Functional dichotomy of A20 in apoptotic and necrotic cell death

Peter Storz, Heike Döppler, Christiane Ferran, Shane T. Grey, Alex Toker

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

ROS (reactive oxygen species) play important roles in the progression of a number of human pathologies. ROS promote cell death, but can also induce gene transcription. The transcription factor NF-κB (nuclear factor κB) plays a critical role in oxidative stress responses. One of the proteins regulated by NF-κB is the zinc-finger protein A20. In TNF (tumour necrosis factor)-α signalling, NF-κB induction of A20 leads to increased cell survival. In the present paper, we show that in response to oxidative stress, A20 actually enhances cell death by necrosis, but not by apoptosis. Exposure of cells to ROS leads to the up-regulation of A20 which acts via a negative-feedback loop to block NF-κB activation and cellular survival. Silencing of A20 by RNAi (RNA interference) increases both the induction of NF-κB and the subsequent survival of cells exposed to high doses of oxidative stress, which, in untreated cells, promotes death by necrosis. Cells which express high basal levels of A20 are less protected from oxidative-stress-induced cell death when compared with cells with lower A20 expression. We also show that A20 regulates NF-κB by blocking the degradation of IκB (inhibitory protein κB) α. These data highlight a novel role for A20 in oxidative stress responses by terminating NF-κB-dependent survival signalling and thus sensitizing cells to death by necrosis.

Original languageEnglish (US)
Pages (from-to)47-55
Number of pages9
JournalBiochemical Journal
Volume387
Issue number1
DOIs
StatePublished - Apr 1 2005
Externally publishedYes

Fingerprint

Oxidative stress
Cell death
Oxidative Stress
Cell Death
Reactive Oxygen Species
Necrosis
Cell Survival
Cells
Survival
Pathology
Transcription
Nuclear Proteins
RNA Interference
Zinc
Proteins
Transcription Factors
Up-Regulation
Tumor Necrosis Factor-alpha
Genes
Chemical activation

Keywords

  • A20
  • Apoptosis
  • Necrosis
  • Nuclear factor κB (NF-κB)
  • Oxidative stress
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Biochemistry

Cite this

Functional dichotomy of A20 in apoptotic and necrotic cell death. / Storz, Peter; Döppler, Heike; Ferran, Christiane; Grey, Shane T.; Toker, Alex.

In: Biochemical Journal, Vol. 387, No. 1, 01.04.2005, p. 47-55.

Research output: Contribution to journalArticle

Storz, P, Döppler, H, Ferran, C, Grey, ST & Toker, A 2005, 'Functional dichotomy of A20 in apoptotic and necrotic cell death', Biochemical Journal, vol. 387, no. 1, pp. 47-55. https://doi.org/10.1042/BJ20041443
Storz, Peter ; Döppler, Heike ; Ferran, Christiane ; Grey, Shane T. ; Toker, Alex. / Functional dichotomy of A20 in apoptotic and necrotic cell death. In: Biochemical Journal. 2005 ; Vol. 387, No. 1. pp. 47-55.
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