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ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53

Damu Tang1, Dongcheng Wu, Atsushi Hirao

  • 1Department of Medicine and Father Sean O'Sullivan Research Institute, St. Joseph's Hospital and McMaster University, 708-25 Charlton Avenue, Hamilton L8N 1Y2, Canada. damut@mcmaster.ca

The Journal of Biological Chemistry
|February 1, 2002
PubMed

Insights

DNA damage activates parallel ERK and p53 pathways, both dependent on ATM. These pathways cooperate in cell cycle arrest and apoptosis following DNA damage.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • DNA damage triggers cellular responses like cell cycle arrest and apoptosis, primarily mediated by p53.
  • Ataxia-telangiectasia mutant (ATM) and Rad-3 are key kinases involved in DNA damage response pathways.

Purpose of the Study:

  • To investigate the role of ERK1/2 (ERK) mitogen-activated protein kinase in DNA damage response.
  • To elucidate the relationship between ERK activation, p53, and ATM in response to various DNA damaging agents.

Main Methods:

  • Treatment of various cell types (primary, immortalized, transformed) with DNA damaging agents (etoposide, adriamycin, IR, UV).
  • Assessment of ERK activation using specific inhibitors (PD98059, U0126) and in ATM-deficient cells.
  • Analysis of p53 stabilization, p21(CIP1) induction, cell cycle arrest, and apoptosis.

Main Results:

  • DNA damage stimuli robustly activate ERK1/2 in multiple cell types.
  • ERK activation is ATM-dependent but p53-independent in response to etoposide.
  • Inhibition of ERK signaling attenuated G(2)/M cell cycle arrest and DNA damage-induced apoptosis, while ERK overexpression sensitized cells to apoptosis.

Conclusions:

  • DNA damage activates parallel ATM-dependent pathways involving ERK and p53.
  • ERK and p53 pathways likely cooperate in regulating cell cycle arrest and apoptosis in response to DNA damage.

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