Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ada gene of Escherichia coli encodes a 39-kDa protein which serves both as a transcriptional activator of the adaptive response to alkylating agents and as a DNA repair enzyme demethylating O6-methyl-guanine and phosphotriester residues. Here, the isolated Ada protein was found to be readily cleaved into two fragments of similar size by treatment with trypsin, chymotrypsin, subtilisin, or V8 protease. The fragments retained their respective methyltransferase activities. The Ada protein is, therefore, comprised of two stable active domains united by a central hinge region of about 10 amino acids. Post-translational modification of the Ada protein by methylation of a specific cysteine residue in the NH2-terminal domain is known to convert it to an efficient transcriptional activator. This residue has now been identified as Cys-69.
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PMID:Functional domains and methyl acceptor sites of the Escherichia coli ada protein. 316 36

It was demonstrated previously that a deoxyribophosphodiesterase (dRpase) activity is associated with the DNA repair enzyme exonuclease I, and that this activity is stimulated by the addition of the E. coli single-stranded DNA-binding protein (Ssb). This activity catalyzes the release of deoxyribose-phosphate groups at apurinic/apyrimidinic (AP) sites in the DNA that have been cleared by the action of an AP endonuclease. We have now used the yeast two-hybrid system to demonstrate that a protein-protein interaction occurs between exonuclease I and Ssb. When the E. coli ssb gene was fused in frame to the DNA-activating domain of the GAL4 transcriptional activator and the exonuclease I gene was fused in frame to the DNA-binding domain, a functional GAL4 transcriptional activator was produced as determined by growth of yeast on selective medium and the measurement of beta-galactosidase activity. We have also demonstrated that Ssb can stimulate the dRpase activity of exonuclease I using double-stranded bacteriophage M13 DNA containing several strand interruptions at incised AP sites. These results suggest that Ssb may be required for efficient base-excision repair in bacteria.
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PMID:Protein-protein interactions between the Escherichia coli single-stranded DNA-binding protein and exonuclease I. 861 28

That mammalian DNA polymerase-beta (beta-pol) gene transcription is upregulated by activated ras and also by phorbol ester (TPA) treatment suggests the involvement of protein kinase C in the gene expression control for this DNA repair enzyme. Yet, the core promoters of the human, bovine and rodent beta-pol genes do not have a TPA response element or other binding site for the transcriptional activator AP-1. Instead, these beta-pol promoters appear to be regulated mainly by proteins binding to the cAMP response element (CRE) centered within 50 bp 5' of the transcriptional start site. In this study, the CRE in the human beta-pol promoter was found to mediate TPA upregulation of the cloned promoter in HeLa cell transient expression experiments. To further examine the role of this CRE in TPA stimulation, we used several mutated promoters that were either deficient in protein binding to the CRE or contained extra CRE sites arranged as tandem repeats. All constructs with at least one functional CRE were upregulated by TPA, whereas mutants lacking CRE protein-binding function were not TPA upregulated. Analyses of HeLa nuclear extract DNA-binding proteins indicated that the beta-pol CRE was bound by CRE-binding protein (CREB) family members CREB-1 and activating transcription factor-1, but not by AP-1 or complexes containg AP-1 subunits. These results suggest that CREB, rather than AP-1 proteins, are required for the CRE-mediated TPA activation of the beta-pol promoter.
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PMID:Human DNA Polymerase-beta Promoter: Phorbol Ester Activation Is Mediated through the cAMP Response Element and cAMP-Response-Element-Binding Protein. 1238 74

Acquisition of temozolomide (TMZ) resistance is a major factor leading to the failure of glioblastoma (GBM) treatment. The exact mechanism by which GBM evades TMZ toxicity is not always related to the expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), and so remains unclear. In this study, TMZ-resistant variants derived from MGMT-negative GBM clinical samples and cell lines were studied, revealing there to be increased specificity protein 1 (Sp1) expression associated with reduced reactive oxygen species (ROS) accumulation following TMZ treatment. Analysis of gene expression databases along with cell studies identified the ROS scavenger superoxide dismutase 2 (SOD2) as being disease-related. SOD2 expression was also increased, and it was found to be co-expressed with Sp1 in TMZ-resistant cells. Investigation of the SOD2 promoter revealed Sp1 as a critical transcriptional activator that enhances SOD2 gene expression. Co-treatment with an Sp1 inhibitor restored the inhibitory effects of TMZ, and decreased SOD2 levels in TMZ-resistant cells. This treatment strategy restored susceptibility to TMZ in xenograft animals, leading to prolonged survival in an orthotopic model. Thus, our results suggest that Sp1 modulates ROS scavengers as a novel mechanism to increase cancer malignancy and resistance to chemotherapy. Inhibition of this pathway may represent a potential therapeutic target for restoring treatment susceptibility in GBM.
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PMID:Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase. 2882 35