By Marie Pieroni
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In the case of FLIP, the splice variant actually possesses a more potent effect than does the full-length protein , rather than producing an isoform with an opposing effect. Comparably, the Smac3 splice variant of Smac/DIABLO contributes to apoptosis by interfering with XIAP activity, similar to Smac/DIABLO, though possibly via a different mechanism . RNA Regulation in Apoptosis The importance of splicing as a mechanism of post-transcriptional regulation that affects the apoptotic response has been emphasized by experiments in which an oligonucleotide successfully blocked the 5 splice site of Bcl-xL , resulting in an upregulation of the pro-apoptotic Bcl-xS [212, 213].
Not surprisingly, this variant promotes apoptosis similarly to BH3-only proteins . 2 Splicing-Mediated Regulation of Caspases Caspases and downstream regulators of caspases are also subject to the regulation of gene expression through alternative splicing. Caspases-3 and -9 can be spliced to generate dominant negative isoforms that lack the catalytic sites of these enzymes [195–199], subsequently acting as anti-apoptotic factors. Regulation of the production of these splice variants has 19 20 RNA Regulation in Apoptosis Pre-mRNA Modified hnRNPs SR proteins hnRNPs SR proteins Splicing Altered Protein product Protein product Promoter of apoptosis ex: Smac, BimEL Alternative splicing Inhibitor of apoptosis ex: Bcl-xL, caspase -9s Normal conditions Altered promotor of apoptosis Promotor of apoptosis ex: Smac3, Bims/BimL ex: Bcl-xs, caspase -9 Apoptotic conditions Fig.
3), and the consequence of this on apoptosis has been described to varying degrees. The Destabilizing A/U Rich Element Among the elements that are known to inﬂuence mRNA decay rates, the most extensively studied is the ARE. Currently, several ‘‘classes’’ of AREs are known to exist ; these are based on the distribution of adenine and uracil nucleotides within the sequence, but they are generally located in the 3 UTR of a message. AREs have been shown repeatedly to confer instability on mRNAs, which has often been demonstrated through their conjugation to an otherwise stable mRNA.