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

Rotem Karni, Elisa De Stanchina, Scott W. Lowe, Rahul Sinha, David Mu, Adrian R. Krainer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

738 Scopus citations

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 languageAmerican English
Pages (from-to)185-193
Number of pages9
JournalNature Structural and Molecular Biology
Volume14
Issue number3
DOIs
StatePublished - Mar 2007
Externally publishedYes

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.

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