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Impact des dérégulations de p53 : du syndrome Li-Fraumeni aux syndromes d'insuffisance médullaire héréditaire

Abstract : TP53 is a tumor suppressor gene mutated in half of human cancers. Most of TP53 mutations affect the core DNA binding domain of the protein, and are located on seven « hotspot » residues. Among them, the Y220C mutation is found in 100 000 new cancer cases per year and in 10 Li-Fraumeni families of cancer predisposition. To study this mutation in vivo, I created a mouse model carrying the Y217C mutation, equivalent to the human Y220C. I showed that not only this mutation inactivates the function of the protein, but that it also confers new oncogenic functions. Moreover, this model is a great tool to evaluate the efficiency of a novel anti-tumoral strategy in vivo. Furthermore, the mouse p53∆31/∆31 model was created in our team and allowed us to demonstrate the negative regulatory role of the C-terminus of p53 in vivo. I used this model to discover the implication of p53 in the regulation of unsuspected cellular pathways in mice but also in humans, and to establish the mechanism of regulation. Surprisingly, these functions are responsible for the promotion of the genomic instability and p53’s high activity can cause bone marrow failure syndromes that predispose to cancer. Our observations have both fundamental and clinical impact for the diagnosis of these diseases and for the therapeutic anti-tumoral strategies according to p53’s status.
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Sara Jaber. Impact des dérégulations de p53 : du syndrome Li-Fraumeni aux syndromes d'insuffisance médullaire héréditaire. Biologie moléculaire. Université Pierre et Marie Curie - Paris VI, 2016. Français. ⟨NNT : 2016PA066242⟩. ⟨tel-01870619⟩

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