Mutations in the SOD2 promoter reveal a molecular basis for an activating protein 2-dependent dysregulation of manganese superoxide dismutase expression in cancer cells.
A primary antioxidant enzyme in mitochondria, manganese superoxide dismutase (MnSOD), plays a critical role in the survival of aerobic life. It is well documented that, compared with normal cell counterparts, MnSOD level is decreased in neoplastic transformed cells but is increased in aggressive cancers. However, the underlying mechanism for the observed dysregulation of MnSOD in cancer is unknown. We have identified previously a unique set of mutations located in the promoter region of the SOD2 gene in several types of cancer cells. We found that a C-to-T transition at -102 and an insertion of A at -93 down-regulate MnSOD transcription by interrupting the formation of a single-stranded loop that is essential for a high level of promoter activity. Here, we show that the additional downstream mutation, C-to-G transversion at -38, creates a binding site for the transcription factors specificity protein 1 (Sp1) and activating protein 2 (AP-2). The promoter function is regulated by the relative levels of Sp1 and AP-2. In cytokine-induced expression of the SOD2 gene, Sp1 cooperates with a transcriptional complex containing nuclear factor-kappaB and nucleophosmin. The presence of AP-2 attenuates this induction. Our results suggest that the high level of MnSOD observed in aggressive cancer cells may be due, in part, to the absence of AP-2 transcriptional repression.
Xu
Yong
Y
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Fang
Fang
F
Dhar
Sanjit K
SK
Bosch
Antonio
A
St Clair
William H
WH
Kasarskis
Edward J
EJ
St Clair
Daret K
DK
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002461:Cell Line, Transformed; D005347:Fibroblasts / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000166:cytology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D000099156:Superoxide Dismutase 2
D016329:Sp1 Transcription Factor; D013482:Superoxide Dismutase; D050656:Transcription Factor AP-2; D000099156:Superoxide Dismutase 2