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Mechanisms of p53 Mutants ‘Gain-of-Function’ Effects in Human Cancer Cells

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dc.contributor.author Tan Boon Shing
dc.date.accessioned 2015-04-23T12:40:48Z
dc.date.accessioned 2018-07-10T08:31:59Z
dc.date.available 2015-04-23T12:40:48Z
dc.date.available 2018-07-10T08:31:59Z
dc.date.issued 2014
dc.identifier.uri http://localhost:8080/xmlui/handle/123456789/2190
dc.description.abstract The p53 tumour suppressor is the most frequently mutated gene in human cancers. Unlike other tumour-suppressor genes, p53 mutations mainly occur as missense mutations within the DNA-binding domain, leading to the stable expression of full-length mutant p53 proteins. A wide range of studies shows that mutant p53 proteins not only lose their tumour suppressor function, but may also actively promote tumourigenesis through gain-of-function (GOF) mechanisms. As such, expression of mutant p53 proteins is commonly associated with poor clinical prognosis and high metastatic rate. Anoikis is a form of apoptosis in response to loss of cell adhesion or inappropriate cell adhesion. Gaining resistance to anoikis may be a general necessity for the tumour cells to metastasise. Here, we showed that p53 R273H contact mutant, but not p53 R175H conformation mutant, suppressed anoikis by down-regulation of BCL2 modifying factor (BMF) expression. Ectopic expression of the activated form of AKT in MDA-MB-468 completely „rescued‟ the apoptotic effects following depletion of endogenous mutant p53, suggesting that p53 R273H mutant promotes anoikis resistance in breast cancer cells through suppression of BMF expression by activating AKT signalling pathway. In addition, our findings also demonstrated that p53 R273H contact mutant regulate the expression of miR-19 and miR-200 family member, suggesting that mutant p53 R273H might promote tumourigenesis through modulation of microRNAs expression. Finally, we showed that ectopic expression of wild-type and mutant p53 in p53-null cells confers differential regulation of metabolic genes, suggesting that wild-type and mutant p53 play a distinct role in regulating cellular metabolism in tumour cells in a cell type dependent context. In summary, our findings suggest a mechanism by which p53 mutants might promote tumorigenesis through 1) regulation of cancer cell survival via AKT-dependent suppression of BMF in a wide range of tumour types; 2) regulation of miRNA expression; and 3) modulation of cancer cell metabolism. en_US
dc.language.iso en en_US
dc.publisher International Medical University en_US
dc.subject Genes, p53 en_US
dc.subject Tumor Suppressor Protein p53 en_US
dc.subject Neoplasms en_US
dc.subject DNA en_US
dc.title Mechanisms of p53 Mutants ‘Gain-of-Function’ Effects in Human Cancer Cells en_US
dc.type Thesis en_US

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