ernative promoter usage and alternative splicing. There 
are three types of alternative splicing events occurring at the C-terminal region of p53, resulting in p53,, and isoforms. p53 in particular is upregulated during replicative cellular senescence, and when overexpressed, p53 induces senescence79, 80. While the mechanism by which p53 promotes senescence is not fully understood, the production of p53 is inhibited by PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19851335 SRSF3, a member of highly conserved order Indirubin-3′-oxime family of splicing factors79. SRSF3 binds to p53 exon i9 and prevents inclusion of the p53-unique exon, resulting in inhibition of cellular senescence. Notably, SRSF3 is highly elevated in various cancers81, 82, suggesting a mechanism by which cancer cells eliminate p53mediated senescence through alternative splicing regulation. Furthermore, two p53-related proteins, p63 and p73, are also extensively regulated by alternative splicing83. While p63 and p73 mutations are rare, aberrant expression of their splice isoforms was frequently observed in human cancers84, however, the functional consequences of this are not yet well studied. Resisting cell death Apoptosis is a programmed cell death that serves as a natural barrier to cancer cells. However, as tumors progress, cancer cells become insensitive to apoptotic signals, eventually leading to advanced malignancy and chemo-resistance85, 86. The apoptotic pathway consists of both upstream regulators and downstream effectors. The death receptor FAS is an upstream regulator that receives extracellular death signals induced by the Fas ligand and processes the signals to the intrinsic apoptotic pathway that carries out the final execution. One of the initial executioners of apoptosis is Caspase-9. Activation of Caspase-9 initiates a cascade of proteolysis leading to consumption and clearance of the cell. Importantly, both Fas and Caspase-9 are regulated by alternative splicing. Splice isoforms of these proteins can have opposing functions to either stimulate or inhibit apoptosis87, 88. In the case of the death receptor Fas, inclusion of variable exon 6 results in the production of the membrane-bound Fas that promotes apoptosis, whereas skipping of variable exon 6 produces a soluble form of Fas that inhibits apoptosis89, 90. The splicing factors TIA-1 and TIAR promote the inclusion of exon 6 by facilitating the U1 snRNP-mediated 5′ splice site recognition and the binding of U2AF to the upstream 3′ splice site, resulting in generation of the pro-apoptotic FAS isoform91. In contrast to these activities, several splicing factors were found to promote the skipping of exon 6. PTB binds to an ESS of exon 6 and promotes exon 6 skipping by inhibiting the binding of U2AF and U2 snRNP to the upstream 3′ splice site91. More recently, HuR, hnRNPC1/C2, and RBM5 were shown to inhibit exon 6 inclusion by antagonizing the function of TIAR and preventing the spliceosome assembly, resulting in the production of the anti-apoptotic Fas isoform9294. These findings suggest that splicing factor-regulated of alternative splicing of the Fas gene may directly control the degree of cell apoptosis. Wiley Interdiscip Rev RNA. Author manuscript; available in PMC 2015 May 10. Liu and Cheng Page 5 Caspase-9 serves as yet another example by which alternative splicing controls cell apoptosis. Alternative splicing of Caspase-9 produces Caspase-9a and Caspase-9b that differ by inclusion or exclusion of a 4-exon cassette, respectively95, 96. Inclusion of the 4-exon cassette results i
