Cadmium down-regulates human OGG1 through suppression of Sp1 activity.
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 gamma-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 gamma-ray-induced 8-oxoG accumulation as well as in gamma-radiation-induced mutation frequency at the HPRT (hypoxanthine-guanine phosphoribosyltransferase) gene locus. These results suggest that cadmium attenuates removal of gamma-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.
Youn
Cha-Kyung
CK
Department of Pharmacology, School of Medicine, Chosun University, 375 Seosuk-dong, Gwangju 501-759, Korea.
Kim
Soo-Hyun
SH
Lee
Do Young
DY
Song
Seung Hee
SH
Chang
In-Youb
IY
Hyun
Jin-Won
JW
Chung
Myung-Hee
MH
You
Ho Jin
HJ
D000818:Animals; D015153:Blotting, Western; D002104:Cadmium / Q000378:metabolism / Q000494:pharmacology*; D019256:Cadmium Chloride / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation; D004330:Drosophila; D005720:Gamma Rays; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic
D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D002104:Cadmium; D006151:Guanosine; C046215:8-hydroxyguanosine; D004247:DNA; D008156:Luciferases; D007041:Hypoxanthine Phosphoribosyltransferase; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D019256:Cadmium Chloride; D010100:Oxygen