| First Author | Zelko IN | Year | 2004 |
| Journal | Free Radic Biol Med | Volume | 37 |
| Issue | 8 | Pages | 1256-71 |
| PubMed ID | 15451065 | Mgi Jnum | J:92943 |
| Mgi Id | MGI:3055240 | Doi | 10.1016/j.freeradbiomed.2004.06.022 |
| Citation | Zelko IN, et al. (2004) Sp1 and Sp3 transcription factors mediate trichostatin a-induced and basal expression of extracellular superoxide dismutase. Free Radic Biol Med 37(8):1256-71 |
| abstractText | 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. |
