Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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 necessary for the survival of aerobic life. Previously, we demonstrated that specificity protein 1 (Sp1) is essential for the basal transcription of the MnSOD gene. We also identified nucleophosmin (NPM), an RNA-binding protein, as an important co-activator of NF-kappaB in the induction of MnSOD by cytokine and tumor promoter. Here, using chromatin immunoprecipitation (ChIP) analysis, we demonstrate that Sp1 and NPM interact in vivo to enhance NF-kappaB-mediated MnSOD induction. Interaction between NPM and Sp1 or NF-kappaB at the promoter and enhancer of the MnSOD gene in vivo were verified by the presence of the PCR products from the promoter and enhancer elements in the ChIP assay. Unexpectedly, we also found p53, another transcription factor, to be a component of the complex detected by ChIP assay. The presence of p53 in this transcription complex was verified by immunoprecipitation of p53 proteins with antibody to Sp1 in nuclear extracts. Using a vector expressing full-length p53 cDNA, we demonstrated that p53 overexpression suppresses MnSOD mRNA and protein levels. Consistent with the negative role of p53 in the expression of the MnSOD gene, expression of small interfering RNA for p53 leads to an increase of MnSOD mRNA and protein levels. Using ChIP assays and immunoprecipitation, we further demonstrated that p53 interacts with Sp1 to suppress both the constitutive and 12-O-tetradecanoylphorbol-13-acetate-stimulated expression of the MnSOD gene. Inhibition of the MnSOD gene by p53 was abolished when Sp1 sites on the MnSOD promoter were mutated or when the Sp1 protein was reduced by siRNA approaches. Because expression of MnSOD protects against cell death, our findings reveal a previously unrecognized mechanism of p53-mediated cell death and demonstrate an intricate relationship between the positive and negative control of MnSOD expression.
 ...
PMID:Specificity protein 1-dependent p53-mediated suppression of human manganese superoxide dismutase gene expression. 1674 Jun 34

Manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant enzyme, is necessary for survival of aerobic life. Previously, we demonstrated that a Sp1-based promoter is essential for constitutive transcription and a NF-kappaB-based intronic enhancer is responsible for cytokine-mediated induction. Here we show that nucleophosmin (NPM), a RNA-binding protein, binds to an 11G single-stranded loop in the promoter region and serves to integrate the Sp1 and NF-kappaB responses. Disruption of the loop structure causes a reduction of both constitutive and inductive transcription due to loss of the binding motif for NPM. Interaction of NF-kappaB.NPM.Sp1 facilitated by binding of NPM to the loop structure in the promoter region appears to comprise the basic complex for the transcriptional stimulation. These results suggest a novel molecular mechanism for communication between the enhancer and the GC-rich promoter.
 ...
PMID:The role of a single-stranded nucleotide loop in transcriptional regulation of the human sod2 gene. 1742 24

A primary antioxidant enzyme in mitochondria, manganese superoxide dismutase (MnSOD), plays a critical role in the survival of aerobic life. It is well documented that, compared with normal cell counterparts, MnSOD level is decreased in neoplastic transformed cells but is increased in aggressive cancers. However, the underlying mechanism for the observed dysregulation of MnSOD in cancer is unknown. We have identified previously a unique set of mutations located in the promoter region of the SOD2 gene in several types of cancer cells. We found that a C-to-T transition at -102 and an insertion of A at -93 down-regulate MnSOD transcription by interrupting the formation of a single-stranded loop that is essential for a high level of promoter activity. Here, we show that the additional downstream mutation, C-to-G transversion at -38, creates a binding site for the transcription factors specificity protein 1 (Sp1) and activating protein 2 (AP-2). The promoter function is regulated by the relative levels of Sp1 and AP-2. In cytokine-induced expression of the SOD2 gene, Sp1 cooperates with a transcriptional complex containing nuclear factor-kappaB and nucleophosmin. The presence of AP-2 attenuates this induction. Our results suggest that the high level of MnSOD observed in aggressive cancer cells may be due, in part, to the absence of AP-2 transcriptional repression.
 ...
PMID:Mutations in the SOD2 promoter reveal a molecular basis for an activating protein 2-dependent dysregulation of manganese superoxide dismutase expression in cancer cells. 1907 33