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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

The two faces of NFkappaB in cell survival responses

Bonnie Graham1, Spencer B Gibson

  • 1Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada.

Cell Cycle (Georgetown, Tex.)
|August 27, 2005
PubMed

Insights

NF-kappaB (NFκB) signaling pathways are activated by diverse stimuli, but histone modifications dictate whether NFκB promotes cell survival or apoptosis. This study reveals how histone deacetylase 1 (HDAC1) influences NFκB target gene expression.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Epigenetics

Background:

  • Nuclear factor kappa B (NFκB) signaling is activated by various stimuli, including growth factors and DNA-damaging agents.
  • Paradoxically, these disparate stimuli often converge on the same NFκB signaling pathways, leading to conflicting outcomes like cell survival and apoptosis.
  • Post-translational modifications of NFκB and associated histones are crucial for selectively targeting NFκB-regulated genes.

Purpose of the Study:

  • To investigate the mechanisms underlying selective NFκB transcriptional regulation.
  • To elucidate the role of histone modifications in determining the cellular response (survival vs. apoptosis) to NFκB activation.
  • To understand how histone deacetylase 1 (HDAC1) influences NFκB-mediated gene expression, particularly for the death receptor 5 (DR5) gene.

Main Methods:

  • Utilized etoposide and epidermal growth factor (EGF) as distinct stimuli to activate NFκB.
  • Analyzed NFκB-induced expression of death receptor 5 (DR5).
  • Investigated the recruitment of histone deacetylase 1 (HDAC1) to the DR5 gene promoter using chromatin immunoprecipitation (ChIP) assays.
  • Examined the effects of HDAC inhibitors on NFκB binding and DR5 expression.

Main Results:

  • NFκB activation by etoposide induced DR5 expression, while EGF treatment did not.
  • HDAC1 was recruited to the DR5 gene promoter by NFκB following EGF treatment, but not etoposide treatment.
  • HDAC inhibitors promoted NFκB binding to the DR5 gene and increased DR5 expression.
  • These findings suggest a model where histone modifications dictate the transcriptional outcome of NFκB activation.

Conclusions:

  • Selective NFκB transcriptional regulation is achieved through context-dependent post-translational modifications of histones.
  • HDAC1 plays a critical role in repressing DR5 expression following growth factor stimulation.
  • HDAC inhibitors can overcome this repression, leading to DR5-mediated apoptosis, highlighting a potential therapeutic strategy.

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