Etudes moléculaires et fonctionnelles des gènes TSAP6 et TCTP

The purpose of my PhD was a functional characterization of the TCTP and TSAP6 genes. These genes are implicated in tumor reversion and form a complex at the protein level. The Tpt1 gene encoding for the TCTP protein is the most differentially expressed one between tumor cells and revertants. It is strongly downregulated in different models of tumor reversion. <br />The analysis of the crystal structure of TCTP reveals two helices, H2-H3, which are homologous to the H5-H6 helices of Bax. These H2-H3 helices of TCTP are implicated in the inhibition of Bax dimer formation and hence, the inhibition of apoptosis. <br />We generated TCTP knockout mice that are lethal during early embryonic development. <br />In parallel, we studied TSAP6,that encodes for a 6 transmembrane domains protein and is a direct transcriptional target of p53. We demonstrate that TSAP6 knockout mice have a microcytic anemia. These mice show a delay in the maturation of reticulocytes with a decrease in the secretion of the Transferrin receptor by the exosomes. More generally, our data indicate, in vivo, that TSAP6 controls the secretion of exosomes induced by the activation of p53. Finally, we show that Sertraline and Thioridazine prevent the formation of a protein complex between TSAP6 and TCTP.