Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Manganese superoxide dismutase (MnSOD) is a primary antioxidant enzyme critical for maintaining normal cell function and for survival. Previously, we cloned the entire MnSOD gene, including a 0.782-kb 5' DNA sequence, from a human embryonic lung fibroblast cell line. Sequence analysis indicates that the promoter of the human MnSOD gene is TATA-less and CAAT-less, and the DNA sequence immediately upstream from the transcription start site is GC rich. To study the function and regulation of the human MnSOD promoter, we cloned a 257-bp sequence (P7) containing the transcription start site and the 5' GC-rich region. Consensus analysis and DNase I footprinting assay indicated that P7 contains multiple Sp1- and AP-2-binding sites. Deletions of the P7 sequence diminished the promoter activity and decreased the response to Sp1 protein. The first three Sp1 consensus sites were required for high promoter activity in mammalian cells and enhanced promoter activity in Drosophila Schneider Line 2 (SL2) cells. In the SL2 cells, Sp1 activated the P7 activity in a dose-dependent manner. In contrast, cotransfections with AP-2 expression vector marginally increased P7 activities in human hepatocarcinoma HepG2 cells. The results suggest that Sp1 is an important regulator for the transcriptional activities of P7, whereas AP-2 is a minor activator for P7 and competes with Sp1 for binding sites which may downregulate P7 function.
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PMID:Transcriptional regulation of the 5' proximal promoter of the human manganese superoxide dismutase gene. 983 1

Manganese superoxide dismutase (Mn-SOD) is a primary antioxidant enzyme whose expression is essential for life in oxygen. Mn-SOD has tumor suppressor activity in a wide variety of tumors and transformed cell systems. Our initial observations revealed that Mn-SOD expression was inversely correlated with expression of AP-2 transcription factors in normal human fibroblasts and their SV-40 transformed counterparts. Thus we hypothesized that AP-2 may down-regulate Mn-SOD expression. To examine the functional role of AP-2 on Mn-SOD promoter transactivation we cotransfected AP-2-deficient HepG2 cells with a human Mn-SOD promoter-reporter construct and expression vectors encoding each of the three known AP-2 family members. Our results indicated that AP-2 could significantly repress Mn-SOD promoter activity, and that this repression was both Mn-SOD promoter and AP-2-specific. The three AP-2 proteins appeared to play distinct roles in Mn-SOD gene regulation. Moreover, although all three AP-2 proteins could repress the Mn-SOD promoter, AP-2alpha and AP-2gamma were more active in this regard than AP-2beta. Transcriptional repression by AP-2 was not a general effect in this system, because another AP-2-responsive gene, c-erbB-3, was transactivated by AP-2. Repression of Mn-SOD by AP-2 was dependent on DNA binding, and expression of AP-2B, a dominant negative incapable of DNA binding, relieved the repression on Mn-SOD promoter and reactivated Mn-SOD expression in the AP-2 abundant SV40-transformed fibroblast cell line MRC-5VA. These results indicate that AP-2-mediated transcriptional repression contributes to the constitutively low expression of Mn-SOD in SV40-transformed fibroblasts and suggest a mechanism for Mn-SOD down-regulation in cancer.
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PMID:A family of AP-2 proteins down-regulate manganese superoxide dismutase expression. 1127 50