Disease relevance of NRF1

• Nuclear respiratory factor 1 plays an essential role in transcriptional initiation from the hepatitis B virus x gene promoter [1].
• We found that stable or transient expression of full-length alpha-Pal/NRF-1 in human neuroblastoma IMR-32 cells significantly induced neurite outgrowth and increased the length of neurites both in medium containing 10% fetal bovine serum and in serum-free medium [2].
• Association between polymorphisms in the nuclear respiratory factor 1 gene and type 2 diabetes mellitus in the Korean population [3].
• Many of the genes dysregulated in both diabetes and 'prediabetes' are regulated by the transcription factor nuclear respiratory factor-1 and the peroxisome proliferator-activated receptor gamma co-activator 1 [4].

High impact information on NRF1

• Nuclear respiratory factor 1 (NRF-1), which induces nuclear-encoded mitochondrial genes, was repressed in expression and activity by cyclin D1 [5].
• Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function [5].
• We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function [6].
• In growing HL-60 cells, footprints at sequences homologous to binding sites for known transcription factors (members of the basic-helix-loop-helix family, nuclear respiratory factor 1, transcription factor Sp1, and upstream binding factor) were detected in the region corresponding to the promoter of the downstream gene [7].
• Both coactivators interact with nuclear respiratory factor 1 (NRF-1) and activate NRF-1 target genes required for respiratory chain expression [8].

Biological context of NRF1

• These factors include general transcription factors such as Sp1 or YY1, as well as transcription factors specific for mitochondrial genes like the nuclear respiratory factors NRF1 and 2 [9].
• These results revealed that alpha-Pal/NRF-1 is an essential transcription factor in the regulation of human IAP gene expression [10].
• The pre-mRNA of nuclear respiratory factor 1, a regulator of mitochondrial biogenesis, is alternatively spliced in human tissues and cell lines [11].
• The shorter transcript will result in an isoform of the protein that lacks the carboxy-terminal part of the DNA binding domain, which might influence transcriptional activation by normal nrf-1 [11].
• Serine phosphorylation within a concise amino-terminal domain in nuclear respiratory factor 1 enhances DNA binding [12].

Anatomical context of NRF1

• Furthermore, overexpression of full-length alpha-Pal/NRF-1 significantly enhanced IAP promoter activity while overexpression of dominant-negative mutant reduced promoter activity both in the cultured human cell lines and primary mouse cortical cells [10].
• We have reported that overexpression of nuclear respiratory factor-1 (NRF-1) and high concentration (50 mM) of glucose increased the promoter activity of the rat Tfam in L6 rat skeletal muscle cells [13].
• Respiratory uncoupling induces delta-aminolevulinate synthase expression through a nuclear respiratory factor-1-dependent mechanism in HeLa cells [14].
• A novel function of transcription factor alpha-Pal/NRF-1: increasing neurite outgrowth [2].
• Among these is the recognition sequence for a nuclear factor designated NRF-1 (nuclear respiratory factor 1) also found in the upstream regions of several other nuclear genes whose products function in the mitochondria [15].

Associations of NRF1 with chemical compounds

• It was concluded that high glucose-induced Tfam transcription in L6 cells might be mediated by NRF-1 [13].
• Role of NRF-1 in bidirectional transcription of the human GPAT-AIRC purine biosynthesis locus [16].
• In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factor-1 and mitochondrial DNA transcription factor A (mtTFA) and stimulated the mitochondrial proliferation [17].
• Thus 17beta-estradiol seemed to exert a dual effect, activating the PI3K-Akt pathway by inhibiting pten mRNA expression and also inhibiting nrf1 and tfam mRNA expression [18].
• However, only genistein led to increases in the cytosolic accumulation and nuclear translocation of Nrf1 and the increased expression of and activity of glutathione peroxidase [19].

Physical interactions of NRF1

• Site-directed mutagenesis and gel electrophoretic mobility shift assay identified a alpha-Pal/NRF-1 binding element within the IAP core promoter [10].

Regulatory relationships of NRF1

• Overexpression of the DNA binding domain of alpha-Pal/NRF-1 in cells enhanced DNA-alpha-Pal/NRF-1 binding in vitro [10].
• In vitro methylation of nuclear respiratory factor-1 binding site suppresses the promoter activity of mitochondrial transcription factor A [20].

Other interactions of NRF1

• Effect of four genes (ALDH1, NRF1, JAM and KBL) on proliferation arrest in a non-small cell bronchopulmonary cancer line [21].
• Increased expression of mitochondrial transcription factor A and nuclear respiratory factor-1 in skeletal muscle from aged human subjects [22].
• Expression of mitochondrial proteins from the nuclear and mitochondrial genomes is coordinated and involves the nuclear-encoded transcription factors NRF-1 and TFAM [23].
• Electrophoretic mobility shift assays demonstrate that the conserved NRF-1 site in primate COX5B promoters is specifically recognized by a factor present in HeLa nuclear extracts [24].
• The mRNA level of the peroxisome proliferator-activated receptor-gamma coactivator-1alpha and its downstream factors, including nuclear respiratory factor 1 and 2, mitochondrial transcription factor A, COXNUCSUB IV, and COXMITSUB I, were significantly reduced in hearts both 12 and 18 wk after ligation compared with sham-operated hearts [25].

Analytical, diagnostic and therapeutic context of NRF1

• We studied transcriptional regulation of the FMR1 gene using protein footprint analysis of the active and inactive gene in vivo . We identified four footprints within the FMR1 promoter region which correspond to consensus binding sites of known transcription factors, alpha-PAL/NRF1, Sp1, H4TF1/Sp1-like and c-myc [26].
• Interestingly, exercise did not affect nuclear respiratory factor 1 (NRF-1) mRNA, a gene induced by PGC-1alpha in cell culture [27].
• Immunocytochemistry showed that whereas Nrf1 gave primarily cytoplasmic staining that was co-incident with that of an endoplasmic-reticulum marker, Nrf2 gave primarily nuclear staining [28].
• Analysis of DHS1 by in vivo footprinting and chromatin immunoprecipitation identified allele-specific interaction with multiple regulatory proteins, including NRF-1, which regulates genes involved in mitochondrial and metabolic functions [29].
• Nuclear respiratory factor 1 expression was analyzed by immunoblots, immunocytochemistry, quantitative electron microscopy, real-time quantitative PCR, and in situ hybridization [30].

References