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J. Biol. Chem., Vol. 280, Issue 26, 25185-25195, July 1, 2005

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Cadmium Down-regulates Human OGG1 through Suppression of Sp1 Activity^*

Cha-Kyung Youn, Soo-Hyun Kim, Do Young Lee, Seung Hee Song, In-Youb Chang¶, Jin-Won Hyun||, Myung-Hee Chung**, and Ho Jin You

From the Departments of Pharmacology and ^¶Anatomy, School of Medicine, and the Research Center for Proteineous Materials, Chosun University, 375 Seosuk-dong, Gwangju 501-759, Korea, the ^||Department of Biochemistry, College of Medicine, Cheju National University, Jeju, Jeju-do 690-756, Korea, and the ^**Department of Pharmacology, College of Medicine, Seoul National University, 28 Yongon-dong, Seoul 110-799, Korea

Cadmium is a well known human and animal carcinogen and is a ubiquitous contaminant in the environment. Although the carcinogenic mechanism of cadmium is a multifactorial process, oxidative DNA damage is believed to be of prime importance. In particular, cadmium suppresses the capacity of cells to repair oxidative DNA damage. In this study, cadmium treatment led to a significant increase in -ray-induced 8-oxoguanine (8-oxoG) formation. Western blotting and semiquantitative reverse transcription-PCR revealed that cadmium treatment caused a decrease in the expression level of human OGG1 (8-oxoguanine-DNA glycosylase-1; hOGG1) in human fibroblast GM00637 and HeLa S3 cells. In addition, the cadmium-mediated decrease in hOGG1 transcription was the result of decreased binding of the transcription factor Sp1 to the hOGG1 promoter. Finally, we show that an increase in the functional hOGG1 expression level could inhibit the cadmium-mediated increase in -ray-induced 8-oxoG accumulation as well as in -radiation-induced mutation frequency at the HPRT (hypoxanthine-guanine phosphoribosyltransferase) gene locus. These results suggest that cadmium attenuates removal of -ray-induced 8-oxoG adducts, which in turn increases the mutation frequency, and that this effect might, at least in part, result from suppression of hOGG1 transcription via inactivation of Sp1 as a result of cadmium treatment.

Received for publication, November 11, 2004 , and in revised form, March 9, 2005.

^* This work was supported by Grant 01-PJ1-PG3-20800-0043 from the Korea Health 21 Research and Development Project, Ministry of Health and Welfare, Republic of Korea. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 82-62-230-6337; Fax: 82-62-233-3720; E-mail: hjyou{at}mail.chosun.ac.kr.

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