Protection from the dark side of NO: signaling and cellular defenses against nitric oxide toxicity

Bruce Demple1

  • 1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA. bdemple@hsph.harvard.edu

IUBMB Life
|April 17, 2004
PubMed

Insights

Cellular resistance to nitric oxide (NO) toxicity involves inducible defense pathways. The enzyme heme oxygenase-1 (HO1) is crucial, with its mRNA stabilization playing a key role in NO resistance.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Toxicology

Background:

  • Nitric oxide (NO) is vital for intercellular signaling and inflammation but can harm non-target cells due to poor membrane containment.
  • Cellular defense mechanisms are activated to mitigate NO-induced damage, prevent apoptosis, and enhance repair systems.

Purpose of the Study:

  • To investigate the genetic and biochemical basis of cellular resistance to nitric oxide (NO) toxicity.
  • To identify the critical heme oxygenase-1 (HO1)-dependent reactions conferring NO resistance.

Main Methods:

  • Studied inducible resistance mechanisms in cellular models.
  • Analyzed the role of heme oxygenase-1 (HO1) in NO-mediated cytotoxicity.
  • Investigated transcriptional activation and mRNA stabilization of HO1 in response to NO exposure in human fibroblasts.

Main Results:

  • Heme oxygenase-1 (HO1) activity is essential for mammalian cell resistance to NO.
  • HO1 induction by NO involves transcriptional activation and, notably, NO-induced mRNA stabilization.
  • mRNA stabilization of HO1 increases with NO exposure levels in human fibroblasts.

Conclusions:

  • Inducible NO resistance pathways are complex, involving novel regulatory mechanisms.
  • Heme oxygenase-1 (HO1) mRNA stabilization is a critical component of cellular defense against NO toxicity.
  • Understanding these pathways offers insights into cellular responses to oxidative stress.

Related Concept Videos

Nitric Oxide Signaling Pathway01:28

Nitric Oxide Signaling Pathway

Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure to...
Paracrine Signaling01:21

Paracrine Signaling

Paracrine signaling allows cells to communicate with their immediate neighbors via secretion of signaling molecules. Such a signal can only trigger a response in nearby target cells because the signal molecules degrade quickly or are inactivated if not taken up. Prominent examples of paracrine signaling include nitric oxide signaling in blood vessels, synaptic signaling of neurons, the blood clotting system, tissue repair/wound healing, and local allergic skin reactions. Nitric oxide as a...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Diversity in Cell Signaling Responses01:22

Diversity in Cell Signaling Responses

The physiological function of a cell and cellular communication are outcomes of a range of extrinsic signals, intracellular signaling pathways, and cellular responses. No two cell types express the same repertoire of signaling components. Receptors are highly selective for their cognate ligands, but once activated, they can alter multiple cellular processes such as DNA transcription, protein synthesis, and metabolic activity. 
Graded and Abrupt Responses
Some signaling systems generate...
Role Of Notch Signalling In Intestinal Stem Cell Renewal01:12

Role Of Notch Signalling In Intestinal Stem Cell Renewal

Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...