erect wing

EVOLUTIONARY HOMOLOGS

Identification and characterization of Erect wing homologs

The P3A2 regulatory protein interacts with specific sites in the control region of the CyIIIa actin gene. This interaction is required to confine expression of a CyIIIa.CAT fusion to the aboral ectoderm, the embryonic territory in which CyIIIa is normally utilized. P3A2 also binds specifically to similar target sites located in the regulatory region of the SM50 gene, which is expressed only in skeletogenic mesenchyme lineages. The P3A2 factor was purified by affinity chromatography from nuclear extracts of 24 h sea urchin embryos, and partial peptide sequences were used to isolate a cDNA clone encoding the complete protein. There are no significant similarities between P3A2 and any other protein in existing sequence data bases. P3A2 thus includes a novel type of DNA-binding domain. To examine the differential utilization of P3A2 in CyIIIa and SM50 genes, the specific affinity of this protein was measured for the various target sites in the regulatory DNAs of each gene, and the core target site sequences identified. The stability of P3A2 complexes formed with SM50 target sites is 50-100 times greater than that of the complexes formed with CyIIIa target sites, though the factor binds to very similar core sequence elements. P3A2 is one of at least twelve different proteins whose interaction with CyIIIa regulatory DNA is required for correct developmental expression. It might be possible to purify most of these regulatory proteins, or any other specific DNA-binding proteins of the sea urchin embryo, by using the simple procedures described for P3A2 (Calzone, 1991).

Portions of NRF-1 are closely related to sea urchin P3A2 and the erect wing (EWG) protein of Drosophila. The region of highest sequence identity with P3A2 and EWG is in the amino-terminal half of the molecule, which was found by deletion mapping to contain the DNA-binding domain, whereas the carboxy-terminal half of NRF-1 from either protein is highly divergent. The DNA-binding domain in these molecules is unrelated to motifs found commonly in DNA-binding proteins; thus, NRF-1, P3A2, and EWG represent the founding members of a new class of highly conserved sequence-specific regulatory factors (Virbasius, 1993).

Erect wing protein contains an unusual DNA binding domain that is homologous to a novel transcription factor termed alpha-Pal. In response to growth, metabolic, and other signals, eukaryotic cells regulate protein biosynthesis through post-translational mechanisms that target the alpha subunit of eukaryotic initiation factor-2 (eIF-2 alpha). Previous efforts to study transcriptional mechanisms underlying this regulation identified alpha-Pal, a transcription factor for the eIF-2 alpha gene. To gain insight into the overall biological function of alpha-Pal, its cDNA has been cloned. Sequence analysis of the encoded protein reveals that alpha-Pal is a putative bZIP transcription factor. Surprisingly, both the protein sequence and the DNA-recognition site (TGCGCATGCGCA) of this human protein are strongly homologous to those of two evolutionarily distant developmental transcription factors: P3A2 and ewg. Since P3A2 directs territory-specific transcription of muscle genes in sea urchin embryos, and ewg apparently directs transcription of flight muscle and neuronal genes in Drosophila embryos, it is likely that alpha-Pal directs similar gene transcription during human embryogenesis. In other studies, genes containing alpha-Pal-binding sequences have been identified as those involved in cellular proliferation, or the growth-responsive metabolic pathways, energy transduction, translation, and DNA replication/repair. Such data suggest that alpha-Pal also functions to modulate the transcription of metabolic genes required for cellular growth (Efiok, 1994).

A negative regulatory factor is required for correct territory-specific gene expression in the sea urchin embryo. The skeletogenic SM50 gene of Strongylocentrotus purpuratus is regulated by this factor, called P3A1. P3A1 contains two sequence elements that belong to the Zn finger class of DNA-binding motifs, and in these regions is most closely similar to the Drosophila Hunchback factor. The P3A1 factor also binds to a similar target sequence in a second gene, CyIIIa, expressed in embryonic aboral ectoderm. Another sea urchin embryo protein factor, P3A2, footprints the same target sites in the SM50 and CyIIIa genes as does P3A1, but lacks the Zn finger sequence motifs and in amino acid sequence is almost entirely dissimilar to P3A1. A deletion analysis of P3A2 delimited the DNA-binding region, revealing that five specific amino acids in the first P3A1 finger region and four in the second P3A1 finger region are also present in equivalent positions in P3A2. The P3A1 and P3A2 factors could function as regulatory antagonists, having evolved similar target specificities from dissimilar DNA-binding domains (Hoog, 1991).

