This study is aimed at investigating the molecular biology of the p53 protein and its relevance to growth control and neoplasia. Wild type (wt) p53 now appears to act as a tumor suppressor, and the high frequency of tumors exhibiting aberrant p53 expression suggests that the abrogation of wt p53 activity may play a major role in human cancer. This study intends to address possible mechanisms underlying the tumor suppressor and anti-proliferative functions of wt p53. One set of experiments will test the hypothesis that wt p53 may promote terminal differentiation. This will entail the introduction of wt p53 expression plasmids into a number of cell types capable of induced differentiation, in an attempt to see whether wt p53 can alleviate the need for added inducers. In parallel, an attempt will be made to isolate cell clones which are resistant to the anti-proliferative effect of wt p53. This, as well as a number of other facets of this project, will rely on the use of a temperature-sensitive p53 mutant, p53vall35. Resistant and sensitive lines will be used for cell fusion, and eventually for the molecular cloning of genes involved in p53-mediated growth regulation. The relevance of p53 aberrations to neoplasia will be further assessed by introducing wt p53 expression into a variety of cell lines, and correlating the outcome with the target cell genotype and the type of vector encoding p53. A mouse model, based on the use of immunocompetent animals, will also be explored in order to investigate in vivo aspects of p53 pertinent to its role in neoplasia. Furthermore, the possibility that certain mutant forms of p53 carry overt oncogenic activities will be tested, using as recipients cells which make no endogenous p53. Finally, the p53 gene promoter will be further characterized, with emphasis on a potential novel regulatory element.
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| Michael, Dan; Oren, Moshe (2003) The p53-Mdm2 module and the ubiquitin system. Semin Cancer Biol 13:49-58 |
| Wang, X; Zalcenstein, A; Oren, M (2003) Nitric oxide promotes p53 nuclear retention and sensitizes neuroblastoma cells to apoptosis by ionizing radiation. Cell Death Differ 10:468-76 |
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| Gottlieb, Tanya M; Leal, Juan Fernando Martinez; Seger, Rony et al. (2002) Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 21:1299-303 |
| Blander, Gil; Zalle, Noa; Daniely, Yaron et al. (2002) DNA damage-induced translocation of the Werner helicase is regulated by acetylation. J Biol Chem 277:50934-40 |
| Oren, Moshe; Damalas, Alexander; Gottlieb, Tanya et al. (2002) Regulation of p53: intricate loops and delicate balances. Ann N Y Acad Sci 973:374-83 |
| Folberg-Blum, Adriana; Sapir, Amir; Shilo, Ben-Zion et al. (2002) Overexpression of mouse Mdm2 induces developmental phenotypes in Drosophila. Oncogene 21:2413-7 |
| Oren, Moshe; Damalas, Alexander; Gottlieb, Tanya et al. (2002) Regulation of p53: intricate loops and delicate balances. Biochem Pharmacol 64:865-71 |
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