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PMID: 17310252 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

Nature structural & molecular biology ·Vol. 14 ·No. 3 ·2007-03-00 ·Pages 185-93

Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR

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.

MeSH Terms
Alternative Splicing Animals Apoptosis Cell Proliferation Cell Transformation, Neoplastic/genetics Eukaryotic Initiation Factor-4E/metabolism Gene Expression Profiling Gene Expression Regulation, Neoplastic HeLa Cells Humans Mice Mice, Nude NIH 3T3 Cells Neoplasms/genetics Nuclear Proteins/genetics Phosphorylation Protein Isoforms/metabolism Proto-Oncogene Mas Proto-Oncogenes/genetics RNA-Binding Proteins Rats Ribosomal Protein S6 Kinases, 70-kDa/metabolism Serine-Arginine Splicing Factors Up-Regulation/genetics
Chemicals
Eukaryotic Initiation Factor-4E MAS1 protein, human Nuclear Proteins Protein Isoforms Proto-Oncogene Mas RNA-Binding Proteins Serine-Arginine Splicing Factors Ribosomal Protein S6 Kinases, 70-kDa ribosomal protein S6 kinase, 70kD, polypeptide 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Karni Rotem
Cold Spring Harbor Laboratory, PO Box 100, Cold Spring Harbor, New York 11724, USA.
de Stanchina Elisa
Lowe Scott W
Sinha Rahul
Mu David
Krainer Adrian R
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9993
DOI
10.1038/nsmb1209
Published
2007-03-00
Epub
2007-00-18
Pages
185-93
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC4595851
Subset
IM
Grants
NCI NIH HHS · P01 CA013106 · United States
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · CA13106 · United States
Corrections
CommentIn
PMID: 17334403
External Links
PubMed source DOI: 10.1038/nsmb1209 PMC Full Text View journal details
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