export, and translational efficiency of its target transcripts are coupled, and their number has been identified experimentally to be around 500. In addition, SRSF1 overexpression was found to increase the ratio between cap-dependent and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19809668 internal ribosome entry site-dependent translation initiation, probably by suppressing the activity of 4E-BP, a competitive inhibitor of cap-dependent translation. Probably related to these properties is the observation that SRSF1 enhances nonsensemediated mRNA decay because SRSF1 overexpression can promote the pioneer round of translation required for NMD to occur. Another class of RNA pol2 transcripts is miRNAs and SRSF1 overexpression in HeLa cells promoted the maturation step of miR-7 and other miRNAs. SRSF1 directly interacts with primary miR transcripts and promotes the Drosha cleavage step generating mature miRNA. Another recently discovered function of SRSF1 is to JW-55 web enhance protein sumoylation. SRSF1 associates with the SUMO E2 conjugating enzyme Ubc9 and enhances SUMO conjugation to RNA processing factors but further details on the regulation or consequences of this modification remain to be identified. It should also be noted that SRSF1 was shown to be involved in chromatin organization and histone modifications such as H3K36me3, which are relevant for splicing decisions. 6. Regulation of SRSF1 by Cytosolic Protein Degradation A specific decrease in SRSF1 protein levels was observed in SRPK1-depleted or SRPIN340-treated colorectal cells, without changes in the corresponding SRSF1 mRNA. This suggests that cytoplasmic SRSF1 localization leads to protein degradation. Indeed, the SRSF1 protein remained stable in such treated cells when incubated with inhibitors MG132 or lactacystin, indicating degradation by the proteasome. It should be noted that studying SFs with proteasome inhibitors needs to be well controlled at the corresponding transcript level because the inhibitors are likely to affect other SFs or transcription factors in the cell. For example, the gene encoding SRSF3 is a direct transcriptional target of -catenin/TCF4 so that inhibition of -catenin degradation will increase expression of SRSF3, which in turn can promote unproductive alternative SRSF1 transcripts. SRSF1 protein expression levels did also not correlate with mRNA expression levels following T cell stimulation. Immunoprecipitation studies showed increased ubiquitylation of SRSF1 in activated T cells and proteasomal but not lysosomal degradation was shown to be involved by blocking with specific inhibitors MG132 and bafilomycin, respectively. Interestingly, T cells from patients with SLE showed increased ubiquitylation of SRSF1 when compared to those from healthy individuals. Downregulation of SRSF1 protein level was further found to occur following inhibition of activity or siRNA-mediated depletion of GSK3 in U87 or U373 glioblastoma cells. Similarly, GSK3 depletion in HT29 colorectal cancer cells led to a reduction in both SRSF1 and SRPK1 protein levels, suggesting an indirect effect of GSK3 on SRSF1 via SRPK1. It has been described that the RS domain, which 
is common to all SR proteins, is required for their proteolytic degradation by the proteasome but further mechanistic details remain to be determined. 8. Role of SRSF1 in Cancer Cell Biology and Tumorigenesis Malignant changes in the cellular genome can either be tumor-initiating driver events or subsequent adaptations required for tumor cell progression. Such changes ei