Differentially expressed genes between oncogene-introduced wild-type and Atf4-/- cells. Mus musculus

During oncogenic transformation, cells acquire genetic mutations that override the normal mechanisms regulating cellular proliferation. Excessive expression of activating transcription factor 4 (ATF4) is often observed in mammalian malignant tumors. However, little is known about the role of ATF4 in the malignant transformation of normal cells. Here, we show that ATF4 promotes oncogene-induced malignant transformation of murine fibroblasts by suppressing the expression of cellular senescence-associated genes. Ectopic expression of oncogenes, H-rasV12 and simian virus 40 large T-antigen, elicited malignant transformation of embryonic fibroblasts from wild-type mice, but not from Atf4-null (Atf4-/-) mice. The oncogenic stresses induced the expression of both Atf4 and cyclin-dependent kinase inhibitor 2a (Cdkn2a), in wild-type cells. Elevated levels of ATF4 successively suppressed the expression of cdkn2a encoding the cellular senescence-associated proteins, p16INK4a and p19ARF, thereby promoting oncogenic transformation. Conversely, the loss of ATF4 caused cellular senescence resulting from the consistent expression of p16INK4a and p19ARF. These findings reveal a novel function of ATF4: that of promoting oncogenic transformation by suppressing cellular senescence. Overall design: Total 2 samples were derived from [1] H-Ras and SV40T expressing vector-transfected wild-type mouse embryonic fibroblasts (MEFs) and [2] H-Ras and SV40T expressing vector-transfected Atf4-/- MEFs