title: Induction of CCAAT/enhancer-binding protein-homologous protein by cigarette smoke through the superoxide anion-triggered PERK-eIF2α pathway.
abstract: 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.
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tagawa
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Hironori
authors.initials: H
authors.lastname: Kato
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakoh
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Saito
authors.forename: Hisashi
authors.initials: H
authors.lastname: Johno
authors.forename: Shuhei
authors.initials: S
authors.lastname: Takahashi
authors.forename: Liubao
authors.initials: L
authors.lastname: Gu
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
authors.forename: Masanori
authors.initials: M
authors.lastname: Kitamura
mesh_terms: D017209:Apoptosis; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology*; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D013481:Superoxides / Q000378:metabolism*; D014026:Nicotiana / Q000633:toxicity*; D051742:Transcription Factor CHOP / Q000096:biosynthesis*; D019892:eIF-2 Kinase / Q000502:physiology*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D017382:Reactive Oxygen Species; D012906:Smoke; D013481:Superoxides; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human