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.
| Original language | English |
|---|---|
| Pages (from-to) | 185-193 |
| Number of pages | 9 |
| Journal | Nature Structural and Molecular Biology |
| Volume | 14 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2007 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank G. Dreyfuss (University of Pennsylvania) for antibodies to hnRNP A1 and A2; D. Pant for advice on statistical tests; A. Rosenberg, M. Nolan and S. Muthuswamy (Cold Spring Harbor Laboratory) for the breast-cancer cell lines; and M. Hemann, L. Zender, R.-M. Xu, A. Neuwald, S. Powers and R. Lucito for helpful discussions. This work was supported by grant CA13106 from the US National Cancer Institute.
