The Role of RYBP in the Regulation of Apoptosis

Hdl Handle:
http://hdl.handle.net/10675.2/318823
Title:
The Role of RYBP in the Regulation of Apoptosis
Authors:
Novak, Rachel Lynn
Abstract:
The tumor suppressor Tp53 is the most frequently mutated gene in human cancer. Tp53 encodes a sequence specific transcription factor termed p53 that activates a number of biological programs contributing to tumor suppression, most notably, the promotion of cell cycle arrest and apoptosis. To identify new regulators of p53’s transcriptional activity, we performed a yeast 2-hyrbid screen and have identified Ring 1 YY1 Binding Protein (Rybp) as a novel p53-interacting partner. Consistent with its role as a transcriptional repressor, we have demonstrated that Rybp inhibits p53-mediated transcription. In addition, Rybp forms a trimeric complex with the critical negative regulator of p53, Mdm2. Mdm2 is an E3 ligase that ubiquitinates p53, targeting it for degradation, and expression of Rybp enhances the Mdm2-mediated ubiquitination. To further investigate the role of Rybp in the regulation of endogenous p53 stability we constructed a recombinant adenovirus expressing Rybp (Ad-Rybp). Ad-Rybp infection inhibited the accumulation of p53 and the induction of p53 target genes in response to genotoxic stress. However, interpretation of the results was confounded by Ad-Rybp infection reducing global mRNA levels. Despite inhibition of p53, Ad-Rybp was a powerful inducer of apoptosis, and we investigated this in more detail. Analysis of a panel of tumor cell and untransformed cell types revealed that Ad-Rybp infection specifically induces apoptosis in tumor cells but not in normal diploid cells. Furthermore, at a low multiplicity of infection, Ad-Rybp sensitizes tumor cells to apoptosis in the presence of the death receptor ligands, Tumor Necrosis Factor alpha (TNFα) and TNF related apoptosis inducing ligand (TRAIL). These results suggest that the tumor-specific killing properties of Rybp may be exploited for therapeutic advantage.
Issue Date:
5-Jun-2014
URI:
http://hdl.handle.net/10675.2/318823
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/304403814?accountid=12365
Type:
Dissertation
Language:
en
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorNovak, Rachel Lynnen
dc.date.accessioned2014-06-05T01:52:29Z-
dc.date.available2014-06-05T01:52:29Z-
dc.date.issued2014-06-05-
dc.identifier.urihttp://hdl.handle.net/10675.2/318823-
dc.description.abstractThe tumor suppressor Tp53 is the most frequently mutated gene in human cancer. Tp53 encodes a sequence specific transcription factor termed p53 that activates a number of biological programs contributing to tumor suppression, most notably, the promotion of cell cycle arrest and apoptosis. To identify new regulators of p53’s transcriptional activity, we performed a yeast 2-hyrbid screen and have identified Ring 1 YY1 Binding Protein (Rybp) as a novel p53-interacting partner. Consistent with its role as a transcriptional repressor, we have demonstrated that Rybp inhibits p53-mediated transcription. In addition, Rybp forms a trimeric complex with the critical negative regulator of p53, Mdm2. Mdm2 is an E3 ligase that ubiquitinates p53, targeting it for degradation, and expression of Rybp enhances the Mdm2-mediated ubiquitination. To further investigate the role of Rybp in the regulation of endogenous p53 stability we constructed a recombinant adenovirus expressing Rybp (Ad-Rybp). Ad-Rybp infection inhibited the accumulation of p53 and the induction of p53 target genes in response to genotoxic stress. However, interpretation of the results was confounded by Ad-Rybp infection reducing global mRNA levels. Despite inhibition of p53, Ad-Rybp was a powerful inducer of apoptosis, and we investigated this in more detail. Analysis of a panel of tumor cell and untransformed cell types revealed that Ad-Rybp infection specifically induces apoptosis in tumor cells but not in normal diploid cells. Furthermore, at a low multiplicity of infection, Ad-Rybp sensitizes tumor cells to apoptosis in the presence of the death receptor ligands, Tumor Necrosis Factor alpha (TNFα) and TNF related apoptosis inducing ligand (TRAIL). These results suggest that the tumor-specific killing properties of Rybp may be exploited for therapeutic advantage.en
dc.language.isoenen
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/304403814?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.-
dc.subjectp53en
dc.subjectapoptosisen
dc.subjectCanceren
dc.subjectRybpen
dc.subjecttranscriptional repressionen
dc.subjectGene Therapyen
dc.titleThe Role of RYBP in the Regulation of Apoptosisen
dc.typeDissertationen
dc.description.advisorPhillips, Andrewen
dc.description.committeeMivechi, Nahid; Bollag, Wendy; Horuzsko, Anatolijen
dc.description.degreeDoctor of Philosophy (Ph.D.)-
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