SpP3A1 and SpP3A2 are DNA-binding proteins that interact specifically with the same target sites in the regulatory domains of the Strongylocentrotus purpuratus CyIIIa gene as well as several other known genes. Both proteins are present in unfertilized eggs, and both enter the embryonic nuclei early in development, but only P3A2 remains present in nuclei at functional concentrations beyond the early gastrula stage. Combined with earlier measurements of P3A site binding at cleavage stages, these measurements show that P3A1 would be replaced by P3A2 at target sites in genes regulated by these factors (Zeller, 1995).

In response to growth, metabolic, and other signals, eukaryotic cells regulate protein biosynthesis through post-translational mechanisms that target the alpha subunit of eukaryotic initiation factor-2 (eIF-2 alpha). Previous efforts to study transcriptional mechanisms underlying this regulation have identified a novel transcription factor (alpha-Pal) for the eIF-2 alpha gene. Sequence analysis of the encoded protein reveals that alpha-Pal is a putative bZIP transcription factor. Both the protein sequence and the DNA-recognition site (TGCGCATGCGCA) of this human protein are strongly homologous to those of two evolutionarily distant developmental transcription factors, P3A2 and EWG. Since P3A2 directs territory-specific transcription of muscle genes in sea urchin embryos, and EWG apparently directs transcription of flight muscle and neuronal genes in Drosophila embryos, it is likely that alpha-Pal directs similar gene transcription during human embryogenesis. Genes containing alpha-Pal-binding sequences are involved in cellular proliferation, or the growth-responsive metabolic pathways, energy transduction, translation, and DNA replication/repair. The DNA synthesis/repair genes include human DNA polmerase alpha subunit, while cellular proliferation genes include PDGF2 and Hepatocyte growth factor-like protein. Such data suggest that alpha-Pal functions to modulate the transcription of metabolic genes required for cellular growth (Efiok, 1994).

Initiation binding receptor (IBR) is a chicken erythrocyte factor (apparent molecular mass, 70 to 73 kDa) that binds to the sequences spanning the transcription initiation site of the histone h5 gene, repressing its transcription. A variety of other cells, including transformed erythroid precursors, do not have IBR but a factor referred to as IBF (68 to 70 kDa) that recognizes the same IBR sites. IBR is a 503-amino-acid-long acidic protein which is 99.0% identical to the recently reported human NRF-1/alpha-Pal factor and highly related to the invertebrate transcription factors P3A2 and erect wing gene product. IBR and IBF are most likely identical proteins, differing in their degree of glycosylation. The factor associates as stable homodimers. The dimer is the relevant DNA-binding species. The evolutionarily conserved N-terminal half of IBR/F harbors the DNA-binding/dimerization domain (outer limits, 127 to 283), one or several casein kinase II sites (37 to 67), and a bipartite nuclear localization signal (89 to 106) which appears to be necessary for nuclear targeting. Binding site selection reveals that the alternating RCGCRYGCGY consensus constitutes high-affinity IBR/F binding sites and that the direct-repeat palindrome TGCGCATGCGCA is the optimal site. A survey of genes potentially regulated by this family of factors revealed genes involved primarily in growth-related metabolism (Gomez-Cuadrado, 1995).

NRF-1 and NRF-2 provide a link between the expression of nuclear and mitochondrial genes

Mitochondrial transcription factor A (mtTFA), the product of a nuclear gene, stimulates transcription from the two divergent mitochondrial promoters and is, most likely, the principal activator of mitochondrial gene expression in vertebrates. The proximal promoter of the human mtTFA gene is highly dependent upon recognition sites for the nuclear respiratory factors, NRF-1 and NRF-2, for activity. These factors have been previously implicated in the activation of numerous nuclear genes that contribute to mitochondrial respiratory function. The affinity-purified factors from HeLa cells specifically bind to the mtTFA NRF-1 and NRF-2 sites through guanine nucleotide contacts that are characteristic for each site. Mutations in these contacts eliminate NRF-1 and NRF-2 binding and also dramatically reduce promoter activity in transfected cells. Although both factors contribute, NRF-1 binding appears to be the major determinant of promoter function. This dependence on NRF-1 activation is confirmed by in vitro transcription using highly purified recombinant proteins that display the same binding specificities as the HeLa cell factors. The activation of the mtTFA promoter by both NRF-1 and NRF-2 therefore provides a link between the expression of nuclear and mitochondrial genes and suggests a mechanism for their coordinate regulation during organelle biogenesis (Virbasius, 1994).

