Signal transduction pathways involved in alternative splicing regulation

MATÍAS BLAUSTEIN; FEDERICO PELISCH; OMAR A. COSO; ALBERTO R. KORNBLIHTT; ANABELLA SREBROW

Bariloche, Argentina

Congreso; Reunión Anual de la Sociedad Argentina de Investigaciones Bioquímicas - SAIB; 2003

Alternative splicing generates distinct proteins from a single gene, and about fifty percent of the human genes undergo this process. Its regulation by extracellular signals is then critical for altering gene expression. Our laboratory studies the effect of extracellular signals triggered by epithelial-mesenchymal interactions on the alternative splicing of fibronectin pre-mRNA. We have previously shown that soluble factors present in a mammary mesenchymal cell-conditioned medium, as well as different growth factors, stimulate the inclusion of the alternatively spliced fibronectin EDI exon in mammary epithelial cells. We now show that the factors that induce the inclusion of EDI strongly activate different signalling cascades, resulting in the phosporylation of different protein kinases. Furthermore, the overexpression of a constitutively active form of Ras (RasV12) stimulates EDI inclusion in a dose-dependent manner. By using different pharmacological inhibitors we conclude that the PI3K pathway is the main responsible for the regulation of EDI splicing in this cellular context. On the other hand, inhibition of the JNK pathway potentiates the effects of different stimuli on the inclusion of this exon. Linkage of transduction pathways to alternative splicing provides a poorly understood way to convert extracellular stimuli into changes in splicing patterns that can result in different physiological responses.