Disease relevance of GABPA

• Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology [1].
• Taken together, this study suggests that identified antioxidant genes, which were upregulated through tBHQ induced Nrf2 stabilization, confer protection on target cells against H2O2-induced apoptotic cell death in neuroblastoma cells as well as the necrotic cell death in the hNSC [2].
• In addition, a single polypeptide of 55 kDa was detected following cross-linking of a partially purified NRF-2 fraction to RCO4, the human ATP synthase beta subunit, or Moloney murine sarcoma virus binding sites [3].
• When RBF-1 site was used for sequence specific DNA affinity purification from erythroleukemia cells, reconstitution assays, immunoblotting analysis and peptide mapping show that the two major co-purified proteins are identical to human E4TF1-60 and -53 proteins [4].
• Although Nrf2 regulated these forms of neuronal toxicity, it was unclear which injury-triggered signal(s) led to Nrf2 activation in vivo [5].

Psychiatry related information on GABPA

• One of the most important cellular defense mechanisms against oxidative stress or electrophiles is mediated by the transcription factor Nrf2 [6].

High impact information on GABPA

• However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival [7].
• The transcription factor Nrf2 has been implicated as the central protein that interacts with the ARE to activate gene transcription constitutively or in response to an oxidative stress signal [8].
• This review focuses on the molecular mechanisms whereby the transcriptional activation mediated by the interaction between the ARE and NF-E2-related factor 2 (Nrf2) is regulated [8].
• The Nrf2 peptide contains two short antiparallel beta-strands connected by two overlapping type I beta-turns stabilized by the aspartate and threonine residues [9].
• Heterodimers of E4TF1-47 and E4TF1-60 weakly stimulated transcription in vitro [10].

Chemical compound and disease context of GABPA

• Nrf2 knockout mice were more sensitive to kainate toxicity, as evidenced by elevated seizure severity, seizure duration, hippocampal neuron damage and mortality [11].

Biological context of GABPA

• Mapping of the human transcription factor GABPA (E4TF1-60) gene to chromosome 21 [12].
• One trapped sequence showed complete homology with nucleotide sequence D13318 of GenBank, which corresponds to the gene for human transcription factor E4TF1-60 (HGMW-approved nomenclature GABPA) [12].
• The predicted amino acid sequence of each cDNA clone revealed that E4TF1-60 had an ETS domain, which is a DNA binding domain common to ets-related transcription factors [13].
• A significant reduction of both steady-state and hypoxia/reoxygenation-mediated prx1 gene expression was shown in Nrf2 knock-out cells [1].
• The results suggest that Nrf2-Keap1-dependent UGT1A1 induction by prooxidants might represent a key adaptive response to cellular oxidative stress that defends against a variety of environmental insults, including electrophile attacks and chemical carcinogenesis [14].

Anatomical context of GABPA

• This change in cellular localization of Nrf2 may be linked to resveratrol-elicited disruption of the Nrf2-Keapl complex in the cytosol, followed by the translocation of Nrf2 to the nucleus where it locates the ARE-containing 5'-promoter region of NQO1 leading to its transcriptional activation [15].
• We report the presence of two nuclear respiratory factor 2 (NRF-2) binding motifs in the 5'-flanking region of the human Tomm70 gene and establish their essential role for promoter activity by using reporter assays in HeLa cells [16].
• Induction of quinone reductase NQO1 by resveratrol in human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear translocation of transcription factor Nrf2 [15].
• Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells [2].
• However, in contrast to Ets-1, which appears to be exclusive to lymphoid tissues, NRF-2 has the broad tissue distribution expected of a regulator of respiratory chain expression [3].

Associations of GABPA with chemical compounds

• Gene mapping experiments including transfections of UGT1A1 reporter gene constructs into HepG2 cells coupled with functional analysis of Nrf2 expression and binding to anti-oxidant-response elements (ARE) resulted in identification of an ARE in the phenobarbital-response enhancer module region of the UGT1A1 gene [14].
• Nrf2 stabilization by tBHQ also was observed in hNSCs [2].
• Moreover, the 2- to 5-fold induction of these enzymes in wild-type mice by the chemoprotective agent oltipraz, which is currently in clinical trials, was almost completely abrogated in the nrf2-deficient mice [17].
• NRF-2 binding and transcriptional activation required a purine-rich core sequence, GGAA [3].
• These experiments provide a biochemical basis for the hypothesis that formation of J-ring compounds generated from oxidation of EPA and DHA in vivo can reach concentrations high enough to induce Nrf2-based cellular defense systems [18].

Other interactions of GABPA

• The present study is aimed to determine whether increased protein stability is a mechanism by which quinone compounds, like tert-butylhydroquinone (tBHQ), may enhance Nrf2-mediated transcriptional activation and subsequent antioxidant protection [2].
• Recent studies indicate that NF-E2 related factor 2 (Nrf2) is a substrate for the ubiquitin-proteasome pathway [2].
• Furthermore, coexpression of E4TF1-60 and E4TF1-53 markedly increased aurora A promoter activity [19].
• Antioxidants may disrupt the Keap-Nrf2 complex, allowing Nrf2 to translocate to the nucleus and mediate expression of Phase II genes via interaction with the ARE [20].
• The introns of APP and E4TF1-60 are 49- and 24-fold smaller in Fugu than in human, and the intergenic distance is compressed at least 100-fold [21].

Analytical, diagnostic and therapeutic context of GABPA

• Microarray analysis showed that those identified antioxidant genes, responsible for antiapoptotic action in IMR-32 cells (J. Li et al., 2002, J. Biol. Chem. 277, 388-394), were also coordinately upregulated through Nrf2-dependent antioxidant responsive element (ARE) activation in hNSC [2].
• The stabilization of Nrf2 by tBHQ in IMR-32 cells was evidenced by a pulse-chase assay showing no significant increase in Nrf2 protein synthesis after tBHQ treatment, and by ubiquitin immunoprecipitation showing that tBHQ stabilized ubiquitinated Nrf2 [2].
• Indirect immunofluorescence using intact cells demonstrated that indomethacin induced the nuclear translocation of Nrf2, a transcription factor believed to regulate GCLC expression [22].
• The binding of Nrf2 to the GPX2 antioxidant response element was confirmed by chromatin immunoprecipation, electrophoretic mobility shift assays, and site-directed mutagenesis [23].
• In this report, using immunocytochemistry, cell fractionation, and chromatin immunoprecipitation analyses, we found that Nrf2 is primarily a nuclear protein and that it is expressed and recruited to the chromatin constitutively to drive basal gene expression [24].

References