Induction of CCAAT/enhancer-binding protein-homologous protein by cigarette smoke through the superoxide anion-triggered PERK-eIF2α pathway

Toxicology. 2011 Sep 5;287(1-3):105-12. doi: 10.1016/j.tox.2011.06.005. Epub 2011 Jun 15.


Cigarette smoke triggers apoptosis through oxidative stress- and endoplasmic reticulum (ER) stress-dependent induction of CCAAT/enhancer-binding protein-homologous protein (CHOP) (Tagawa et al., 2008. Free Radic. Biol. Med. 45, 50-59). We investigated roles of individual reactive oxygen/nitrogen species in the transcriptional induction of CHOP by cigarette smoke. Exposure of bronchial epithelial cells to O(2)(-), ONOO(-) or H(2)O(2) induced expression of CHOP, whereas NO alone did not. Induction of CHOP mRNA by cigarette smoke extract (CSE) was attenuated by scavengers for O(2)(-), ONOO(-) or NO, whereas scavenging H(2)O(2) did not affect the induction of CHOP. Like CSE, O(2)(-) and ONOO(-) caused activation of the CHOP gene promoter. Scavengers for O(2)(-), ONOO(-) or NO attenuated CSE-triggered activation of the CHOP gene promoter. CSE, O(2)(-) and ONOO(-) induced phosphorylation of protein kinase-like ER kinase (PERK) and eukaryotic translation initiation factor 2α (eIF2α) and caused induction of downstream activating transcription factor 4 (ATF4). Scavengers for O(2)(-), ONOO(-) or NO attenuated induction of ATF4 by CSE. Furthermore, dominant-negative inhibition of the PERK-eIF2α pathway exclusively suppressed CSE-triggered induction of CHOP and consequent apoptosis. These results suggest that O(2)(-) and ONOO(-) are selectively involved in CSE-triggered induction of CHOP and that the PERK-eIF2α pathway plays a crucial role in the induction of CHOP and apoptosis downstream of the particular reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cells, Cultured
  • Eukaryotic Initiation Factor-2 / physiology*
  • Humans
  • Reactive Oxygen Species / metabolism
  • Signal Transduction*
  • Smoke / adverse effects*
  • Superoxides / metabolism*
  • Tobacco / toxicity*
  • Transcription Factor CHOP / biosynthesis*
  • eIF-2 Kinase / physiology*


  • DDIT3 protein, human
  • Eukaryotic Initiation Factor-2
  • Reactive Oxygen Species
  • Smoke
  • Superoxides
  • Transcription Factor CHOP
  • PERK kinase
  • eIF-2 Kinase