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Expression levels of MDM2 and MDMX proteins and their associated effects on P53 in human liposarcomas

Touqan, Nader (2014) Expression levels of MDM2 and MDMX proteins and their associated effects on P53 in human liposarcomas. M.D. thesis, University of Leeds.

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Abstract

Background: Inactivation of wild type P53 by its main cellular inhibitors, MDM2 and MDMX, is a well-recognised feature of tumour formation in liposarcomas (LS). MDM2 over-expression has been detected in approximately 80% of liposarcomas, but only limited information is available about MDMX expression levels. On commencing this work, we were not aware of any study that had described the patterns of MDM2 and MDMX co-expression in liposarcomas. Such information has become more pertinent as various novel MDM2 and / or MDMX single and dual affinity antagonist compounds have emerged as alternative approaches for potential targeted therapeutic strategies in LS. Methods: After appropriate optimisation and confirmation of experimental techniques, a case series of 64 pathologically characterised liposarcomas of various sub-types was analysed by immunohistochemistry, to simultaneously assess the expression levels of P53, MDM2 and MDMX. P53 mutation status was investigated in cases that over-expressed P53. Results: 83% of cases over-expressed MDM2 and 69% co-expressed MDMX at varying relative levels. The relative expression levels of the two proteins with respect to each other were subtype-dependent. This apparently affected the detected levels of P53 directly, in two distinct patterns. Diminished levels of P53 were observed when MDM2 was significantly higher in relation to MDMX, suggesting a dominant role for MDM2 in the degradation of P53. Higher levels of P53 were noted with increasing MDMX levels, suggesting an interaction between MDM2 and MDMX that resulted in reduced efficiency of MDM2 when degrading P53. No increased incidence of P53 mutations was detected in cases that over-expressed P53 compared to the general population of LSs. Conclusions: The results of the study indicated that complex dynamic interactions between MDM2 and MDMX proteins may directly affect the cellular levels of P53 in human liposarcomas. This suggests that careful characterisation of all these markers will be necessary when considering in vivo evaluation of novel MDM blocking compounds as a therapeutic strategy to restore wild type P53 functions.

Item Type: Thesis (M.D.)
Keywords: STS, Liposarcoma, P53, MDM2, MDMX, targeted therapy, nutlins
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Genetics (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds)
Identification Number/EthosID: uk.bl.ethos.635381
Depositing User: Mr Nader Touqan
Date Deposited: 11 Feb 2015 10:46
Last Modified: 25 Nov 2015 13:47
URI: http://etheses.whiterose.ac.uk/id/eprint/7283

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