The gene encoding the splicing factor SF2/ASF is a proto-oncogene

Abstract

Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. We have tested whether some alternative splicing factors are involved in cancer. We found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1. Moreover, slight overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. We further show that SF2/ASF controls alternative splicing of the tumor suppressor BIN1 and the kinases MNK2 and S6K1. The resulting BIN1 isoforms lack tumor-suppressor activity; an isoform of MNK2 promotes MAP kinase-independent eIF4E phosphorylation; and an unusual oncogenic isoform of S6K1 recapitulates the transforming activity of SF2/ASF. Knockdown of either SF2/ASF or isoform-2 of S6K1 is sufficient to reverse transformation caused by the overexpression of SF2/ASF in vitro and in vivo. Thus, SF2/ASF can act as an oncoprotein and is a potential target for cancer therapy.For about three-quarters of human genes, individual or partial exons can be included in or excluded from different versions of the mature messenger RNA by alternative splicing 1 . Many alternative splicing factors combinatorially affect this process to determine which mRNA isoforms will serve as the templates for protein synthesis in a given cell type, developmental stage or physiological state 2 .SR proteins are a family of RNA-binding proteins that are essential for splicing. They act at multiple steps of spliceosome assembly and function in both constitutive and regulated splicing. Some heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, which rapidly associate with nascent transcripts, have been implicated in the repression of certain alternative splicing events 2 . hnRNP and SR proteins can have antagonistic effects on the alternative splicing of particular exons in several genes 2 . Both types of factor can bind directly to precursor (pre)-mRNA transcripts, eliciting changes in the alternative splicing of various pre-mRNA substrates in a concentration-dependent manner, both in vitro and in transfection experiments 3,4 . Thus, changes in the expression of these proteins can affect the Reprints and permissions information is available online at

E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

“…39 Interestingly, some SR proteins are overexpressed in ovarian cancer 40 and SF2/ASF was recently assessed as a proto-oncogene in human tumors. 41 Therefore, it remains to be determined whether alterations of both E2F1 and SC35 proteins could cooperate to promote carcinogenesis.…”

Regulating the regulators: Serine/arginine‐rich proteins under scrutiny

“…In particular, over-expression of SRSF1 has been shown to be sufficient to transform cells in culture. SRSF1-overexpressing murine immortal fibroblasts developed fibrosarcomas when injected into nude mice (30), and SRSF1-overexpressing mouse mammary epithelial cells COMMA1-D promoted invasive mammary tumors when engrafted into cleared mammary-gland fat pads of syngeneic mice. Furthermore, over-expression of SRSF1 enhanced proliferation and delayed apoptosis in a 3-D cell culture model that recapitulates different aspects of normal mammary gland morphogenesis, leading to larger epithelial acini (31).…”

Mutant SOD1 and mitochondrial damage alter expression and splicing of genes controlling neuritogenesis in models of neurodegeneration

“…To validate this event we performed a semiquantitative PCR with two forward primers and a single reverse primer. This type of competitive PCR reactions have been used previously to detect variations in expression of 5'-and 3'-terminal exons (Karni, et al, 2007;Yamamoto, et al, 2009). As shown in Figure 6C, both upon PQ treatment and in G93A-SOD1 cells the amount of the PCR fragment corresponding to the mRNA transcribed from the distal promoter increased relative to the shorter fragment corresponding to the mRNA transcribed from the alternative, internal promoter, thus confirming the microarray prediction.…”