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Carcinogenesis Advance Access published online on July 25, 2007
Carcinogenesis, doi:10.1093/carcin/bgm163
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Chronic exposure to 12-O-tetradecanoylphorbol-13-acetate represses sod2 induction in vivo: The negative role of p50

Sanjit Kumar Dhar, Yong Xu, Teresa Noel and Daret K. St. Clair

Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536

Corresponding author: Daret K. St. Clair, Ph. D., Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, Tel: 1-859-257-3956, Fax: 1-859-323-1059, E-mail: dstcl00{at}uky.edu

It is well documented that the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) can activate MnSOD expression. However, it is unclear how repeated exposure to TPA following a single application of tumor initiator 7, 12-dimethylbenz-(a)-anthracene (DMBA) causes tumor development. We generated transgenic mice expressing human MnSOD promoter- and enhancer-driven luciferase reporter gene and used a non-invasive imaging system to investigate the effects of TPA on MnSOD expression in vivo. Our data indicate that TPA initially activates MnSOD expression, but this positive effect declines after repeated applications. Changes in MnSOD expression in vivo were verified by measuring MnSOD mRNA and protein levels. Using chromatin immunoprecipitation (ChIP) coupled to Western analysis of the transcription factors known to be essential for the constitutive and TPA-induced transcription of MnSOD, we found that TPA treatment leads to both activation and inactivation of MnSOD gene transcription. During the activation phase, the levels of p50, p65, Sp1, and NPM increase after TPA treatments. Sustained treatments with TPA lead to further increase of p50 but not p65, Sp1 or NPM, suggesting that excess p50 may have inhibitory effects leading to the suppression of MnSOD. Alteration of p50 levels by expressing p50 cDNA or p50 siRNA in mouse epithelial (JB6) cells confirms that p50 is inhibitory to MnSOD transcription. These findings identify p50 as having a negative effect on MnSOD induction upon repeated applications of TPA and provide an insight into a cause for the reduction of MnSOD expression during early stages of skin carcinogenesis.

Key Words: MnSOD • TPA • p50 • Sp1 • ChIP assay • transgenic mice

Received March 6, 2007; revised July 12, 2007; accepted July 12, 2007.


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