Nucleolar NF-κB/RelA mediates apoptosis by causing cytoplasmic relocalization of nucleophosmin

N. Khandelwal, J. Simpson, G. Taylor, S. Rafique, A. Whitehouse, J. Hiscox, L. A. Stark*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

In a number of contexts, and particularly in response to cellular stress, stimulation of the NF-kappaB (NF-κB) pathway promotes apoptosis. One mechanism underlying this pro-apoptotic activity is nucleolar sequestration of RelA, which is reported to cause cell death by repressing NF-κB-driven transcription. Here, we identify a novel and distinct nucleolar activity of RelA that induces apoptosis. We demonstrate, using a viral nucleolar localization signal (NoLS)-RelA fusion protein, that direct targeting of RelA to the nucleolus mediates apoptosis, independent of NF-κB transcriptional activity. We demonstrate a requirement for nucleophosmin (NPM, B23.1) in this apoptotic effect, and the apoptotic effect of stress-induced nucleolar RelA. We show by multiple approaches that nucleolar translocation of RelA is causally involved in the relocalization of NPM from the nucleolus to the cytoplasm and that RelA-induced cytoplasmic NPM mediates apoptosis by facilitating the mitochondrial accumulation of BAX. These data uncover a novel stress-response pathway and mechanism by which RelA promotes apoptosis, independent of its effects on NF-κB transcriptional activity. These findings are relevant to the design of novel anticancer agents that target RelA to this compartment.
Original languageEnglish
Pages (from-to)1889-1903
Number of pages15
JournalCell Death and Differentiation
Volume18
Issue number12
DOIs
Publication statusPublished - Dec 2011

Keywords

  • PROGRAMMED CELL-DEATH
  • aspirin
  • PROTEIN
  • RELA
  • NPM
  • nucleoli
  • ACTIVATION
  • B23
  • TUMOR-SUPPRESSOR
  • BAX
  • TRANSCRIPTION
  • CANCER-CELLS
  • NUCLEAR TRANSLOCATION
  • COLORECTAL-CANCER

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