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Dissertation
The codon 72 polymorphism of p53 regulates interaction with NF-kB and transactivation of genes involved in immunity and inflammation
Doctor of Philosophy (Ph.D.), Drexel University
Feb 2011
DOI:
https://doi.org/10.17918/00000729
Abstract
The p53 tumor suppressor gene continues to be distinguished as the most frequently mutated gene in human cancer. The goal of this research is to understand how this protein induces programmed cell death (apoptosis) in normal and tumor cells. Within the p53 coding region is a common polymorphism at codon 72 that effect's p53's transcriptional and apoptotic functions. The first objective of this research was to identify functional differences between these codon 72 variants in an inbred mouse model. Toward this end, we used the Hupki ( Humanized p53 knock- in) mouse, which expresses a mouse-human chimeric p53 gene, in order to create mice containing P72 and R72 alleles. In the thymus of P72 mice we find that this variant induces increased apoptosis following ionizing radiation, relative to R72, along with increased transactivation of a subset of p53 target genes; these include murine Caspase 4/11 , which we show is a direct p53 target gene. Interestingly, the majority of these genes are known NF-[kappa]B targets and are involved in immunity and inflammation. We show that Caspase 4/11 requires both p53 and NF-[kappa]B for full induction after DNA damage and that the P72 variant shows increased interaction with p65 ReIA, a subunit of NF-[kappa]B. Consistent with these findings, we show that P72 mice have a markedly enhanced response to inflammatory challenge, compared to R72. Our data indicate that the codon 72 polymorphism impacts p53's role in innate immunity and inflammation. The second objective of proposed research was to better elucidate p53's apoptotic role at mitochondria. Toward this goal we identified caspase-3 as a novel mitochondrial p53-interacting protein. We find that tumor-derived mutant forms of p53 retain the ability to interact with mitochondrial caspase 3. Further, we find that mutant forms of p53 inhibit the ability of procaspase 3 to become proteolytically activated by Caspase 9. These data suggest that tumor-derived mutants of p53 may be selected for in tumor cells due to their ability to bind and inhibit the activation of Caspase 3. These combined data shed light on p53's tumor suppressive function in human cancer.
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Details
- Title
- The codon 72 polymorphism of p53 regulates interaction with NF-kB and transactivation of genes involved in immunity and inflammation
- Creators
- Amanda Kay Frank
- Contributors
- Maureen Murphy (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 190 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014970222504721