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The splicing-factor oncoprotein SF2/ASF activates mTORC1

Rotem Karni1, Yoshitaka Hippo, Scott W Lowe

  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. rotemka@ekmd.huji.ac.il

Proceedings of the National Academy of Sciences of the United States of America
|October 4, 2008
PubMed

Insights

The splicing factor SF2/ASF activates the mTORC1 pathway, driving cancer cell transformation. Inhibiting mTORC1 shows promise for treating SF2/ASF-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • The splicing factor SF2/ASF is an oncoprotein overexpressed in numerous cancers.
  • The mechanistic target of rapamycin (mTOR) signaling pathway is frequently activated in cancer.
  • mTOR inhibitors are under investigation as anticancer therapeutics.

Purpose of the Study:

  • To investigate the role of the mTOR signaling pathway in SF2/ASF-mediated cellular transformation.
  • To determine which branch of the mTOR pathway is affected by SF2/ASF.
  • To assess the therapeutic potential of targeting mTOR in SF2/ASF-driven cancers.

Main Methods:

  • Assessed mTOR pathway activity via phosphorylation of S6K and eIF4EBP1 in SF2/ASF-transformed cells.
  • Utilized rapamycin to inhibit mTOR activity.
  • Employed shRNA to knock down mTOR, Raptor, and Rictor components.

Main Results:

  • SF2/ASF specifically activates the mTORC1 pathway, evidenced by increased S6K and eIF4EBP1 phosphorylation, without affecting mTORC2 signaling (Akt phosphorylation).
  • mTORC1 activation by SF2/ASF is crucial for cellular transformation, as rapamycin treatment inhibited this process both in vitro and in vivo.
  • Knockdown of mTOR, Raptor, or Rictor using shRNA eliminated the tumorigenic potential of SF2/ASF-overexpressing cells.

Conclusions:

  • SF2/ASF activates mTORC1 independently of upstream PI3K/Akt signaling, and this activation is essential for its oncogenic function.
  • SF2/ASF-driven cancers may exhibit heightened sensitivity to mTOR inhibitors, suggesting a potential targeted therapy approach.

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