4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [corrected] induces CRM1-dependent p53 nuclear accumulation in human bronchial epithelial cells.
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [corrected] (NNK), a known tobacco-specific human lung carcinogen, is notorious for causing DNA damage. The tumor suppressor gene p53 has multiple functions in response to DNA damage. Besides being regulated by posttranslational modifications (PTMs), p53 function is modulated by nucleocytoplasmic shuttling factors (NSFs). In this study, the alterations of p53 protein after NNK exposure and the molecular mechanisms involved p53 PTMs and NSFs in human bronchial epithelial cells BEAS-2B were investigated. NNK induced p53 nuclear accumulation and upregulated the expression of p21, a p53 target gene. Among the five NSFs examined, chromosomal region maintenance 1 (CRM1), interacting with p53 and exporting p53 from nucleus to cytoplasm, was significantly downregulated after NNK exposure. Increases of p53 phosphorylation and poly(ADP-ribosyl)ation were found in NNK-treated cells as compared with the controls. The upregulation of p53 poly(ADP-ribosyl)ation was induced by the enhanced expression of poly(ADP-ribose) polymerase 1 after NNK exposure. Collectively, p53 went through PTMs in response to DNA damage, and the modified p53 had a tendency for nuclear accumulation, which could result from CRM1 downregulation. Consequently, the activation of p53 led to subsequent induction of its downstream targets. These data could facilitate the better understanding of chemical carcinogenesis induced by NNK.
Chen
Lixia
L
Department of Environmental Toxicology, Texas Tech University, Lubbock, Texas 79409, USA.
Shao
Changxia
C
Cobos
Everardo
E
Wang
Jia-Sheng
JS
Gao
Weimin
W
D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D028884:Karyopherins / Q000096:biosynthesis*; D009602:Nitrosamines / Q000633:toxicity*; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000097606:Exportin 1 Protein
D002273:Carcinogens; D028884:Karyopherins; D009602:Nitrosamines; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone