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Sp3 repression of polymorphic human NRH:quinone oxidoreductase 2 gene promoter.

Abstract
Human NRH:quinone oxidoreductase 2 (NQO2) gene-containing 29-bp deletion/insertion polymorphic promoters were found to be associated with susceptibility to Parkinson's disease. Here, we demonstrate that the NQO2 gene is differentially expressed by the polymorphic promoters in human fibroblasts and Hep-G2 cells transfected with NQO2 gene reporter constructs. Promoter containing the 29-bp insertion polymorphism demonstrated significantly lower NQO2 gene expression. Deletion mutagenesis and DNase I footprinting analysis of the promoter without the 29-bp insertion identified three protected regions (region A, B, and C). Band- and supershift and transfection assays showed binding of transcription factor Sp1 to regions A and B, which regulated expression of the NQO2 gene. Similar studies of the NQO2 gene promoter with the 29-bp insertion polymorphism showed that regions A and C were identical and contributed similarly as in the promoter without the 29-bp insertion to NQO2 gene expression. However, region B was found to be inserted with 29-bp DNA element and bound to both Sp1 and Sp3. Binding of Sp3 led to repression of NQO2 gene transcription by the promoter containing the 29-bp insertion polymorphism. These studies also suggest that alterations in NQO2 activity might be an important factor in susceptibility to Parkinson's disease.
AuthorsWei Wang, Anil K Jaiswal
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 37 Issue 8 Pg. 1231-43 (Oct 15 2004) ISSN: 0891-5849 [Print] United States
PMID15451063 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • DNA-Binding Proteins
  • Recombinant Fusion Proteins
  • SP3 protein, human
  • Transcription Factors
  • Sp3 Transcription Factor
  • Luciferases
  • NRH - quinone oxidoreductase2
  • Quinone Reductases
Topics
  • Alleles
  • Base Sequence
  • Binding Sites
  • Blotting, Western
  • Cell Line, Tumor (enzymology)
  • Cells, Cultured (enzymology)
  • DNA Footprinting
  • DNA-Binding Proteins (metabolism)
  • Female
  • Fibroblasts (enzymology)
  • Gene Expression Regulation, Enzymologic (genetics)
  • Genes, Reporter
  • Genetic Predisposition to Disease
  • HeLa Cells (enzymology)
  • Hepatoblastoma (pathology)
  • Hepatocytes (enzymology)
  • Humans
  • Liver Neoplasms (pathology)
  • Luciferases (biosynthesis, genetics)
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Parkinson Disease (enzymology, genetics)
  • Polymorphism, Genetic
  • Promoter Regions, Genetic (genetics)
  • Quinone Reductases (genetics)
  • Recombinant Fusion Proteins (biosynthesis, genetics)
  • Sequence Deletion
  • Sp3 Transcription Factor
  • Transcription Factors (metabolism)
  • Transcription, Genetic (genetics)
  • Transfection

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