Nuclear respiratory factor 1 (NRF-1) is a transcription factor that acts on nuclear genes encoding respiratory subunits and components of the mitochondrial transcription and replication machinery. The NRF-1 gene spans approximately 65 kilobases (kb) and has 11 exons and 10 introns, ranging in size from 0.8 to 15 kb. NRF-1 mRNA is expressed at very low levels in rat tissues compared with cytochrome c and, unlike cytochrome c, is most abundantly expressed in lung and testis (Gopalakrishnan, 1995).

Transcription factor nuclear respiratory factor 1 (NRF-1) was originally identified as an activator of the cytochrome c gene and subsequently found to stimulate transcription through specific sites in other nuclear genes whose products function in the mitochondria. These include subunits of the cytochrome oxidase and reductase complexes and a component of the mitochondrial DNA replication machinery. A functional recognition site for NRF-1 is present in the ATP synthase gamma-subunit gene extending the proposed respiratory role of NRF-1 to complex V. In addition, biologically active NRF-1 sites are found in genes encoding the eukaryotic translation initiation factor 2 alpha-subunit and tyrosine aminotransferase, both of which participate in the rate-limiting step of their respective pathways of protein biosynthesis and tyrosine catabolism. The recognition sites from each of these genes form identical complexes with NRF-1 as established by competition binding assays, methylation interference footprinting, and UV-induced DNA cross-linking. Cloned oligomers of each NRF-1 binding site also stimulate the activity of a truncated cytochrome c promoter in transfected cells. The NRF-1 binding activities for the various target sites copurified approximately 33,000-fold and resided in a single protein of 68 kDa. These observations further support a role for NRF-1 in the expression of nuclear respiratory genes and suggest it may help coordinate respiratory metabolism with other biosynthetic and degradative pathways (Chau, 1995).

Structure of Erect wing homologs

Nrf1 (nuclear factor-erythroid 2 p45 subunit-related factor 1) and Nrf2 regulate ARE (antioxidant response element)-driven genes. At its N-terminal end, Nrf1 contains 155 additional amino acids that are absent from Nrf2. This 155-amino-acid polypeptide includes the N-terminal domain (NTD, amino acids 1-124) and a region (amino acids 125-155) that is part of acidic domain 1 (amino acids 125-295). Within acidic domain 1, residues 156-242 share 43% identity with the Neh2 (Nrf2-ECH homology 2) degron of Nrf2 that serves to destabilize this latter transcription factor through an interaction with Keap1 (Kelch-like ECH-associated protein 1). The function of the 155-amino-acid N-terminal polypeptide was examined in Nrf1, along with its adjacent Neh2-like subdomain. Activation of ARE-driven genes by Nrf1 was negatively controlled by the NTD (N-terminal domain) through its ability to direct Nrf1 to the endoplasmic reticulum. Ectopic expression of wild-type Nrf1 and mutants lacking either the NTD or portions of its Neh2-like subdomain into wild-type and mutant mouse embryonic fibroblasts indicates that Keap1 controls neither the activity of Nrf1 nor its subcellular distribution. Immunocytochemistry showed that whereas Nrf1 gave primarily cytoplasmic staining that is co-incident with that of an endoplasmic-reticulum marker, Nrf2 gives primarily nuclear staining. Attachment of the NTD from Nrf1 to the N-terminus of Nrf2 produces a fusion protein that is redirected from the nucleus to the endoplasmic reticulum. Although this NTD-Nrf2 fusion protein exhibits less transactivation activity than wild-type Nrf2, it is nevertheless still negatively regulated by Keap1. Thus Nrf1 and Nrf2 are targeted to different subcellular compartments and are negatively regulated by distinct mechanisms (Zhang, 2006).

Expression of antioxidant and phase 2 xenobiotic metabolizing enzyme genes is regulated through cis-acting sequences known as antioxidant response elements. Transcriptional activation through the antioxidant response elements involves members of the CNC (Cap 'n' Collar) family of basic leucine zipper proteins including Nrf1 and Nrf2. Nrf2 activity is regulated by Keap1-mediated compartmentalization in the cell. Given the structural similarities between Nrf1 and Nrf2, attempts were made to investigate whether Nrf1 activity is regulated similarly to Nrf2. Nrf1 also resides normally in the cytoplasm of cells. Cytoplasmic localization however, is independent of Keap1. Colocalization analysis using green fluorescent protein-tagged Nrf1 and subcellular fractionation of endogenous Nrf1 and fusion proteins indicate that Nrf1 is primarily a membrane-bound protein localized in the endoplasmic reticulum. Membrane targeting is mediated by the N terminus of the Nrf1 protein that contains a predicted transmembrane domain, and deletion of this domain resulted in a predominantly nuclear localization of Nrf1 that significantly increased the activation of reporter gene expression. 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. These results suggest that Nrf1 is normally targeted to the endoplasmic reticulum membrane and that endoplasmic reticulum stress may play a role in modulating Nrf1 function as a transcriptional activator (W. Wang, 2006).

