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Mol. Cell. Biol. doi:10.1128/MCB.00565-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Protein Kinase C-dependent Control of Bcl-x Alternative Splicing

RNA/RNP Group. Département de microbiologie et d'infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada. J1H 5N4

^* To whom correspondence should be addressed. Email: Benoit.Chabot{at}USherbrooke.ca.

	Abstract

The alternative splicing of Bcl-x generates the pro-apoptotic Bcl-x_S protein and the anti-apoptotic isoform Bcl-x_L. Bcl-x splicing is coupled to signal transduction since ceramide, hormones and growth factors alter the ratio of the Bcl-x isoforms in different cell lines. Here we report that the protein kinase C (PKC) inhibitor and apoptotic inducer staurosporine switches the production of Bcl-x towards the x_S mRNA isoform in 293 cells. The increase in Bcl-x_S elicited by staurosporine likely involves signaling events that affect splicing decisions because it requires active transcription, no new protein synthesis, and is independent of caspases activation. Moreover, the increase in Bcl-x_S is reproduced with more specific inhibitors of PKC. Alternative splicing of the receptor tyrosine kinase Axl is similarly affected by staurosporine in 293 cells. In contrast to 293 cells, PKC inhibitors do not influence the alternative splicing of Bcl-x and Axl in cancer cell lines, suggesting that these cells have sustained alterations that uncouple splicing decisions from PKC-dependent signaling. Using minigenes, we show that an exonic region located upstream of the Bcl-x_S 5' splice site is important to mediate the staurosporine shift in Bcl-x splicing. When transplanted to other alternative splicing units, portions of this region confer splicing modulation and responsiveness to staurosporine, suggesting the existence of factors that couple splicing decisions with PKC signaling.

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