Journal Article

4-(Methylnitro-Samino)-1-(3-Pyridyl)-1-Butanone Induces CRM1-Dependent P53 Nuclear Accumulation in Human Bronchial Epithelial Cells

Lixia Chen, Changxia Shao, Everardo Cobos, Jia-Sheng Wang and Weimin Gao

in Toxicological Sciences

Volume 116, issue 1, pages 206-215
Published in print July 2010 | ISSN: 1096-6080
Published online April 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq123
4-(Methylnitro-Samino)-1-(3-Pyridyl)-1-Butanone Induces CRM1-Dependent P53 Nuclear Accumulation in Human Bronchial Epithelial Cells

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4-(Methylnitro-samino)-1-(3-pyridyl)-1-butanone (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.

Keywords: 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone; p53; chromosomal region maintenance 1; nucleocytoplasmic shuttling factors; poly(ADP-ribose) polymerase 1

Journal Article.  6241 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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