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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

Nrf2 signaling and cell survival

Suryakant K Niture1, James W Kaspar, Jun Shen

  • 1Department of Pharmacology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.

Toxicology and Applied Pharmacology
|June 23, 2009
PubMed

Insights

The Nrf2 (Nuclear factor erythroid 2-related factor 2) and INrf2 (inhibitor of Nrf2) proteins form an auto-regulatory loop. This loop controls cellular defense genes, protecting cells from oxidative stress and promoting survival.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of stress response

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating cellular defense against oxidative and electrophilic stress.
  • The inhibitor of Nrf2 (INrf2) protein targets Nrf2 for degradation under basal conditions, acting as a crucial regulator of Nrf2 stability and activity.

Purpose of the Study:

  • To elucidate the intricate regulatory mechanisms governing Nrf2 activity and its interaction with INrf2.
  • To understand how oxidative and electrophilic stress signals modulate Nrf2 localization and degradation.
  • To investigate the auto-regulatory feedback loop between Nrf2 and INrf2.

Main Methods:

  • The study likely involved molecular biology techniques to investigate protein-protein interactions, cellular localization, and gene expression.
  • Analysis of post-translational modifications (phosphorylation, ubiquitination) of Nrf2 and INrf2.
  • Investigating the role of specific signaling pathways (PKC, GSK-3beta) and proteins (Fyn, Prothymosin-alpha) in Nrf2 regulation.

Main Results:

  • Under stress, Nrf2 dissociates from INrf2, translocates to the nucleus, and activates protective genes via the antioxidant response element (ARE).
  • Specific modifications (e.g., INrf2 Cys151, Nrf2 Ser40 phosphorylation) facilitate Nrf2 release and nuclear entry.
  • A delayed stress response involves GSK-3beta and Fyn, leading to Nrf2 phosphorylation, nuclear export, and degradation, alongside INrf2-mediated nuclear degradation.
  • An auto-regulatory loop exists where Nrf2 controls INrf2 transcription, and INrf2 degrades Nrf2 in both cellular compartments.

Conclusions:

  • The dynamic interplay between Nrf2 and INrf2, involving stress-induced modifications and degradation pathways, precisely controls Nrf2 levels and target gene activation.
  • This auto-regulatory mechanism ensures rapid adaptation to oxidative/electrophilic stress and promotes cell survival.
  • Fine-tuning of Nrf2 activity is critical for cellular defense and maintaining homeostasis.

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