Disease relevance of Nrf1

• Hypoxia led to a decline of Nrf1 and 16S rRNA levels also through a mechanism blocked with PK11195 [1].
• We report here that mice with somatic inactivation of nrf1 in the liver developed hepatic cancer [2].

High impact information on Nrf1

• The consensus binding sequence (T/C)GCGCA(C/T)GCGC(A/G) of NRF-1 includes a noncanonical CA(C/T)GCG Myc:MAX binding site [3].
• In this study, we establish a link between the induction of NRF-1 target genes and sensitization to apoptosis on serum depletion [3].
• Cytochrome c and other nuclear-encoded mitochondrial genes are regulated by the transcription factor nuclear respiratory factor-1 (NRF-1) [3].
• The cDNA-encoded protein was indistinguishable from the authentic HeLa cell factor on denaturing gels, displayed the expected NRF-1 DNA-binding specificity, and made the same guanine nucleotide contacts as HeLa NRF-1 on binding known NRF-1 recognition sites [4].
• In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes [2].

Biological context of Nrf1

• The CCAAT enhancer-binding protein (C/EBP)beta and Nrf1 interact to regulate dentin sialophosphoprotein (DSPP) gene expression during odontoblast differentiation [5].
• Further, this interaction was found to be dependent on phosphorylation at Ser(599) of Nrf1 [5].
• Loss of Nrf1 function resulted in liver cell apoptosis in late-gestation chimeric fetuses [6].
• Our results also suggest that Nrf1 may promote cell survival by maintaining redox balance and protecting embryonic hepatocytes from TNF-mediated apoptosis during development [6].
• By RT-PCR and Northern analysis, Nrf1 was expressed in all tissues examined, and Northern analysis on adult tissues revealed a complex banding pattern suggesting extensive alternative splicing [7].

Anatomical context of Nrf1

• In fully differentiated odontoblasts, the loss of interaction between Nrf1 and C/EBPbeta results in an increased DSPP transcription [5].
• The expression of Ppargc1a and Nrf1 was also stimulated by n-3 polyunsaturated fatty acids in 3T3-L1 cells [8].
• We show by chimera analysis that Nrf1 is essential for the hepatocyte lineage [6].
• Mouse embryonic stem cells lacking Nrf1 developed normally and contributed to most tissues in adult chimeras where Nrf1 is normally expressed [6].
• Nrf1 is targeted to the endoplasmic reticulum membrane by an N-terminal transmembrane domain. Inhibition of nuclear translocation and transacting function [9].

Associations of Nrf1 with chemical compounds

• In addition, cells deficient in Nrf1 were sensitized to the cytotoxic effects of tumor necrosis factor (TNF) [6].
• Our results indicate that Nrf1 plays a role in the regulation of genes involved in glutathione synthesis and suggest a basis for a correspondingly low GSH concentration and reduced stress response [10].
• Treatment with tunicamycin, an endoplasmic reticulum stress inducer, caused an accumulation of a smaller form of Nrf1 that correlated with detection of Nrf1 in the nucleus by biochemical fractionation and immunofluorescent analysis [9].
• A novel splice variant of Nrf1 with a 411 bp deletion of the serine-rich region, resulting in an overall structure reminiscent of the BTB and CNC homology (Bach) proteins, was isolated from the corresponding DC18 cells [11].
• Interestingly, a fraction of the blastocysts from heterozygous matings had reduced staining intensity with rhodamine 123 and NRF-1(-/-) blastocysts had markedly reduced levels of mitochondrial DNA (mtDNA) [12].

Regulatory relationships of Nrf1

• In undifferentiated odontoblasts, Nrf1 and C/EBPbeta repress DSPP promoter activity individually and synergistically by cooperatively interacting with each other [5].

Other interactions of Nrf1

• Changes in the expression of nuclear respiratory factor-2/GA-binding protein a and peroxisome proliferator-activated-receptor gamma coactivator-1 (increase) were opposite to those of nuclear respiratory factor-1 and Sp1 (decrease) during the developmental and differentiation-dependent induction of mitochondrial biogenesis in brown fat [13].

Analytical, diagnostic and therapeutic context of Nrf1

• The sequences of the cDNAs that were cloned from the screen were identical to NRF-1, a result that was confirmed by further electrophoretic mobility shift assay experiments [14].
• COX17 basal promoter activity was abrogated by site-directed mutagenesis of Sp1, NRF-1 and NRF-2 binding sites [15].

References