P53 transactivation-domain mutant mice reveal context-specific differences in P53's mechanism of action
Abstract/Contents
- Abstract
- The p53 protein suppresses tumorigenesis by inducing cell cycle arrest, apoptosis, or cellular senescence. At the molecular level p53 plays a central role as a transcriptional activator, and p53 has two amino-terminal transactivation domains important for this role. However, the contribution of each of these domains to p53 activity has not been determined in vivo. To analyze transactivation domain requirements for p53 function, we have generated a series of p53 knock-in mouse models in which we replaced the endogenous p53 gene with transactivation mutants containing point mutations in the first (p53^25,26), second (p53^53,54), or both (p53^25,26,53,54) p53 transactivation domains. These experiments are the first to address the unique contribution of each of the p53 transactivation domains in vivo. By gene expression microarray, we determined that these mutants represent an allelic series of p53 transactivation mutants, whereby p53^53,54 retains wild-type p53 transactivation potential, p53^25,26,53,54 loses nearly all p53-dependent transactivation, and p53^25,26 exhibits a severely compromised transactivation phenotype. Experiments comparing all three transactivation domain mutants in cell culture and mouse models have unveiled important differences in the function of the two transactivation domains. Apoptosis or cell-cycle arrest downstream of acute DNA damage rely on the first transactivation domain and robust p53 transactivation, while senescence and tumor suppression in response to oncogene activation can occur without the full transactivation function of p53. These results implicate unique p53 transcriptional programs in acute DNA damage responses and tumor suppression, and mechanistically distinguish these two p53 response pathways. Further, we have uncovered striking differences in the developmental phenotypes of these different mutant mice, leading to conclusions about the activity of p53 tetramers.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Brady, Colleen Ann |
|---|---|
| Associated with | Stanford University, Program in Cancer Biology. |
| Primary advisor | Attardi, Laura |
| Thesis advisor | Attardi, Laura |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Lipsick, Joseph Steven, 1955- |
| Thesis advisor | Sage, Julien |
| Advisor | Brunet, Anne, 1972- |
| Advisor | Lipsick, Joseph Steven, 1955- |
| Advisor | Sage, Julien |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Colleen Ann Brady. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Ph.D. Stanford University 2011 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Colleen Ann Brady
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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