p53 in a Genetic Model: Illuminating Adaptive Radiation Responses
| dc.contributor.advisor | Abrams, John M. | en |
| dc.creator | Sogame, Naoko | en |
| dc.date.accessioned | 2010-07-12T17:56:46Z | |
| dc.date.available | 2010-07-12T17:56:46Z | |
| dc.date.issued | 2005-05-03 | |
| dc.description.abstract | When cells are challenged by genotoxic stress, the tumor suppressor protein p53 promotes adaptive responses, including cell cycle arrest, DNA repair, or apoptosis. How these distinct fates are specified through an action of a single protein is not known. To study its functions in vivo we produced a targeted mutation at the Drosophila p53 (Dmp53) locus. I show that Dmp53 is required for damage-induced apoptosis but not for cell cycle arrest. Dmp53 function is also required for damage-induced transcription of two tightly linked cell death activators, reaper and sickle. When challenged by ionizing radiation, Dmp53 mutants exhibit radiosensitivity and genomic instability, indicating in our model, apoptosis is important for maintenance of genomic stability in response to ionizing radiation. I also examined a global transcriptional change in response to ionizing radiation in the absence of Dmp53. Only 35 genes were constantly radiation responsive in wild type animals and Dmp53 was required for induction of a vast majority of the genes. The Radiation Induced p53 Dependent (RIPD) genes include genes implicated in apoptosis and DNA repair as well as genes with unknown functions. The functional significance of RIPD genes for the activation of apoptosis was tested using RNAi. Thus far, I uncovered ribonucleotide reductase large subunit (RnrL) as a novel Dmp53 target that is necessary for induction of caspase activation. Taken together, my study supports the notion that core ancestral functions of the p53 gene family are intimately coupled to cell death and possibly DNA repair as an adaptive response. | en |
| dc.format.digitalOrigin | born digital | en |
| dc.format.medium | Electronic | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 60625878 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/405 | |
| dc.language.iso | en | en |
| dc.subject | Genes, p53 | en |
| dc.subject | Cell Survival | en |
| dc.subject | Apoptosis | en |
| dc.title | p53 in a Genetic Model: Illuminating Adaptive Radiation Responses | en |
| dc.type | Thesis | en |
| dc.type.genre | dissertation | en |
| dc.type.material | Text | en |
| thesis.date.available | 2005-05-03 | |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Genetics and Development | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |