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

R Karni, E de Stanchina, SW Lowe, R Sinha… - Nature structural & …, 2007 - nature.com
R Karni, E de Stanchina, SW Lowe, R Sinha, D Mu, AR Krainer
Nature structural & molecular biology, 2007nature.com
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 …
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.
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