Many cancers overexpress ATF4, a stress-induced transcription factor that 
promotes cell survival under hypoxic conditions and other stresses of the tumor 
microenvironment, but the potential contributions of ATF4 to oncogenesis itself 
have been little explored. Here, we report that ATF4 promotes oncogene-induced 
neoplastic transformation by suppressing the expression of cellular 
senescence-associated genes. Strikingly, primary embryo fibroblasts from 
ATF4-deficient mice were resistant to transformation by coexpression of 
H-ras(V12) and SV40 large T antigen. In wild-type cells these oncogenes induced 
expression of the murine Atf4 gene along with the cyclin-dependent kinase 
inhibitor Cdkn2a, which encodes the cell senescence-associated proteins p16INK4 
and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of 
these proteins and drive oncogenic transformation. Conversely, genetic ablation 
of ATF4 led to constitutive expression of p16INK4a and p19ARF, triggering 
cellular senescence. Our findings define a central function for ATF4 in 
promoting oncogenic transformation by suppressing a central pathway of cellular 
senescence.