Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2
Blaydes, J.P., Gire, V., Rowson, J. M. and Wynford-Thomas, D. (1997) Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2. Oncogene, 14, (15), 1859-1868.
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A significant proportion of human cancers express high levels of p53 protein in the absence of an underlying mutation in the gene. Using transformed (Vh1) and non-transformed (FRTL-5) rat thyroid epithelial cell lines as a model, we have examined the mechanisms by which high levels of wild-type p53 may be tolerated. Stable transfection with p53-dependent reporter constructs demonstrated that the 'excess' wild-type p53 in Vh1 cells is not associated with a comparable increase in p53-dependent transcription (though the response to u.v. irradiation is retained). Mdm-2, which binds p53 and inhibits its transactivation activity, is overexpressed in Vh1 cells in the absence of gene amplification and in a p53-dependent manner. Furthermore disruption of p53-mdm-2 complex formation in Vh1 cells by microinjection of an antibody to the p53-binding domain of mdm-2 resulted in a dramatic increase in p53-dependent transcription. Since only a small proportion of the p53 in Vh1 cells was found to be in complex with mdm-2 (the majority of unbound protein being in a latent form), this suggests that mdm-2 selectively binds a pool of p53 that would otherwise be active as a sequence-specific activator of transcription. We suggest that, in some types of tumour, the 'sensitivity' of the p53-driven mdm-2 feedback loop may be sufficient to prevent free, active p53 reaching the level required for growth arrest or apoptosis, making them an ideal target for therapies designed to disrupt p53-mdm-2 interactions.
|Subjects:||R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)|
|Divisions:||University Structure - Pre August 2011 > School of Medicine > Cancer Sciences
|Date Deposited:||20 Jul 2010 14:15|
|Last Modified:||27 Mar 2014 19:10|
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