The differences in fluorescence were readily visible on cells under a fluorescent microscope

ulated both by the cellular localization of the splicing kinases and by the unique specificity of SRPK1 for structural features within SRSF1 and of CLK1 for Ser-Pro dipeptide phosphorylation.47 Interestingly, PRP4K has also been shown to phosphorylate SRSF1 in vitro,48 is nuclear and resides predominately in splicing speckle domains, suggesting PRP4K may too be involved in the sequential phosphorylation of SRSF1. Alternative splicing in tumorigenesis Alternative splicing occurs in an estimated 95% of human gene transcripts enhancing transcriptome complexity and proteome diversity in higher eukaryotes.49 The most frequent alternative splicing event is the choice to include or skip an exon, termed a cassette exon. Other events involve the inclusion of one of 2 mutually exclusive exons, the use of alternative 30 and 50 splice sites, intron retention and the use of PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19841886 alternative promoters or poly sites.50 Alternative splicing also occurs in the 30 and 50 untranslated regions of mRNA which can alter mRNA 282 Nucleus Volume 6 Issue 4 stability and/or translation efficiency.51 Dysregulation of alternative splicing can render an mRNA transcript inactive by introducing a stop codon, alter the protein-coding function or even result in the transcript encoding a protein of opposing function. Given the striking ability through which alternative splicing can alter the proteome, it is perhaps not surprising that this system is frequently manipulated throughout the process of tumorigenesis.52-54 In fact, changes in alternative splicing have been found to affect nearly every aspect of tumor biology including metabolism, apoptosis, cell cycle control, invasion, metastasis and angiogenesis. While the molecular mechanism of alternative splicing has been shown to play a prominent role in tumorigenesis, there is limited knowledge of the regulation of these alternative splicing events observed in human cancers. One emerging mechanism of regulation is through altered expression of the splicing kinases, stemming from the observation that several of these kinases are overexpressed in various human cancers. The remainder of this review will focus on the 3 families of splicing kinases and the specific roles they have been identified to play in tumorigenesis and the response to chemotherapy. Splicing kinases and their role in tumorigenesis and therapeutic response to chemotherapy SRPK Family SRPK1, perhaps the most widely studied splicing kinase, has been shown to directly MedChemExpress Danoprevir regulate pathways essential to the development, growth and dissemination of cancer. A number of proteins have been shown to be directly phosphorylated by SRPK1 including SC35,11 SRp20,11 SRp55,11 SRSF1,11 Tra2b166 and RBM4.67 Of these, the most well characterized with respect to tumorigenesis are SRSF1 and RBM4. SRSF1 is a prototypical member of the SR protein family which, in addition to its role in splicing regulation, has also been shown to regulate nuclear export,42 mRNA stability,68 miRNA processing,69 translation,43 and nonsense-mediated mRNA decay.70 While the oncogenic potential of SRSF1 is likely due to a combination of the above mentioned functions, it is the splicing function which has been most extensively studied. Several SRPK1-SRSF1 mediated alternative splice events have been linked to tumorigenesis, but for the purpose of this review, we will focus on 3 splice events each effecting different aspects of tumorigenesis. Rac1, a member of the Rho GTPase family, is involved in the regula