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Vol. 10, Issue 6, 1693-1703, June 1999
Department of Molecular and Cell Biology, University of
California-Berkeley, Berkeley, California 94720-3204
An increase in the level of active, GTP-bound Ras is not necessary
for transformation of chicken embryo fibroblasts (CEF) by v-Src. This
suggests that other Ras-independent pathways contribute to
transformation by v-Src. To address the possibility that activation of
phosphatidylinositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR/FRAP), represents one of these pathways, we have
examined the effect of simultaneous inhibition of the Ras-MAPK and
PI3K-mTOR pathways on transformation of CEF by v-Src.
Transformation was assessed by the standard parameters of morphological
alteration, increased hexose uptake, loss of density inhibition, and
anchorage-independent growth. Inhibition of the Ras-MAPK pathway by
expression of the dominant-negative Ras mutant HRasN17 or by addition
of the MAPK kinase (MEK) inhibitor PD98059 reduced several of
these parameters but failed to block transformation. Similarly,
inhibition of the PI3K-mTOR pathway by addition of the PI3K inhibitor
2-[4-morpholinyl]-8-phenyl-4H-1-benzopyran-4-one (LY294002) or the
mTOR inhibitor rapamycin, although reducing several parameters of
transformation, also failed to block transformation. However,
simultaneous inhibition of signaling by the Ras-MAPK pathway and the
PI3K-mTOR pathway essentially blocked transformation. These data
indicate that transformation of CEF by v-Src is mediated by two
parallel pathways, the Ras-MAPK pathway and the PI-3K-mTOR pathway,
which both contribute to transformation. The possibility that
simultaneous activation of other pathways is also required is not excluded.
Corresponding author. E-mail address:
smartin{at}socrates.berkeley.edu.
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