Distinct requirements for Ras oncogenesis in human versus mouse cells.
The spectrum of tumors associated with oncogenic Ras in humans often differs from those in mice either treated with carcinogens or engineered to sporadically express oncogenic Ras, suggesting that the mechanism of Ras transformation may be different in humans. Ras stimulates primarily three main classes of effector proteins, Rafs, PI3-kinase, and RalGEFs, with Raf generally being the most potent at transforming murine cells. Using oncogenic Ras mutants that activate single effectors as well as constitutively active effectors, we find that the RalGEF, and not the Raf or PI3-kinase pathway, is sufficient for Ras transformation in human cells. Thus, oncogenic Ras may transform murine and human cells by distinct mechanisms, and the RalGEF pathway--previously deemed to play a secondary role in Ras transformation--could represent a new target for anti-cancer therapy.
Department of Pharmacology, Division of Neurology, Duke University Medical Center, Durham North Carolina 27710, USA.
Nesrin M
NM
Hamad
Joel H
JH
Elconin
Antoine E
AE
Karnoub
Wenli
W
Bai
Jeremy N
JN
Rich
Robert T
RT
Abraham
Channing J
CJ
Der
Christopher M
CM
Counter
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D020935:MAP Kinase Signaling System; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism / Q000502:physiology*
D020726:ral Guanine Nucleotide Exchange Factor; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins