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

Nat Struct Mol Biol. 2007 Mar;14(3):185-93. doi: 10.1038/nsmb1209. Epub 2007 Feb 18.

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.

Publication types

  • Research Support, N.I.H., Extramural

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-Oncogenes / genetics*
  • RNA-Binding Proteins
  • Rats
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Serine-Arginine Splicing Factors
  • Up-Regulation / genetics

Substances

  • Eukaryotic Initiation Factor-4E
  • Nuclear Proteins
  • Protein Isoforms
  • RNA-Binding Proteins
  • Serine-Arginine Splicing Factors
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1