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Journal of Lipid Research, Vol. 47, 892-897, May 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Short Communication

SRp30a (ASF/SF2) regulates the alternative splicing of caspase-9 pre-mRNA and is required for ceramide-responsiveness

Autumn Massiello^* and Charles E. Chalfant^1,*,

^* Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298
Research and Development, Hunter Homes McGuire Veterans Administration Medical Center, Richmond, VA 23249

Published, JLR Papers in Press, February 27, 2006.

¹ To whom correspondence should be addressed. e-mail: cechalfant{at}vcu.edu

ABSTRACT

Two splice variants are derived from the caspase-9 gene, proapoptotic caspase-9a and antiapoptotic caspase-9b, by either the inclusion or exclusion of an exon 3, 4, 5, and 6 cassette. Previous studies from our laboratory have shown that the alternative splicing of caspase-9 and the phosphorylation status of SR proteins, a conserved family of splicing factors, are regulated by chemotherapy and ceramide via the action of protein phosphatase-1. In this study, a link between ceramide, SR proteins, and the alternative splicing of caspase-9 was established. The downregulation of SRp30a in A549 cells by RNA interference technology resulted in an increase in the caspase-9b splice variant, with a concomitant decrease in the caspase-9a splice variant, thereby significantly decreasing the caspase-9a/9b ratio from 1.67 ± 0.11 to 0.56 ± 0.08 (P < 0.005). The specific downregulation of SRp30a also inhibited the ability of exogenous ceramide treatment to induce the inclusion of the exon 3, 4, 5, and 6 cassette. Therefore, we have identified SRp30a as an RNA trans-acting factor that functions as a major regulator of caspase-9 pre-mRNA processing and is required for ceramide to mediate the alternative splicing of caspase-9.

Supplementary key words RNA cis-element • RNA trans-acting factor • A549 cells

Abbreviations: Apaf-1, apoptotic protease activating factor-1; PP1, protein phosphatase-1; RNAi, RNA interference; siRNA, silencer RNA

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