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Contribution of the DNA binding domain of p53 to regulation of its stability

Lukashchuk, Natalia (2008) Contribution of the DNA binding domain of p53 to regulation of its stability. PhD thesis, University of Glasgow.

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Abstract

Tumour suppressor p53 is frequently mutated in cancers. While wild type p53 is normally a rapidly degraded protein, mutant forms of p53 are stabilised and accumulate to high levels in tumour cells. Several studies have shown that mutant p53 acquires oncogenic properties and actively contributes to tumourigenesis. It is therefore important to understand how the stability of mutant p53 is regulated. This thesis shows that mutant and wild type p53 are ubiquitinated and degraded through overlapping but distinct pathways. While Mdm2 can drive the degradation of both mutant and wild type p53, this study suggests that the ability of Mdm2 to function as a ubiquitin ligase is less important in the degradation of mutant p53, which is heavily ubiquitinated in an Mdm2-independent manner. The contribution of Mdm2 to the degradation of mutant p53 may reflect an ability of Mdm2 to deliver the ubiquitinated mutant p53 to the proteasome. Ubiquitination does not efficiently target mutant p53 for the proteasomal degradation, however ubiquitinated p53 mutants localize to the cytoplasm. This thesis suggests the role for the chaperone-associated ubiquitin ligase CHIP in ubiquitination of mutant p53, although other unidentified ubiquitin ligases appear to contribute. Interaction of mutant p53 with its family member p73 decreases ubiquitination, suggesting p73 can play a role in regulation of stability of mutant p53.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: ubiquitination, degradation, mutant p53, nutlin, Mdm2
Subjects: Q Science > QH Natural history > QH301 Biology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Supervisor's Name: Vousden, Prof. Karen
Date of Award: 2008
Depositing User: Dr Natalia Lukashchuk
Unique ID: glathesis:2008-528
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Dec 2008
Last Modified: 10 Dec 2012 13:19
URI: http://theses.gla.ac.uk/id/eprint/528

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