Mutation of Erect wing homologs

Not really finished (nrf), a larval-lethal mutation in zebrafish generated by retroviral insertion, causes specific retinal defects. Analysis of mutant retinae reveals an extensive loss of photoreceptors and their precursors around the onset of visual function. These neurons undergo apoptosis during differentiation, affecting all classes of photoreceptors, suggesting an essential nrf function for the development of all types of photoreceptors. In the mutant, some photoreceptors escape cell death, are functional, and, as judged by opsin expression, belong to at least three classes of cones and one class of rods. The protein encoded by nrf is related to Drosophila Erect wing and is a close homolog of human Nuclear Respiratory Factor 1 and avian Initiation Binding Repressor, transcriptional regulators binding the upstream consensus sequence RCGCRYGCGY. At 24 hours of development, prior to neuronal differentiation, nrf is expressed ubiquitously throughout the developing retina and central nervous system. At 48 hours of development, expression of nrf is detected in the ganglion cell layer, in the neurons of the inner nuclear layer, and in the optic nerve and optic tracts, and, at 72 hours of development, is no longer detectable by in situ hybridization. Mutants contain no detectable nrf mRNA and die within 2 weeks postfertilization as larvae with reduced brain size. On the basis of its similarity with NRF-1 and IBR, nrf is likely involved in transcriptional regulation of multiple target genes, including those that encode mitochondrial proteins, growth factor receptors and other transcription factors. This demonstrates the power of insertional mutagenesis as a means for characterizing novel genes necessary for vertebrate retinal development (Becker, 1998).

In vitro studies have implicated nuclear respiratory factor 1 (NRF-1) in the transcriptional expression of nuclear genes required for mitochondrial respiratory function, as well as for other fundamental cellular activities. This study investigated he in vivo function of NRF-1 in mammals by disrupting the gene in mice. A portion of the NRF-1 gene that encodes the nuclear localization signal and the DNA-binding and dimerization domains was replaced through homologous recombination by a beta-galactosidase-neomycin cassette. In the mutant allele, beta-galactosidase expression is under the control of the NRF-1 promoter. Embryos homozygous for NRF-1 disruption die between embryonic days 3.5 and 6.5. beta-Galactosidase staining was observed in growing oocytes and in 2. 5- and 3.5-day-old embryos, demonstrating that the NRF-1 gene is expressed during oogenesis and during early stages of embryogenesis. Moreover, the embryonic expression of NRF-1 did not result from maternal carryover. While most isolated wild-type and NRF-1^+/- blastocysts can develop further in vitro, the NRF-1^-/- blastocysts lack this ability despite their normal morphology. 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). The depletion of mtDNA did not coincide with nuclear DNA fragmentation, indicating that mtDNA loss was not associated with increased apoptosis. These results are consistent with a specific requirement for NRF-1 in the maintenance of mtDNA and respiratory chain function during early embryogenesis (Huo, 2001).

The Nrf1 transcription factor belongs to the CNC subfamily of basic leucine zipper proteins. Knockout of Nrf1 is lethal in mouse embryos, but nothing is known about the cell types that absolutely require its function during development. This study shows by chimera analysis that Nrf1 is essential for the hepatocyte lineage. Mouse embryonic stem cells lacking Nrf1 developed normally and contributed to most tissues in adult chimeras where Nrf1 is normally expressed. Nrf1-deficient cells contribute to fetal, but not adult, liver cells. Loss of Nrf1 function results in liver cell apoptosis in late-gestation chimeric fetuses. Fetal livers from mutant embryos exhibit increased oxidative stress and impaired expression of antioxidant genes, and primary cultures of nrf1^-/- fetal hepatocytes are sensitive to tert-butyl hydroperoxide-induced cell death, suggesting that impaired antioxidant defense may be responsible for the apoptosis observed in the livers of chimeric mice. In addition, cells deficient in Nrf1 are sensitized to the cytotoxic effects of tumor necrosis factor (TNF). These results provide in vivo evidence demonstrating an essential role of Nrf1 in the survival of hepatocytes during development. The results also suggest that Nrf1 may promote cell survival by maintaining redox balance and protecting embryonic hepatocytes from TNF-mediated apoptosis during development (Chen, 2003).

