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" The opposing roles of wt p53 and mutant p53 in the regulation of cell death "
Perry Stambolsky
V. O. Rotter, Moshe
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Latin Dissertation
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| Language of Document
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English
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| Record Number
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54893
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| Doc. No
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TL24847
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| Call number
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3461785
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| Main Entry
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Perry Stambolsky
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| Title & Author
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The opposing roles of wt p53 and mutant p53 in the regulation of cell death\ Perry Stambolsky
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| College
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The Weizmann Institute of Science (Israel)
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| Date
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2008
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| Degree
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Ph.D.
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| student score
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2008
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| Page No
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82
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| Abstract
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My thesis deals with two different faces of the p53 protein; wild type (wt) p53 as a tumor suppressor, and mutp53 as a cancer promoter. Together, the work presented in this thesis demonstrates the complex nature of p53, and the different roles that it plays in cancerrelated processes. The first part of the thesis addresses the function of wt p53, which plays a pivotal role in suppressing tumorigenesis by maintaining genomic stability and inducing cell cycle arrest or apoptosis. Specifically, I show that expression of the AIF gene is regulated by basal levels of p53. Under normal conditions in the absence of overt apoptotic signals, the constitutive induction of AIF by p53 may highlight a cytoprotective maintenance function, based on the activity of AIF as a free radical scavenger. AIF is a mitochondrial protein involved in apoptosis, primarily in caspase independent contexts. Given an apoptotic signal, elevated AIF levels result in increased caspase independent apoptotic death. The second part of the thesis deals with the biochemistry and biology of cancer-associated mutp53 (mutp53) isoforms. Once p53 is mutated, it not loses its tumor suppressor activity, but it also acquires new oncogenic function. The mechanisms underlying this gain of function are still largely under investigation. The work described in my thesis offers one of the first specific mechanistic insights into mutp53 action. I describe a cross talk between mutp53 and VDR (vitamin D receptor) on several molecular and functional levels. I suggest that, through a physical interaction between mutp53 and VDR physically, VDR is able to recruit mutp53 to its cognate responsive element present in the promoters of VDR target genes. On the other hand mutp53 increases VDR levels in the nucleus and is able to influence the expression of different VDR target genes. This probably accounts for the observed phenotype, namely a protective, anti apoptotic effect of vitamin D in cells harboring mutp53, compared to a growth inhibitory and cell death promoting effect exerted by vitamin D in cells expressing wt p53.
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| Subject
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Biological sciences; Cancer promoters; Protein functionality; Tumor suppressors; Wild type p53; Molecular biology; 0307:Molecular biology
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| Added Entry
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V. O. Rotter, Moshe
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The Weizmann Institute of Science (Israel)
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