The splicing-factor oncoprotein SF2/ASF activates mTORC1.
The splicing factor SF2/ASF is an oncoprotein that is up-regulated in many cancers and can transform immortal rodent fibroblasts when slightly overexpressed. The mTOR signaling pathway is activated in many cancers, and pharmacological blockers of this pathway are in clinical trials as anticancer drugs. We examined the activity of the mTOR pathway in cells transformed by SF2/ASF and found that this splicing factor activates the mTORC1 branch of the pathway, as measured by S6K and eIF4EBP1 phosphorylation. This activation is specific to mTORC1 because no activation of Akt, an mTORC2 substrate, was detected. mTORC1 activation by SF2/ASF bypasses upstream PI3K/Akt signaling and is essential for SF2/ASF-mediated transformation, as inhibition of mTOR by rapamycin blocked transformation by SF2/ASF in vitro and in vivo. Moreover, shRNA-mediated knockdown of mTOR, or of the specific mTORC1 and mTORC2 components Raptor and Rictor, abolished the tumorigenic potential of cells overexpressing SF2/ASF. These results suggest that clinical tumors with SF2/ASF up-regulation could be especially sensitive to mTOR inhibitors.
Karni
Rotem
R
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. rotemka@ekmd.huji.ac.il
Hippo
Yoshitaka
Y
Lowe
Scott W
SW
Krainer
Adrian R
AR
D000818:Animals; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins; D012326:RNA Splicing; D016601:RNA-Binding Proteins; D051381:Rats; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
C519510:Crtc1 protein, rat; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000068103:Serine-Arginine Splicing Factors; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases