activates Bnip3 and the intrinsic death pathway in ventricular myocytes. Circ Res. 2008;102(4):472-9.
Abstract: Apoptotic cell death of cardiac myocytes plays an important pathological role after a myocardial infarction and during heart failure. Apoptotic myocytes are not regenerated because of the restricted ability of terminally differentiated cardiac myocytes to undergo cell division. Because ventricular function is directly related to the number of active muscle cells, the inappropriate loss or premature death of cardiac myocytes results in reduced cardiac performance. Bnip3 was previously identified by Dr. Lorrie Kirshenbaum’s laboratory as a critical mediator of hypoxia-induced apoptosis in the heart. Importantly, his lab established that the cytoprotective actions of NF-κB during hypoxia included the transcriptional repression of Bnip3. However, the mechanism by which NF-κB acted as a transcriptional repressor was undefined. The present work strongly supports the hypothesis that NF-κB-mediated inhibition of Bnip3 transcription is dependent on the recruitment of the corepressor protein HDAC1. Immunoprecipitation experiments revealed that HDAC1 and p65 NF-κB formed protein-protein interactions. ChIP assays demonstrated that HDAC1 and p65 NF-κB associated with the Bnip3 promoter. HDAC1-mediated repression of Bnip3 was lost in cells deficient for p65 NF-κB, and restored upon repletion of p65. A second avenue of investigation described in this work demonstrated that the cell cycle factor E2F-1 directly activated Bnip3 transcription. Earlier work by Dr. Kirshenbaum found that adenovirus-mediated overexpression of E2F-1 in ventricular myocytes induced apoptosis. Herein, it is shown that E2F-1-mediated cell death is largely Bnip3-dependent because functional loss of Bnip3 inhibited E2F-1-induced cell death. Concerning hypoxia, Bnip3 expression is dependent upon the loss of p65/HDAC1-mediated repression, and on the presence of transcriptionally active E2F-1. During hypoxia, overexpression of p65, HDAC1, or Rb, an endogenous inhibitor of E2F-1-dependent transcription, attenuated hypoxia-induced Bnip3 transcription. Based on these findings, future therapies may be designed to repress Bnip3 gene expression after a myocardial infarction, thereby averting cardiac cell death and preserving cardiac function post-infarction.
URI: http://hdl.handle.net/1993/3172
Appears in Collection(s):FGS - Electronic Theses & Dissertations (Public)

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