Overexpression of tumor-derived mutant p53 is a common event in tumorigenesis, suggesting an advantageous selective pressure in cancer initiation and progression. Given that p53 is found to be mutated in 50% of all human cancers, restoration of mutant p53 to its wild type biological function has been a widely sought after avenue for cancer therapy. Most research efforts have largely focused on restoration of mutant p53 by artificial means given that p53 has some degree of conformational flexibility allowing for introduction of short peptides and artificial compounds. Recently, theoretical modeling and studies focused on restoration of mutant p53 by physiological means has raised the question of whether there are effective therapies worth exploring that focus on global physiological mechanisms of restoration of p53. Herein, we provide computational analysis of the thermodynamic stabilities of both wild-type and mutant p53 core domains by studying their respective minimum potential energies. Also, it is widely accepted that wild type p53 is modulated by various acetyl transferases as well as deactylases, but whether this mechanism of p53 modulation can be exploited for physiological restoration of mutant p53 remains under intense investigation. Using prostate cancer cell lines representative of varying stages of aggressiveness as a model, we show that ID4 dependent acetylation promotes mutant p53 DNA-binding capabilities to its wild type consensus sequence, thus regulating p53-dependent target genes leading to subsequent cell cycle arrest and apoptosis. Specifically, we identify that ID4 promotes acetylation of K373 and to a lesser extent K320, in turn regulating p53-dependent biological activities. Together, our data provides computational analysis of the core domain of certain mutant forms of p53 and a molecular understanding of ID4 dependent acetylation that suggests a strategy of enhancing p53 acetylation at sites K373 and K320, critical sites of post translational modification of p53, that may serve as a viable mechanism of physiological restoration of mutant p53 to its wild type biological function.
| Identifer | oai:union.ndltd.org:auctr.edu/oai:digitalcommons.auctr.edu:cauetds-1089 |
| Date | 16 May 2016 |
| Creators | Morton, Derrick J, Jr. |
| Publisher | DigitalCommons@Robert W. Woodruff Library, Atlanta University Center |
| Source Sets | Atlanta University Center |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University |
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