scence or induced stress stimuli of the vascular endothelium result in preferential cytoplasmic localization of SRSF1 and the underlying mechanism was postulated to involve nuclear import of SRPK1 and consequently lack of constitutive cytosolic SRSF1 phosphorylation. In contrast, hyperphosphorylation of SRSF1 was observed during the DNA damage response and caused altered subnuclear distribution and changes in alternative splicing pattern of target genes. Another posttranslational modification involved in SRSF1 localization is the methylation of three arginine residues located in a region between the two RRM domains. Lack of methylation in a triple-Ala mutant turned SRSF1 predominantly cytoplasmic, whereas a triple-Lys substitution maintaining the positive charge localized to nuclear speckles, as the wild-type protein. How the respective protein arginine methyltransferases are regulated and contribute to the nuclear-cytoplasmic transitions of SRSF1 is poorly understood. Once in the nucleus, the long noncoding RNA MALAT1 interacts with SRSF1, which is important for the recruitment of other SR proteins into nuclear speckles. 5. Functional Consequences of Nuclear versus Cytoplasmic SRSF1 Elesclomol price concentrations Relative concentrations of antagonizing or 
competing SFs are important determinants in alternative splicing regulation. For example, SRSF1 generally displays a stimulatory role in splicing when bound to exons and its function in alternative splicing in vitro can be antagonized by the activity of hnRNP A proteins in a concentration-dependent manner. In vivo, competition between SFs can originate from the relative ratios of such antagonists expressed in different tissues or developmental stages, creating tissue or stage-specific patterns of 4 splicing. In addition, the dynamic regulation of subcellular SF localization allows cells to modulate PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19809024 the effective nuclear concentration of a given SF and alter the pattern of expressed splicing variants in response to external stimuli. For example, the subnuclear distribution of SRSF1 changes during the DNA damage response following hyperphosphorylation and results in a shift in the alternative splicing pattern of target genes that control cell survival. Also, drug-induced disruption of nuclear speckles with concomitant release of SRSF1 into the nucleoplasm induced changes in alternative splicing events. And endothelial senescence is associated with a scattered distribution of SRSF1 throughout the cytoplasm. This leads to the expression of alternative isoforms of target genes such as endoglin, vascular endothelial growth factor A, tissue factor, or lamin A that integrate into a common molecular senescence program. Vice versa, epithelial cells treated with insulinlike growth factor-1 displayed nuclear translocation of SRSF1, which was dependent on SPRK1/2 activity. BioMed Research International 7. Impact of Posttranslational Modification on Other RNA-Related Functions of SRSF1 SRSF1 has been shown to facilitate the nuclear export of spliced mRNAs to which it is bound through its interaction with the TAP/NXF1 receptor. Interestingly, this adaptor function implies partial dephosphorylation of its RS domain for cytoplasmic translocation, suggesting the phosphorylation status of SRSF1 serves to regulate nuclear export of some mRNPs. The subsequent ribosomal translation of transcripts containing a SRSF1-targeted ESE is also stimulated, both in vivo and in vitro. Thus, SRSF1-mediated alternative splicing, mRNA