The p53 response is differentially regulated by numerous mechanisms initiated by stress.
Item
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Title
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The p53 response is differentially regulated by numerous mechanisms initiated by stress.
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Identifier
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AAI3169995
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identifier
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3169995
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Creator
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White, David E.
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Contributor
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Adviser: Jill Bargonetti
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Date
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2005
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular
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Abstract
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When the living environment is favorable, the p53 response is stringently suppressed by the cell. Activation of p53 by genotoxic stress leads to the initiation of growth suppressive pathways. These pathways are mediated, in part, from the protein products of genes upregulated by p53. We found that Mdm2 protein co-localized with p53 on the p53 binding sites of target genes prior to activation. Once p53 is activated, Mdm2 briefly dissociated from p53. At later timepoints, however, Mdm2 was found to reassociate with p53 on chromatin. The reformation of this inhibitory complex correlated with decreased transcription from these target genes. We also found that the induction of growth arrest or apoptotic pathways by p53 did not correlate with the expression of p53 target genes. The level of p53 protein and p53 target gene expression required to shift a cell from a growth arrest to an apoptotic cell fate differ according to the damaging agent used. In examining the p53-dependent and independent apoptotic pathways induced by mitomycin C (MC) and its derivative 10-decarbamoyl mitomycin C (D-MC), we found that MC and D-MC induced cell death in cells expressing wild type p53 provoked slightly different apoptotic pathways. MC treatment promoted the stabilization of p73, greater levels of p53 phosphorylation at serine 15, but the p53 induced by this drug exhibited less transcriptional activity than the p53 protein induced by D-MC. In a p53 null environment, however, only D-MC was capable of inducing apoptosis. The apoptotic pathway utilized by D-MC occurred independently of p53 apoptotic target gene activation and was found to be dependent on both caspase and serine protease activity.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
