Ing the interaction between SRSF1 and the ribosomal protein RPL5, we recently described a role of SRSF1 in the nucleolar stress pathway, wherein SRSF1 stabilizes the interaction between RPL5 and the E3 ubiquitin ligase MDM2. Sequestration of MDM2 in this complex results in stabilization of the p53 tumor suppressor, which then mediates the stress response. Regulation of SRSF1 
expression Consistent with the many processes that it regulates, SRSF1 is an essential gene and SRSF1null mice are embryonic lethal. Tissue-specific deletion of SRSF1 in mouse heart leads to lethality about 6-8 weeks after birth, due to heart failure. These mice have defective Ca2+ metabolism, seemingly PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/1984928 due to mis-splicing of the Ca2+/calmodulin-dependent kinase II, leading to a defective contractile apparatus and cardiomyopathy. Knockdown of the SRSF1 orthologue in C. elegans also leads to late embryonic lethality. Furthermore, loss of SRSF1 expression in chicken DT-40 cells triggers cell-cycle arrest in the G2-phase and apoptosis. On the other hand, Neuromedin N overexpression of SRSF1 in immortal rodent fibroblasts or human mammary epithelial cells leads to oncogenic transformation, with increased cellular proliferation and protection against apoptosis. Presumably to prevent the deleterious consequences of its misregulation, the level of SRSF1 is tightly controlled within the cell. SRSF1 negatively autoregulates its expression through multiple post-transcriptional and translational mechanisms. SRSF1 regulates splicing of its own transcript and keeps a check on its overexpression by promoting the expression of PTC-containing splice isoforms that are targeted to NMD. SRSF1 also regulates its expression at the translational level, by shifting the 
association of its mRNA from polysomes to monosomes–indicative of decreased translation efficiency. Furthermore, the SRSF1 transcript itself is subject to silencing by the miR-7 microRNA, which as outlined above, is one of the miRNA targets processed more efficiently through SRSF1 binding, thereby generating a negative-feedback loop. SRSF1 and cancer Despite the above-mentioned regulatory mechanisms to maintain constant SRSF1 levels, SRSF1 is overexpressed in many different cancer types, and it is a potent proto-oncogene. SRSF1 is located on Chromosome 17q23, a locus that is commonly amplified in certain tumors, correlating with poor prognosis. We found that slight overexpression of SRSF1 results in oncogenic Indirubin-3′-oxime chemical information transformation of immortalized rodent fibroblasts and human mammary epithelial cells, with the cells acquiring higher proliferative capacity, resistance to apoptosis, and forming malignant tumors upon orthotropic transplantation into mouse models. Furthermore, SRSF1 overexpression in lung Mol Cancer Res. Author manuscript; available in PMC 2015 September 01. Das and Krainer Page 7 adenocarcinoma cells results in a more aggressive phenotype and confers resistance to anticancer drugs like carboplatin and paclitaxel. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Among the positive regulators of SRSF1 that contribute to its overexpression in cancer are the oncogenic transcription factor MYC and the splicing regulator Sam68. We found SRSF1 to be a direct transcriptional target of MYC, containing two functional noncanonical E-boxes in its promoter. MYC, which is itself a potent oncogene aberrantly expressed in cancer, positively associates with SRSF1 expression in lung and breast tumors, and is responsible f.Ing the interaction between SRSF1 and the ribosomal protein RPL5, we recently described a role of SRSF1 in the nucleolar stress pathway, wherein SRSF1 stabilizes the interaction between RPL5 and the E3 ubiquitin ligase MDM2. Sequestration of MDM2 in this complex results in stabilization of the p53 tumor suppressor, which then mediates the stress response. Regulation of SRSF1 expression Consistent with the many processes that it regulates, SRSF1 is an essential gene and SRSF1null mice are embryonic lethal. Tissue-specific deletion of SRSF1 in mouse heart leads to lethality about 6-8 weeks after birth, due to heart failure. These mice have defective Ca2+ metabolism, seemingly PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/1984928 due to mis-splicing of the Ca2+/calmodulin-dependent kinase II, leading to a defective contractile apparatus and cardiomyopathy. Knockdown of the SRSF1 orthologue in C. elegans also leads to late embryonic lethality. Furthermore, loss of SRSF1 expression in chicken DT-40 cells triggers cell-cycle arrest in the G2-phase and apoptosis. On the other hand, overexpression of SRSF1 in immortal rodent fibroblasts or human mammary epithelial cells leads to oncogenic transformation, with increased cellular proliferation and protection against apoptosis. Presumably to prevent the deleterious consequences of its misregulation, the level of SRSF1 is tightly controlled within the cell. SRSF1 negatively autoregulates its expression through multiple post-transcriptional and translational mechanisms. SRSF1 regulates splicing of its own transcript and keeps a check on its overexpression by promoting the expression of PTC-containing splice isoforms that are targeted to NMD. SRSF1 also regulates its expression at the translational level, by shifting the association of its mRNA from polysomes to monosomes–indicative of decreased translation efficiency. Furthermore, the SRSF1 transcript itself is subject to silencing by the miR-7 microRNA, which as outlined above, is one of the miRNA targets processed more efficiently through SRSF1 binding, thereby generating a negative-feedback loop. SRSF1 and cancer Despite the above-mentioned regulatory mechanisms to maintain constant SRSF1 levels, SRSF1 is overexpressed in many different cancer types, and it is a potent proto-oncogene. SRSF1 is located on Chromosome 17q23, a locus that is commonly amplified in certain tumors, correlating with poor prognosis. We found that slight overexpression of SRSF1 results in oncogenic transformation of immortalized rodent fibroblasts and human mammary epithelial cells, with the cells acquiring higher proliferative capacity, resistance to apoptosis, and forming malignant tumors upon orthotropic transplantation into mouse models. Furthermore, SRSF1 overexpression in lung Mol Cancer Res. Author manuscript; available in PMC 2015 September 01. Das and Krainer Page 7 adenocarcinoma cells results in a more aggressive phenotype and confers resistance to anticancer drugs like carboplatin and paclitaxel. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Among the positive regulators of SRSF1 that contribute to its overexpression in cancer are the oncogenic transcription factor MYC and the splicing regulator Sam68. We found SRSF1 to be a direct transcriptional target of MYC, containing two functional noncanonical E-boxes in its promoter. MYC, which is itself a potent oncogene aberrantly expressed in cancer, positively associates with SRSF1 expression in lung and breast tumors, and is responsible f.
