Journal Article

The Repressive Effect of NF-κB on p53 by Mot-2 Is Involved in Human Keratinocyte Transformation Induced by Low Levels of Arsenite

Yuan Li, Min Ling, Yuan Xu, Shoulin Wang, Zhong Li, Jianwei Zhou, Xinru Wang and Qizhan Liu

in Toxicological Sciences

Volume 116, issue 1, pages 174-182
Published in print July 2010 | ISSN: 1096-6080
Published online April 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq109
The Repressive Effect of NF-κB on p53 by Mot-2 Is Involved in Human Keratinocyte Transformation Induced by Low Levels of Arsenite

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Inorganic arsenic is a ubiquitous environmental contaminant associated with an increased risk of skin hyperkeratosis and cancer. Although several hypotheses that relate to arsenic-induced carcinogenesis have been suggested, the mechanism of action remains obscure. In the present study, molecular mechanisms underlying the inactivation of p53 function and the genomic instability in malignant transformation of the human keratinocyte cell line, HaCaT, induced by low levels of arsenic were investigated. Our results show that long-term exposure of HaCaT cells to sodium arsenite (1.0μM) increases their proliferation, causes DNA double-strand breaks, and induce anchorage-independent growth. In arsenite-exposed cells, the levels of phospho-p53, p21, and mdm2 increase at early times after exposure. The levels, however, decrease with longer times. Interaction of the promoter of mot-2 (a p53 inhibitor) with nuclear factor κB (NF-κB) was established by Southwestern and Western blot assays. Blockage of NF-κB prevents the increases of arsenite-induced mot-2 levels, and knockdown of mot-2 facilitates the nuclear translocation of p53, indicating that, in HaCaT cells exposed to arsenite, NF-κB inhibits p53 function by mot-2. Moreover, inactivation of NF-κB facilitated p53-mediated DNA repair and prevented arsenite-induced malignant transformation. Together, the results suggest that the repressive effect of NF-κB on p53 by mot-2 leads to genomic instability, which is involved in arsenite-induced malignant transformation of human keratinocytes.

Keywords: arsenic; DNA double-strand breaks; malignant transformation; mot-2; nuclear factor κB; p53

Journal Article.  4848 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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