p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

A. Marchetti, B. Cecchinelli, M. D'Angelo, G. D'Orazi, M. Crescenzi, A. Sacchi, S. Soddu

Research output: Contribution to journalArticlepeer-review


Stimulation of the Ras/MAPK cascade can either activate p53 and promote replicative senescence and apoptosis, or degrade p53 and promote cell survival. Here we show that p53 can directly counteract the Ras/MAPK signaling by inactivating ERK2/MAPK. This inactivation is due to a caspase cleavage of the ERK2 protein and contributes to p53-mediated growth arrest. We found that in Ras-transformed cells, growth arrest induced by p53, but not p21Waf1, is associated with a strong reduction in ERK2 activity, phosphorylation, and protein half-life, and with the appearance of caspase activity. Likewise, DNA damage-induced cell cycle arrest correlates with p53-dependent ERK2 downregulation and caspase activation. Furthermore, caspase inhibitors or expression of a caspase-resistant ERK2 mutant interfere with ERK2 cleavage and restore proliferation in the presence of p53 activation, indicating that caspase-mediated ERK2 degradation contributes to p53-induced growth arrest. These findings strongly point to ERK2 as a novel p53 target in growth suppression.

Original languageEnglish
Pages (from-to)596-607
Number of pages12
JournalCell Death and Differentiation
Issue number6
Publication statusPublished - Jun 2004


  • Caspases
  • Growth arrest
  • p53 target
  • Protein degradation
  • Signal transduction

ASJC Scopus subject areas

  • Cell Biology


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