Pre-mRNA alternative splicing is a major mechanism of diversification of genetic information in evolued eukaryotes. The expression of about 70% of genes is regulated by this mechanism. During late erythroid development, the inclusion of exon 16 in the mature 4.1R mRNA is a major event that is essential for the corresponding protein function. This process is inhibited in MEL cells overexpressing the oncoprotein Spi-1/PU.1. My thesis work aims to understand the mechanism of this inhibition by studying the role of PI3K signal transduction pathway and its effects on Spi-1/PU.1 in the first place, then its effects on the SR protein family. I showed that PI3K inhibition leads to the activation of hemoglobin synthesis and to the inclusion of exon 16. Moreover, I showed that the phosphorylation mediated by the PI3K pathway is necessary for both the differentiation-inhibiting activity of Spi-1/PU.1 and concurrent inclusion of exon 16. Finally, I showed that the Srp40 splicing factor is an activator of the exon 16 inclusion. Overexpression of Srp40 in MEL cells lineage activates exon 16 inclusion independently of the differentiation.
