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Published online March 19, 2007
doi:10.1083/jcb.200701005
The Journal of Cell Biology, Vol. 176, No. 7, 929-939
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Paronetto et al.
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Article

The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x



Maria Paola Paronetto1,2, Tilman Achsel2, Autumn Massiello3,4, Charles E. Chalfant3,4, and Claudio Sette1,2

1 Department of Public Health and Cell Biology, Section of Anatomy, University of Rome Tor Vergata, 00133 Rome, Italy
2 Laboratory of Neuroembryology, Institute of Experimental Neuroscience, Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico, 00143 Rome, Italy
3 Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298
4 Research and Development, Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA 23249

Correspondence to Claudio Sette: claudio.sette{at}uniroma2.it

The RNA-binding protein Sam68 is involved in apoptosis, but its cellular mRNA targets and its mechanism of action remain unknown. We demonstrate that Sam68 binds the mRNA for Bcl-x and affects its alternative splicing. Depletion of Sam68 by RNA interference caused accumulation of antiapoptotic Bcl-x(L), whereas its up-regulation increased the levels of proapoptotic Bcl-x(s). Tyrosine phosphorylation of Sam68 by Fyn inverted this effect and favored the Bcl-x(L) splice site selection. A point mutation in the RNA-binding domain of Sam68 influenced its splicing activity and subnuclear localization. Moreover, coexpression of ASF/SF2 with Sam68, or fusion with an RS domain, counteracted Sam68 splicing activity toward Bcl-x. Finally, Sam68 interacted with heterogenous nuclear RNP (hnRNP) A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated Bcl-x(s) splicing. Our results indicate that Sam68 plays a role in the regulation of Bcl-x alternative splicing and that tyrosine phosphorylation of Sam68 by Src-like kinases can switch its role from proapoptotic to antiapoptotic in live cells.

Abbreviations used in this paper: GSG, GRP33/Sam68/GLD1; hnRNP, heterogenous nuclear RNP; SR, serine/arginine; STAR, signal transduction and activation of RNA.


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