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

doi:10.1038/nsmb1209

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 journal › Article › peer-review

790 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 language	English
Pages (from-to)	185-193
Number of pages	9
Journal	Nature Structural and Molecular Biology
Volume	14
Issue number	3
DOIs	https://doi.org/10.1038/nsmb1209
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.

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title = "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.",

author = "Rotem Karni and \{De Stanchina\}, Elisa and Lowe, \{Scott W.\} and Rahul Sinha and David Mu and Krainer, \{Adrian R.\}",

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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AU - Mu, David

AU - Krainer, Adrian R.

N1 - 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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N2 - 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.

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

Abstract

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