Or SRSF1 overexpression in at least a subset of lung tumors. SRSF1 expression is also regulated at the level of splicing, in response to the splicing factor Sam 68. Sam68 activity switches alternative splicing of the SRSF1 transcript from the NMDtargeted isoforms to the full-length, translatable isoform, thus Neuromedin N resulting in an increase in SRSF1 protein levels. MYC- and Sam68-mediated SRSF1 overexpression is associated with oncogenic phenotypes, such as increased cell-proliferation, anchorage-independent growth, cell motility and invasion, and epithelial-mesenchymal transition. The strong oncogenic potential of SRSF1 is in all likelihood a cumulative reflection of its various different functions. However, the splicing function of SRSF1 has been the most extensively characterized in this context, and multiple SRSF1-regulated alternative splicing events have been identified that contribute to its role in tumorigenesis. Among these are several apoptosis regulators: BIN1, BCL2L11 and MCL1. SRSF1 overexpression promotes the formation of the non-apoptotic isoforms of these three genes: the BIN1 +12A isoform, which is unable to interact with and activate MYC-mediated apoptosis; the BIM 1 and 2 isoforms, which lack the BH3 domain required for proapoptotic function; and the anti-apoptotic MCL1L isoform. Another important malignant-tumor characteristic regulated by SRSF1 is cell motility and invasion. SRSF1 alters the splicing of the macrophage stimulating protein tyrosine kinase receptor RON, promoting skipping of exon 11. The resulting protein isoform induces EMT and enhances cell motility. SRSF1 also regulates alternative splicing of factors affecting cellular signaling pathways, proliferation, and cell-cycle progression. As mentioned above, these factors include RPS6KB1, which encodes the protein S6 kinase 1, a downstream effector in the PI3K/Akt/mTOR signaling pathway, and MKNK2, an effector in the MAPK/ERK pathway. We identified a novel, short S6K1 isoform that is positively regulated by SRSF1. This p31-S6K1 isoform has recently been shown to be oncogenic and is an important mediator of SRSF1-mediated transformation. SRSF1-mediated activation of the mTORC1 pathway is an essential contributor to its oncogenic activity. Inhibition of mTORC1 signaling by rapamycin treatment abrogates SRSF1’s ability to transform cells both in vitro and in vivo. mTORC1 is 
a key regulator of cell growth and translation, and its activation by SRSF1 promotes translation of the anti-apoptotic factor Survivin in non-small cell lung carcinomas, making them insensitive to cell-death cues. Recently, SRSF1 was also shown to enhance translation of -catenin through mTOR activation, leading to activation of the Wnt signaling pathway, an important contributor to oncogenesis. Mol Cancer Res. Author manuscript; available in PMC 2015 September 01. Das and Krainer Page 8 Analysis of various SRSF1 domain-deletion mutants revealed that RRM1 is critical for oncogenic activity in mammary epithelial cells and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19847069 in a liver-progenitor xenograft model. SRSF1 mutants lacking RRM1 are impaired in their ability to alter splicing of the apoptosis regulators BIM1 and BIN1. The get 487-52-5 differential effect of RRM1 and RRM2 mutants on splicing of SRSF1 indicates the different substrate-specificity of these two RRMs. To distinguish between the nuclear functions of SRSF1 and the cytoplasmic functions, in the context of oncogenesis, a nuclearretained SRSF1 chimeric protein, fused to the nuclear retention sign.Or SRSF1 overexpression in at least a subset of lung tumors. SRSF1 expression is also regulated at the level 
of splicing, in response to the splicing factor Sam 68. Sam68 activity switches alternative splicing of the SRSF1 transcript from the NMDtargeted isoforms to the full-length, translatable isoform, thus resulting in an increase in SRSF1 protein levels. MYC- and Sam68-mediated SRSF1 overexpression is associated with oncogenic phenotypes, such as increased cell-proliferation, anchorage-independent growth, cell motility and invasion, and epithelial-mesenchymal transition. The strong oncogenic potential of SRSF1 is in all likelihood a cumulative reflection of its various different functions. However, the splicing function of SRSF1 has been the most extensively characterized in this context, and multiple SRSF1-regulated alternative splicing events have been identified that contribute to its role in tumorigenesis. Among these are several apoptosis regulators: BIN1, BCL2L11 and MCL1. SRSF1 overexpression promotes the formation of the non-apoptotic isoforms of these three genes: the BIN1 +12A isoform, which is unable to interact with and activate MYC-mediated apoptosis; the BIM 1 and 2 isoforms, which lack the BH3 domain required for proapoptotic function; and the anti-apoptotic MCL1L isoform. Another important malignant-tumor characteristic regulated by SRSF1 is cell motility and invasion. SRSF1 alters the splicing of the macrophage stimulating protein tyrosine kinase receptor RON, promoting skipping of exon 11. The resulting protein isoform induces EMT and enhances cell motility. SRSF1 also regulates alternative splicing of factors affecting cellular signaling pathways, proliferation, and cell-cycle progression. As mentioned above, these factors include RPS6KB1, which encodes the protein S6 kinase 1, a downstream effector in the PI3K/Akt/mTOR signaling pathway, and MKNK2, an effector in the MAPK/ERK pathway. We identified a novel, short S6K1 isoform that is positively regulated by SRSF1. This p31-S6K1 isoform has recently been shown to be oncogenic and is an important mediator of SRSF1-mediated transformation. SRSF1-mediated activation of the mTORC1 pathway is an essential contributor to its oncogenic activity. Inhibition of mTORC1 signaling by rapamycin treatment abrogates SRSF1’s ability to transform cells both in vitro and in vivo. mTORC1 is a key regulator of cell growth and translation, and its activation by SRSF1 promotes translation of the anti-apoptotic factor Survivin in non-small cell lung carcinomas, making them insensitive to cell-death cues. Recently, SRSF1 was also shown to enhance translation of -catenin through mTOR activation, leading to activation of the Wnt signaling pathway, an important contributor to oncogenesis. Mol Cancer Res. Author manuscript; available in PMC 2015 September 01. Das and Krainer Page 8 Analysis of various SRSF1 domain-deletion mutants revealed that RRM1 is critical for oncogenic activity in mammary epithelial cells and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19847069 in a liver-progenitor xenograft model. SRSF1 mutants lacking RRM1 are impaired in their ability to alter splicing of the apoptosis regulators BIM1 and BIN1. The differential effect of RRM1 and RRM2 mutants on splicing of SRSF1 indicates the different substrate-specificity of these two RRMs. To distinguish between the nuclear functions of SRSF1 and the cytoplasmic functions, in the context of oncogenesis, a nuclearretained SRSF1 chimeric protein, fused to the nuclear retention sign.