Mechanism of MnSOD Expression in Normal and Tumor Cells

Grants and Contracts Details

Description

The overall goal of this research is to define the molecular mechanisms for the regulation of manganese superoxide dismutase (MnSOD) expression in normal and tumor cells. It has been repeatedly shown that increased expression of MnSOD effectively protects normal tissues and cultured cells from oxidative stress mediated tissue injury and cell death and that expression of MnSOD suppresses neoplastic transformation and tumorigenecity. Previous studies have found mutations in tumor cells in the 5' proximal promoter of the human MnSOD gene, which lead to a reduced expression of MnSOD and an increase in a binding site for the transcription factor AP-2. These results suggest that AP-2 may play a negative role in controlling the basal expression of the human MnSOD gene in tumor cells. Induction studies using deletion/mutation analysis and transcription assays identified a complex regulatory region in the intron of the human MnSOD gene necessary for the induction of MnSOD by tumor necrosis factor alpha (TNF) and interleukin-1 beta (IL-1). In this application, we will investigate the role of AP-2 in the basal and induced expression of human MnSOD in tumor cells using sense and antisense approaches. The cis-acting elements required to induce the expression of human MnSOD will be mapped at the nucleotide levels by mutation analysis and in vivo footprinting assays. Transcription enhancers involved in the induction of MnSOD will be evaluated using coimmunoprecipitation and fusion protein strategies. The interaction between mitochondrial respiratory function and the effect of TNF on MnSOD induction will be elucidated in cultured cells using stable transfection approaches. Finally, the role of mitochondrial antioxidant status and TNF receptors in the induction of MnSOD will be evaluated in animals using transgenic and knockout approaches. The results obtained from this study should direct the development of strategies to modulate MnSOD activity in normal and tumor cells for the control of cancer development and the protection of normal tissue from oxidative stress-mediated injury during cancer treatment.
StatusFinished
Effective start/end date12/1/898/31/10

Funding

  • National Cancer Institute: $1,205,631.00

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