REGULATION OF ALTERNATIVE SPLICING IN THEMAMMARY GLAND DIFFERENTIATION

PELISCH, F; BLAUSTEIN, M; QUADRANA, L; SREBROW, A

Pinamar, Argentina

Congreso; XLI Reunion Anual de la Sociedad Argentina de Investigacion en Bioquímica y Biologia Molecular; 2005

Sociedad Argentina de Investigacion en Bioquímica y Biologia Molecular (SAIB)

Alternative splicing generates distinct proteins from a single gene. Fibronectin (FN) plays a key role in cell adhesive andmigratory behaviour and provides a paradigmatic model of alternative splicing. We have previously shown that growthfactors (GF) secreted by mesenchymal cells up-regulate FNEDI and IIICS exon inclusion in mammary epithelial cells via PI3K and, on the contrary, a basement membrane-like extracellular matrix down-modulates EDI and IIICS inclusion. Moreover, siRNA and inhibitor data show that this effect is entirely dependent on the activation of JNK. Furthermore, the BM inhibits the effects of GF on alternativesplicing, consistent with the opposite roles reported for PI3K and JNK. The effect of GF is reproduced upon over-expression of a constitutively active form of AKT, and the latter is inhibited by the over-expression of JNK. On the other hand, the role of the dephosphorylation of ERK observed upon treatment with the BM is further investigated.These results strengthen our understanding of how extracellular stimuli are converted into changes in splicing patterns.