The gene encoding the splicing factor SF2/ASF is a proto-oncogene.
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.
Karni
Rotem
R
Cold Spring Harbor Laboratory, PO Box 100, Cold Spring Harbor, New York 11724, USA.
de Stanchina
Elisa
E
Lowe
Scott W
SW
Sinha
Rahul
R
Mu
David
D
Krainer
Adrian R
AR
D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics*; D016601:RNA-Binding Proteins; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D015854:Up-Regulation / Q000235:genetics
D039561:Eukaryotic Initiation Factor-4E; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1