Disease relevance of Nfe2l2

• In summary, we show for the first time that mice lacking Nrf2 are more susceptible to DSS-induced colitis [1].
• Treatment of mouse hepatoma (Hepa) cells with 50 microm CdCl(2) increased the amount of Nrf2 protein in a time-dependent manner; induction was observed within 30 min, prior to the accumulation of HO-1 mRNA [2].
• We previously reported that Nrf2-deficient female mice develop lupus-like autoimmune nephritis (Kidney Int 60:1343-1353, 2001) [3].
• METHODS: To investigate the mechanism whereby Nrf2 contributes to the susceptibility to autoimmune diseases, we generated nrf2-/-lpr/lpr mice [3].
• Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates [4].

Psychiatry related information on Nfe2l2

• These data also introduce Nrf2-mediated ARE transcription as a potential target of preventative therapy in neurodegenerative disorders such as Huntington's disease [5].

High impact information on Nfe2l2

• 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 [6].
• We postulate that Keap1 and Nrf2 constitute a crucial cellular sensor for oxidative stress, and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel Nrf2 nuclear shuttling mechanism [7].
• Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain [7].
• Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction [8].
• We found a somatic mutation and a gene variation in human lung cancer cells that change glycine to cysteine in the DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2 [8].

Chemical compound and disease context of Nfe2l2

• Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis [1].
• Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive CS-induced emphysema than was found in wild-type littermates [9].
• With doses of butylated hydroxytoluene that are tolerated by wild-type mice, the Nrf2(-/-) mice succumb from acute respiratory distress syndrome [10].
• Here we show that Nrf2 protects against the ovarian toxicity of 4-vinylcyclohexene diepoxide (VCD) in mice [11].
• Moreover, in contrast to AA, l-buthionine-(S,R)-sulfoximine toxicity is not prevented by plasmid Nrf2 probably because protective GSH cannot be synthesized [12].

Biological context of Nfe2l2

• Regulatory motifs for CREB-binding protein and Nfe2l2 transcription factors in the upstream enhancer of the mitochondrial uncoupling protein 1 gene [13].
• NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development [14].
• Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound [15].
• In addition, no evidence was found for reciprocal upregulation of NF-E2 or Nrf-2 protein in fetal liver cells deficient for either factor [16].
• Interestingly, the expression of various key players involved in wound healing was significantly reduced in early wounds of the Nrf2 knockout animals, and the late phase of repair was characterized by prolonged inflammation [15].

Anatomical context of Nfe2l2

• Using chromatin immunoprecipitation assays in NIH 3T3 cells, we show that heme, an inducer of ho-1, promotes displacement of Bach1 from the MafK-occupied ho-1 enhancers, which is followed by Nrf2 binding to these elements [17].
• Fetal liver cells deficient for both NF-E2 and Nrf-2 expressed normal levels of alpha- and beta-globin [16].
• In a search for KGF-regulated genes in keratinocytes, we identified the gene encoding the transcription factor NF-E2-related factor 2 (Nrf2) [15].
• In L929 fibroblasts, significant activation of an HO-1 enhancer-reporter fusion gene was observed only with the CNC-bZIP class of proteins with Nrf2 exhibiting the highest level of trans-activation, between 25- and 30-fold [18].
• The murine Nrf 2 gene is expressed not only in erythroid cells, but also in the 3T3 murine fibroblast cell line [19].

Associations of Nfe2l2 with chemical compounds

• The transcription factor NF-E2-related factor 2 (Nrf2) plays an essential role in the mammalian response to chemical and oxidative stress through induction of hepatic phase II detoxification enzymes and regulation of glutathione (GSH) [20].
• Furthermore, Nrf2 was shown to be functionally active, as assessed by the induction of epoxide hydrolase, heme oxygenase-1, and glutamate cysteine ligase gene expression [20].
• Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice [20].
• For each compound, greater than 60% depletion of GSH was achieved; however, in the case of BSO, this depletion did not cause nuclear translocation of Nrf2 [20].
• Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene [21].

Physical interactions of Nfe2l2

• Inducers disrupt the Keap1-Nrf2 complex by modifying two (C273 and C288) of the 25 cysteine residues of Keap1 [22].
• In this study we sought to determine the identity of the specific constituent that collaboratively interacts with Nrf2 to bind to the Maf recognition element in vivo [23].
• Alternatively, Nrf2 bound to antioxidant-responsive element-like-2 sequence of osteocalcin promoter [24].

Regulatory relationships of Nfe2l2

• Taken together, our results reveal novel roles of the KGF-regulated transcription factors Nrf2 and possibly Nrf3 in the control of gene expression and inflammation during cutaneous wound repair [15].
• These results suggest that PI3K/Akt signaling regulates Nrf2 activation by hyperoxia [25].
• We demonstrate that Cul3-Keap1 complexes regulate Nrf2 polyubiquitination both in vitro and in vivo [26].
• Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation [24].
• Furthermore, Foxo3a is degraded through the 26S proteasome pathway in untreated cells and is induced by VCD via both Nrf2-dependent transcription and protein stabilization [11].

Other interactions of Nfe2l2

• In conclusion, GSH depletion alone is insufficient for Nrf2 activation: a more direct interaction is required, possibly involving chemical modification of Nrf2 or Keap1, which is facilitated by the prior loss of GSH [20].
• Nrf2 does not homodimerize, but CNC-bZIP.small Maf protein heterodimers and Nrf2 [18].
• cDNA cloning of murine Nrf 2 gene, coding for a p45 NF-E2 related transcription factor [19].
• Activation of the mouse heme oxygenase-1 gene by 15-deoxy-Delta(12,14)-prostaglandin J(2) is mediated by the stress response elements and transcription factor Nrf2 [27].
• The inhibition of Akt activity using a pharmacological inhibitor markedly attenuated Nrf2 translocation and ARE-driven expression [25].
• An oligonucleotide microarray demonstrated the transactivation of Nrf2 target genes by Galpha12 gene knockout [28].

Analytical, diagnostic and therapeutic context of Nfe2l2

• Purified PMF-1 did not bind any of the PCR fragments alone, but when added with Nrf-2, decreased the magnitude of the gel shift for one of the fragments (PRE located at -2060 relative to the transcription start site) [29].
• Nrf2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis following 1 week of oral administration of 1% DSS [1].
• 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 [30].
• Using immunohistochemistry, we localized the transcription factors Nrf2, which regulates expression of antioxidant and detoxification protein, and c-Fos, a marker of neuronal activation [31].
• By electrophoretic mobility shift assay, recombinant Nrf2 binds the ARE of the GCS(L) and GCS(H) promoters [32].

References