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- Title
The gene encoding the splicing factor SF2/ASF is a proto-oncogene.
- Authors
Karni, Rotem; de Stanchina, Elisa; Lowe, Scott W.; Sinha, Rahul; Mu, David; Krainer, Adrian R.
- 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.
- Subjects
RNA splicing; PROTO-oncogenes; EXONS (Genetics); TUMORS; GENE amplification; FIBROBLASTS; SARCOMA
- Publication
Nature Structural & Molecular Biology, 2007, Vol 14, Issue 3, p185
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb1209