Control of the cell response to chemotherapy by modulating degradation of p53 protein isoforms

We demonstrated that the p53 tumour suppressor gene expresses at least twelve different p53 proteins due to alternative splicing, alternative initiation of translation and alternative promoter usage. We determined that p53 isoform proteins are expressed in normal human tissue in a tissue dependent manner. P53 isoforms are abnormally expressed in a wide range of cancer and are associated with breast cancer prognosis.

P53 isoforms can bind DNA and can modulate gene-expression in a promoter dependent manner, regulating thus cell cycle progression, apoptosis, angiogenesis, senescence and differentiation. We demonstrated that p53 protein isoforms are degraded by the proteasome and are regulated by MDM2. The aim of the project is to characterise novel ubiquitin ligase that regulate degradation and stability of p53 protein isoforms and to develop novel drugs regulating it. We have already identified several ubiquitin ligases that can modulate the degradation of p53 protein isoforms.

The candidate will use a wide variety of techniques of biochemistry, molecular and cellular biology, including ubiquitinylation assay, protein degradation assay, co-immunoprecipitation , site directed mutagenesis, time-lapse, flow-cytometry, western-blot, quantitative PCR (Taqman), cell culture, luciferase reporter assay, immunofluorescent microscopy.

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Dr Jean-Christophe Bourdon
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