Ras/MEK signaling suppresses Myc-dependent apoptosis in cells transformed by c-myc and activated ras

Cooperation of myc and activated ras has been suggested to cause malignant cell transformation but the mechanism is still unknown. Here we isolated a transformed cell line in which activation of c-Mye and Ras are independentl y controllable, and show that after establishment of the transformed state by c-myc and activated ras, removal of activated Ras initiates apoptosis th at is dependent on c-Myc activity. Apoptosis is also initiated by an inhibi tor of MEK (MAPK/ERK kinase), a kinase downstream of Ras, and apoptosis is blocked by activated Mek1. These results suggest that one of the conditions required for establishment of the transformed state is a block of apoptosi s involving MEK activity. We tested the effect of MEK inhibition on cells t ransformed by various oncogenes, Suppression of apoptosis by MEK; is not cr itical in general, but in cells transformed by c-myc plus a gene that activ ates the MAPK cascade it is necessary to avoid cell death, Activated Ras/ME K did not suppress c-myc-dependent apoptosis due to serum-limitation. Overe xpression of chicken bcl-xL suppressed apoptosis under serum-limiting condi tions, but not apoptosis initiated by Ras/MEK inhibition in cells transform ed by myc and activated ras. Altogether, these results suggest the existenc e of a novel el regulatory mechanism for myc-dependent apoptosis in certain transformed cells.