Stress-regulated transcription factor ATF4 promotes neoplastic transformation by suppressing expression of the INK4a/ARF cell senescence factors

Michiko Horiguchi, Satoru Koyanagi, Akinori Okamoto, Satoshi O. Suzuki, Naoya Matsunaga, Shigehiro Ohdo

Research output: Contribution to journalArticle

36 Citations (Scopus)

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-rasV12 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.

Original languageEnglish
Pages (from-to)395-401
Number of pages7
JournalCancer Research
Volume72
Issue number2
DOIs
Publication statusPublished - Jan 15 2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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