They are much larger, with only short stubby processes

t 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 in production of the pro-apoptotic Caspase-9a, whereas exclusion of this cassette generates the anti-apoptotic Caspase-9b. It has been reported that the ratio of Caspase-9a to Caspase-9b is greatly decreased in non-small cell lung cancer 97, 98. Ectopic expression of Caspase-9b caused an increase in anchorage-independent growth and tumorigenic PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19850903 capacity of NSCLC cells, while depletion of Caspase-9b resulted in decreased tumorigenicity. Examination of the mechanisms regulating Caspase-9 alternative splicing led to the identification of the heterogeneous nuclear ribonucleoprotein L. hnRNP L binds to an purine-rich ESS in exon 3 of Caspase-9 and facilitates skipping of the 4-exon cassette. This favors the production of Caspase-9b in NSCLC cells, thereby contributing to tumorigenesis98. By contrast, SRSF1 promotes Caspase-9 exon inclusion, thus generating the Caspase-9a isoform and increasing chemosensitivity of NSCLC cells97, 99. Many other apoptotic-associated genes are also subjected to alternative splicing regulation. For example, the Bcl-x gene is alternatively spliced to produce the pro-survival Bcl-x and the pro-apoptotic Bcl-x86, 100, 101. Caspase-8 alternative splicing generates the proapoptotic factor Caspase-8a and its antagonizer Caspase-8L102. In both cases, the prosurvival isoforms, Bcl-x and Caspase-8L are upregulated in cancer103106. Collectively, these data emphasize the prevalence of alternative splicing dysregulation in apoptotic genes in cancer and suggest that the manipulation of alternative splicing favoring an apoptotic direction of these genes could be used as a unique therapeutic strategy to induce cancerspecific cell death. Enabling replicative immortality Unlike normal cells, cancer cells are capable of unlimited replication and division that allow them to bypass Relebactam web senescence and cell death, and eventually grow into macroscopic tumors. One of the key features that enable tumor cells to overcome senescence and cell death is telomere maintenance, which is the result of expression of telomerase107. The protein component of telomerase, human telomerase reverse transcriptase, catalyzes the synthesis of telomere and is found highly expressed in normal stem cells as well as c