Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization (original) (raw)

  1. Frederique Zindy1,
  2. Christine M. Eischen2,
  3. David H. Randle1,4,
  4. Takehiko Kamijo1,3,
  5. John L. Cleveland2,4,
  6. Charles J. Sherr1,3,4,5, and
  7. Martine F. Roussel1,4
  8. Departments of 1Tumor Cell Biology and2Biochemistry, and 3Howard Hughes Medical Institute, St. Jude Children’s Research Hospital, Memphis Tennessee 38105 USA; 4Department of Biochemistry, University of Tennessee College of Medicine, Memphis Tennessee 38163 USA

Abstract

Establishment of primary mouse embryo fibroblasts (MEFs) as continuously growing cell lines is normally accompanied by loss of the p53 or p19ARF tumor suppressors, which act in a common biochemical pathway. myc rapidly activates ARF and_p53_ gene expression in primary MEFs and triggers replicative crisis by inducing apoptosis. MEFs that survive myc_overexpression sustain p53 mutation or ARF loss during the process of establishment and become immortal. MEFs lacking_ARF or p53 exhibit an attenuated apoptotic response to_myc_ ab initio and rapidly give rise to cell lines that proliferate in chemically defined medium lacking serum. Therefore,ARF regulates a p53-dependent checkpoint that safeguards cells against hyperproliferative, oncogenic signals.

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