What regulates the alternative splicing of the TP53 gene and how can we take control of it to change cell fate outcome in response to cellular stress?

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 we can take control of the cell response to cellular stress by using siRNA specific to p53 isoforms. The aim of the project is to characterise the alternative splicing process of the p53 gene and to develop novel drugs regulating it. We have already identified molecules that modify the alternative splicing of p53 and change thus the cell response to stress in a p53 isoform dependent manner.

The candidate will use a wide variety of techniques of molecular and cellular biology, including p53 mini-gene, ChIP, RNA-IP, site directed mutagenesis, time-lapse, flow-cytometry, western-blot, quantitative PCR (Taqman), cell culture, luciferase reporter assay, immunofluorescent microscopy.

CV and recommendation letter required.

Dr Jean-Christophe Bourdon
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Self funding