Abstract
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.
Highlights
CAMP-responsive element-binding proteins (CREB) and activating transcription factors (ATF) are basic region leucine zipper proteins, which act as transcriptional activators or repressors
We found that embryonic fibroblasts prepared from Atf4-null (Atf4À/À) mice showed resistance to oncogenic transformation induced by concomitant expression of protooncogenic RAS (H-rasV12) and simian virus 40 large T antigen (SV40LT)
To characterize the role of Activating transcription factor-4 (ATF4) in oncogenic transformation, we prepared Mouse embryonic fibroblasts (MEF) from wild-type and Atf4À/À mice, and infected the cells concomitantly with retrovirus vectors expressing the H-rasV12 and the SV40LT [4]. These oncogenes were expressed in wild-type and Atf4À/À cells (Supplementary Fig. S2A)
Summary
CAMP-responsive element-binding proteins (CREB) and activating transcription factors (ATF) are basic region leucine zipper proteins, which act as transcriptional activators or repressors. To characterize the role of ATF4 in oncogenic transformation, we prepared MEFs from wild-type and Atf4À/À mice, and infected the cells concomitantly with retrovirus vectors expressing the H-rasV12 and the SV40LT [4]. SV40LT into Atf4À/À cells caused a significant and consistent increase in the expression of p16INK4a and p19ARF at both mRNA and protein levels (P < 0.05; Fig. 2B and C).
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