Tumor suppression by manganese superoxide dismutase

StClair, D

doi:10.3892/or.3.3.429

Cited by 1 publication

(2 citation statements)

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“…Much evidence implicates reactive oxygen species (ROS) as a critical etiological factor in a variety of pathological conditions, including aging [1], atherosclerosis [2] and neurodegenerative diseases, such as amyotrophic lateral sclerosis [3] and Parkinson's disease [4]. Additionally, it has been suggested that ROS may play a role in tumour development by inducing DNA damage, enhancing tumour promotion and stimulating cell proliferation [5]. Antioxidant enzymes play an important role in protecting cells from oxidative stresses.…”

Section: Introductionmentioning

confidence: 99%

“…These results suggest that Sp1 and AP-2 may have opposite roles in regulating transcription of the human SOD2 gene. Because it has been well documented that increased expression of MnSOD suppresses tumorigenesis [5], differential regulation of the basal promoter activity may play an important role in the development of cancer. In the present study, we performed in-depth analysis of the human SOD2 promoter and the roles of Sp1 and AP-2 on the transcriptional regulation of the human SOD2 gene.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional regulation of the human manganese superoxide dismutase gene: the role of specificity protein 1 (Sp1) and activating protein-2 (AP-2)

Porntadavity

Clair

2002

Biochemical Journal

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Manganese superoxide dismutase (MnSOD) plays an important role in regulating cellular redox conditions. Expression of MnSOD has been shown to protect against damage by oxidative stress and to suppress the malignant phenotype of human cancer cells. We have previously cloned the human MnSOD (SOD2) gene and analysed its 5′ proximal promoter, which has been characterized by a lack of a TATA or CAAT box and the presence of multiple GC boxes. To define further the molecular mechanisms for the regulation of MnSOD expression, multiple transcription factor-binding motifs containing overlapping specificity protein 1 (Sp1)- and activator protein (AP)-2-binding sites were identified by DNase I footprinting analysis. Functional studies in three cell lines with different levels of Sp1 and AP-2 proteins suggested that the cellular levels of these proteins may differentially regulate transcription via GC-binding motifs in the human SOD2 promoter. Co-transfection of an Sp1 expression vector resulted in an increase in the transcription of the promoter-driven reporter gene. In contrast, co-transfection of the AP-2 expression vector caused a decrease in transcription. Direct mutagenesis analysis of Sp1- and AP-2-binding sites showed that Sp1 is essential for transcription of the human SOD2 gene, whereas AP-2 plays a negative role in the transcription. Immunoprecipitation of Sp1 and AP-2 proteins demonstrated that Sp1 interacts with AP-2 in vivo. Two-hybrid analysis revealed that interaction between Sp1 and AP-2 plays both a positive and negative role in the transcription of the reporter gene in vivo. Taken together, our data indicate that AP-2 down-regulates transcription of the human SOD2 gene via its interaction with Sp1 within the promoter region. These findings, coupled with our previous observation that several cancer cell lines have mutations in the promoter region of the human MnSOD gene, which lead to an increase in an AP-2-binding site and a decrease in the promoter activity, signal the importance of understanding the promoter structure and the regulation of the human SOD2 gene by Sp1 and AP-2.

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