GEA 3162, a peroxynitrite donor, induces Bcl-2-sensitive, p53-independent apoptosis in murine bone marrow cells

Emma L. Taylor, John T. Li, Joan C. Tupper, Adriano G. Rossi, Robert K. Winn, John M. Harlan

Research output: Contribution to journalArticlepeer-review

Abstract

Apoptosis may be regulated by oxidants such as peroxynitrite (ONOO). The tumour suppressor, p53, has been reported to play a crucial role in apoptosis induced by oxidants, therefore we assessed the ability of a ONOO donor, GEA 3162, to activate caspases and induce mitochondrial permeability in a p53-deficient murine bone marrow cell line, Jaws II. Furthermore, these cells were stably transfected with Bcl-2, in order to investigate the impact of this survival protein on ONOO-induced apoptosis. GEA 3162 activated caspases and induced loss of mitochondrial membrane potential in Jaws II cells. In particular, caspases 3 and 2 were activated, alongside minor activation of caspases 8 and 9, and
apoptosis was partially dependent upon p38 MAP kinase activation, with little or no role for JNK. Overexpression of Bcl-2 abolished activation of all caspases and reduced the change in mitochondrial membrane potential. Thus, we have demonstrated that the ONOO donor, GEA 3162, induces apoptosis in Jaws II murine myeloid cells despite lacking functional p53, via a pathway that principally involves caspases 2 and 3 and mitochondrial changes. This is blocked by overexpression of Bcl-2 via a mechanism that does not appear to merely reflect
stabilisation of the mitochondrial membrane.
Original languageEnglish
Pages (from-to)1039-1049
JournalBiochemical Pharmacology
Volume74
Issue number7
DOIs
Publication statusPublished - 1 Oct 2007

Keywords

  • Peroxynitrite
  • Apoptosis
  • Caspase
  • p53
  • Bcl-2
  • Myeloid

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