totic isoform of this gene, suggesting that FAST and TIA1 take part to a positive regulative circuitry that enhances Fas-dependent apoptosis once activated. Furthermore FAST is also endowed with an intrinsic splicing activity, independent from TIA1. It was observed that FAST can modulate the splicing of the FGFR2 reporter gene in the same direction of TIA1, favoring the inclusion of exon III b but independently from this RBP. Thus, FAST can directly and indirectly affect splicing, and it would International Journal of Cell Biology be interesting to determine how many targets are influenced by this kinase in T cells. 7.4. Aurora Kinase A. AURKA was identified in a high-throughput siRNA screening for factors involved in the regulation of AS of two apoptotic genes: BCL-X and MCL1. Among several regulators identified by the screen, authors noticed a peculiar enrichment for proteins involved in the regulation of the cell cycle. They focused their study on AURKA, a kinase involved in the regulation of centrosomal splitting that is frequently upregulated in cancers, where it is supposed to promote aneuploidy. AURKA was demonstrated to positively regulate splicing of the antiapoptotic variant – through stabilization of SRSF1. Cells depleted of AURKA showed reduced levels of SRSF1, which then resulted in increased levels PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19820119 of the – pro-apoptotic variant. Moreover, since AURKA is activated at the G2/M phase of the cell cycle, the authors suggested that this kinase links BCL-X splicing regulation to cell cycle progression. These observations suggest that, in addition to the effects on centrosome duplication, upregulation of AURKA can favor neoplastic transformation also by promoting antiapoptotic splice variants. 8. Splicing Factor Kinases in Cancer and Other Human Diseases Due to the important role played by the AS process in the control of gene expression, any alterations of its regulation can profoundly modify important cellular processes, thus resulting in a potential cause of disease. Altered expression, activity, or subcellular localization of splicing factor kinases can be among the causes of the aberrant splicing events associated to several diseases, particularly neurodegenerative pathologies and cancer. Aberrant inclusion of exon 10 of the TAU gene is a well-known example of pathogenetic splicing event, caused by the deregulated activity or expression of splicing factor kinases. TAU protein is a TG-101348 cost microtubule associated protein, which controls assembly and stability of microtubules. Exon 10 of the TAU gene encodes for one of the four microtubule binding domain repeats of the TAU protein and regulates its affinity for microtubules and, consequently, its ability to induce their polymerization. Alternative inclusion of exon 10 leads to the production of either 4R-tau or 3R-tau, and equal levels of these two isoforms seem to be essential for normal function of the human brain. Alteration of the normal ratio 1: 1 between the 4R and the 3R isoform, in both directions, has been observed in several cases of Alzheimer’s disease; moreover, nearly half of the mutations in the TAU gene associated with FTDP-17 affects exon 10 splicing, both inhibiting or promoting its inclusion, strongly suggesting that a proper regulation of this splicing event is essential for the maintenance of the healthy balance between 4R and 3R isoforms. Several reports have highlighted or suggested a strong correlation between aberrant splicing of International Journal of Cell Bi
