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Zelko, I.N. et al.

Sp1 and Sp3 transcription factors mediate trichostatin A- induced and basal expression of extracellular superoxide dismutase.

Extracellular superoxide dismutase (EC-SOD) is the major extracellular antioxidant enzyme and may play a critical role in the pathogenesis of a variety of pulmonary, neurological, and cardiovascular diseases. We report here that exposure to the deacetylase inhibitor trichostatin A (TSA) induces EC-SOD mRNA levels in mIMCD3 and Hepa 1-6 cells, but reduces EC-SOD mRNA levels in MLg cells. To determine the molecular mechanism of TSA-mediated EC-SOD gene regulation, we analyzed EC-SOD's proximal promoter region, which revealed two previously unknown but putative Sp1 cis elements. Transfection of systematically truncated 5'-flanking sequences revealed that the second Sp1 binding site contributes up to 70% of the constitutive EC-SOD promoter activity. Binding of Sp1 and Sp3 transcription factors to this region was confirmed by DNase I footprinting, electrophoretic mobility shift assay, super-shift assay, and chromatin immunoprecipitation. A dominant-negative Sp1 construct considerably reduced EC-SOD promoter activity in mammalian cells, whereas coexpression of Sp1 and Sp3 greatly enhanced reporter activity in SL2 cells. An EC-SOD promoter-reporter construct showed from 5- to 14-fold induction after exposure to TSA, whereas deletion of the Sp1 binding site significantly reduced reporter activation. These results are consistent with Sp1/Sp3 transcription factors providing essential TSA-dependent and basal transcription of the EC-SOD gene and may represent a novel pharmacological pathway for regulating EC-SOD levels in tissue.[1]

References

Sp1 and Sp3 transcription factors mediate trichostatin A-induced and basal expression of extracellular superoxide dismutase. Zelko, I.N., Folz, R.J. Free Radic. Biol. Med. (2004) [Pubmed]

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