The University of Kentucky (UK) has announced that Dr. Daret St. Clair, the James Graham Brown Endowed Chair and professor of toxicology, has published the first comprehensive study that provides insight into the relationship between two types of suppressors in cancerous tumors. The results will enhance the understanding of transcriptional mechanisms in carcinogenesis. The study was supported by a National Cancer Institute research grant and was published in the November 1, 2011 issue of Cancer Research. Dr. St. Clair and her team generated transgenic mice expressing a luciferase reporter gene under the control of human MnSOD promoter-enhancer elements and investigated the changes of MnSOD transcription using the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-l3-acetate (TPA) multistage skin carcinogenesis model. Manganese superoxide dismutase (MnSOD) plays a critical role in the survival of aerobic life, and its abnormal expression has been implicated in carcinogenesis and tumor resistance to therapy. Despite extensive studies in MnSOD regulation and its role in cancer, when and how the alteration of MnSOD expression occurs during the process of tumor development in vivo are unknown. The current results show that MnSOD expression was suppressed at a very early stage, but increased at late stages of skin carcinogenesis. The suppression and subsequent restoration of MnSOD expression were mediated by two transcription factors, Sp1 and p53. Exposure to DMBA and TPA activated p53 and decreased MnSOD expression via p53-mediated suppression of Sp1 binding to the MnSOD promoter in normal appearing skin and benign papillomas. In squamous cell carcinomas, Sp1 binding increased due to loss of functional p53. Dr. St.
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