CONCERTED REGULATION OF ALTERNATIVE SPLICING AND TRANSLATION BY EXTRACELLULAR CUES

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

Pinamar, Argentina

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

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

Alternative pre-mRNA splicing is the most important source ofprotein diversity in vertebrates. Regulation of this process by extracellular cues represents a key event in the control of geneexpression. We used the fibronectin (FN) gene as a model to studythe linkage between the cellular microenvironment and the splicing machinery. We found that growth factors up-regulate theinclusion of the FN EDA alternative exon via PI 3-kinase. We alsofound that growth factors alter translation of reporter mRNAs containing a FN EDA exonic splicing enhancer. The effects atboth splicing and translation levels are mediated by AKT andinhibited by knocking-down specific Serine/Arginine-rich (SR) splicing factors. Finally, we demonstrated that AKTphosphorylates SR proteins in vitro and that its over-expressionelicits opposite effects to those evoked by the previously described SR protein kinases Clk/Sty and SRPK on SR protein localizationand alternative splicing. These results show how SR proteinactivity is modified in response to extracellular cues leading to a concerted regulation of splicing and translation.