d target genes is formed by the apoptosis regulators BIN1, BCL2L11, BCL-XL, ICAD, and MCL1, with SRSF1 overexpression in cancer cells promoting the formation of their respective antiapoptotic splice variants. Several target genes belong to PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19809668 the Bcl-2 family of proteins, which regulate whether the Bak and Bax proteins 5 can cause mitochondrial outer membrane permeabilization and cytochrome c release as the trigger for intrinsic apoptosis induction. The Bcl-2 family comprises both get 1022150-57-7 proapoptotic and antiapoptotic proteins, depending on their BH domain composition, and it is the balance between both types of proteins that determines whether the mitochondrial pathway to apoptosis is activated. Regarding BIM, several SRSF1-induced transcript variants were described lacking exons 2, 3, or 4 which encode the BH3 domain. This domain binds antiapoptotic Bcl-2 family members and is necessary for induction of apoptosis by BIM. Similarly, SRSF1 expression promotes inclusion of exon 2 of the BH3 domaincontaining gene MCL-1 giving rise to the antiapoptotic MCL-1L isoform in both breast cancer and choriocarcinoma cells. Overexpression of SRSF1 also promotes generation of the antiapoptotic isoform BCL-XL. BIN1 has tumor-suppressor activity by interacting with and activating MYC-mediated apoptosis, except when exon 12A is included by SRSF1-mediated alternative splicing, because the resulting antiapoptotic BIN1+12A isoform is unable to interact with MYC. Furthermore, SRSF1 was shown to modulate exclusion of exon 5 of the mRNA encoding the inhibitor of caspase-activated DNase, a regulator of the DNase responsible for DNA fragmentation during apoptosis. A parallel group of SRSF1-regulated target genes is involved in cellular signaling pathways related to proliferation and 
cell cycle progression. Examples of genes from this group are CCND1, RPS6KB1, RON, RAC1, and MKNK2 genes. SRSF1 increases expression of the cyclin D1b oncogene which arises from alternative splicing of the CCND1 transcript, and harbors enhanced oncogenic functions not shared by full-length cyclin D1 . In this case, SRSF1 blocks recognition of the CCND1 exon 4-intron 4 boundary, thus repressing inclusion of exon 5 so that a nuclear protein with a unique C-terminus is generated. SRSF1 also promotes the inclusion of exon 5 into the pre-mRNAs of TEAD-1, a transcription factor normally involved in cell differentiation and cell cycle arrest in myoblasts. The RPS6KB1 gene encodes the protein S6 kinase 1, a substrate for the cell growth regulating kinase mTOR. Excess SRSF1 promoted an increase in S6K1 variants by including one to three alternative cassette exons between exons 6 and 7 that are normally skipped and include a proper stop codon. These short S6K1 isoforms have a truncated kinase domain and lack the mTOR-regulated C-terminus but are able to bind to and activate the mTORC1 complex. This activation of the mTORC1 complex occurs independent of the classical PI3K/AKT pathway and leads to phosphorylation of eIF4EBP1, releasing its inhibitory effect on cap-dependent translation. In addition, there is evidence that SRSF1 itself participates in a complex with mTORC1 to enhance translation efficiency of its target transcripts, for example, survivin and -catenin. RON encodes a receptor tyrosine kinase in breast and colon tumors and SRSF1 promotes skipping of exon 11 by binding to an enhancer element in the competing exon 12. 6 The resulting isoform Ron is constitutively active and promotes cell moti