Over the past decade, alternative splicing has been progressively recognized as a major mechanism regulating gene expression patterns in different tissues and disease states through the generation of multiple mRNAs from the same gene transcript. This process requires the joining of selected exons or usage of different pairs of splice sites and is regulated by gene-specific combinations of RNA-binding proteins. One archetypical splicing regulator is SRSF1, for which we review the molecular mechanisms and posttranscriptional modifications involved in its life cycle. These include alternative splicing of SRSF1 itself, regulatory protein phosphorylation events, and the role of nuclear versus cytoplasmic SRSF1 localization. In addition, we resume current knowledge on deregulated SRSF1 expression in tumors and describe SRSF1-regulated alternative transcripts with functional consequences for cancer cell biology at different stages of tumor development.

The expression of a gene is initiated by its transcription into a precursor messenger RNA (mRNA), which is then further processed and spliced into a mature mRNA. Splicing is regulated through the interaction between RNA-binding proteins (RBPs) and their cognate splicing regulatory sequence elements (SREs) in the mRNA. This is especially important for alternative splicing where multiple mRNAs can be generated from the same pre-mRNA through the joining of selected exons or usage of different pairs of splice sites [1].

The number of genes encoding RBPs in the human genome is currently estimated to be around 860 [2, 3], far below the number of around 200 000 transcripts that can be produced from the roughly 21 000 human protein-coding genes. Therefore, a key principle in splicing regulation is that the interaction of RNA-binding proteins with SREs is not a one-to-one relationship: each SRE motif can be recognized by multiple alternative RBPs and most splicing factors can recognize two or more SRE motifs. This is particularly relevant for alternative splicing events, the regulation of which involves a complex network of competing protein-RNA interactions so that individual exons can be controlled by multiple factors [4, 5]. Among the RBPs, the major classes of splicing factors that control splice site recognition are the families of Serine/Arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). These proteins act by selecting splice sites for recognition by the spliceosome through binding to intronic or exonic splice enhancer and silencer elements and promoting or destabilizing protein interactions with spliceosome components. One of the best studied factors is SRSF1, formerly known as ASF or SF2 [6]. SRSF1 is a prototypical splicing factor mostly recruited to SREs classified as exonic splicing enhancers (ESEs). SRSF1 recognizes degenerate purine-rich sequence motifs [7, 8] and its binding promotes recognition of both constitutive and alternative exons during spliceosomal assembly. The current knowledge about its regulation will be the focus of this review. The described principles of regulation also apply to many other SR proteins and RBPs.

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 (systemic lupus erythematosus) showed increased ubiquitylation of SRSF1 when compared to those from healthy individuals.

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