title: Stress-regulated transcription factor ATF4 promotes neoplastic transformation by suppressing expression of the INK4a/ARF cell senescence factors.
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.
authors.affiliation: Department of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Horiguchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Akinori
authors.initials: A
authors.lastname: Okamoto
authors.forename: Satoshi O
authors.initials: SO
authors.lastname: Suzuki
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009857:Oncogenes; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D051701:Activating Transcription Factor 4