REGULATION OF ICH-1 PRE-MESSENGER-RNA ALTERNATIVE SPLICING AND APOPTOSIS BY MAMMALIAN SPLICING FACTORS

The importance of alternative splicing in regulating apoptosis has bee n suggested by findings of functionally antagonistic proteins generate d by alternative splicing of several genes involved in apoptosis, Amon g these, Ich-1 (also named as caspase-2) encodes a member of the caspa se family of proteases, Two forms of Ich-1 are produced as a result of alternative splicing: Ich-1L, which causes apoptosis, and Ich-1S, whi ch prevents apoptosis, The precise nature of Ich-1 alternative splicin g and its regulation remain unknown. Here, we show that the production of Ich-1L land Ich-1S transcripts results from alternative exclusion or inclusion of a 61-bp exon, Several splicing factors can regulate Ic h-1 splicing. Serine-arginine-rich proteins SC35 and ASF/SF2 promote e xon skipping, decreasing the ratio of Ich-1S to Ich-1L transcripts; wh ereas heterogeneous nuclear ribonucleoprotein A1 facilitates exon incl usion, increasing this ratio. Furthermore, in cultured cells, SC35 ove rexpression increases apoptosis; whereas heterogeneous nuclear ribonuc leoprotein A1 overexpression decreases apoptosis. These results provid e the first direct evidence that splicing factors can regulate Ich-1 a lternative splicing and suggest that alternative splicing may be an im portant regulatory mechanism for apoptosis.