Nrf1 and Nrf2 are members of the CNC family of bZIP transcription factors that exhibit structural similarities, and they are co-expressed in a wide range of tissues during development. Nrf2 has been shown to be dispensable for growth and development in mice. Nrf2-deficient mice, however, are impaired in oxidative stress defense. Loss of Nrf1 function in mice results late gestational embryonic lethality. To determine whether Nrf1 and Nrf2 have overlapping functions during early development and in the oxidative stress response, mice were generated that are deficient in both Nrf1 and Nrf2. In contrast to the late embryonic lethality in Nrf1 mutants, compound Nrf1, Nrf2 mutants die early between embryonic days 9 and 10 and exhibit extensive apoptosis that is not observed in the single mutants. Loss of Nrf1 and Nrf2 leads to marked oxidative stress in cells that is indicated by elevated intracellular reactive oxygen species levels and cell death that is reversed by culturing under reduced oxygen tension or the addition of antioxidants. Compound mutant cells also show increased levels of p53 and induction of Noxa, a death effector p53 target gene, suggesting that cell death is potentially mediated by reactive oxygen species activation of p53. Moreover, expression of genes related to antioxidant defense is severely impaired in compound mutant cells compared with single mutant cells. Together, these findings indicate that the functions of Nrf1 and Nrf2 overlap during early development and to a large extent in regulating antioxidant gene expression in cells (Leung, 2003).

Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. Mice with somatic inactivation of nrf1 in the liver developed hepatic cancer. Before cancer development, mutant livers exhibit steatosis, apoptosis, necrosis, inflammation, and fibrosis. 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. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer (Xu, 2005).

The Nrf2 transcription factor is a key player in the cellular stress response through its regulation of cytoprotective genes. This study determined the role of Nrf2-mediated gene expression in keratinocytes for skin development, wound repair, and skin carcinogenesis. To overcome compensation by the related Nrf1 and Nrf3 proteins, a dominant-negative Nrf2 mutant (dnNrf2) was expressed in the epidermis of transgenic mice. The functionality of the transgene product was verified in vivo using mice doubly transgenic for dnNrf2 and an Nrf2-responsive reporter gene. Surprisingly, no abnormalities of the epidermis were observed in dnNrf2-transgenic mice, and even full-thickness skin wounds healed normally. However, the onset, incidence, and multiplicity of chemically induced skin papillomas were strikingly enhanced, whereas the progression to squamous cell carcinomas was unaltered. Evidence is provided that the enhanced tumorigenesis results from reduced basal expression of cytoprotective Nrf target genes, leading to accumulation of oxidative damage and reduced carcinogen detoxification. These results reveal a crucial role of Nrf-mediated gene expression in keratinocytes in the prevention of skin tumors and suggest that activation of Nrf2 in keratinocytes is a promising strategy to prevent carcinogenesis of this highly exposed organ (auf dem Keller, 2006).

Transcriptional targets of Erect wing homologs

Using genome-wide analysis of transcription factor occupancy, this study investigated the mechanisms underlying three mammalian growth arrest pathways that require the pRB tumor suppressor family. It was found that p130 and E2F4 cooperatively repress a common set of genes under each growth arrest condition and showed that growth arrest is achieved through repression of a core set of genes involved not only in cell cycle control but also mitochondrial biogenesis and metabolism. Motif-finding algorithms predicted the existence of nuclear respiratory factor-1 (NRF1) binding sites in E2F target promoters, and genome-wide factor binding analysis confirmed these predictions. NRF1, a factor known to regulate expression of genes involved in mitochondrial function, is a coregulator of a large number of E2F target genes. These studies provide insights into E2F regulatory circuitry, suggest how factor occupancy can predict the expression signature of a given target gene, and reveal pathways deregulated in human tumors (Cam, 2003).

In vertebrates, mitochondrial DNA (mtDNA) transcription is initiated bidirectionally from closely spaced promoters, HSP and LSP, within the D-loop regulatory region. Early studies demonstrated that mtDNA transcription requires mitochondrial RNA polymerase and Tfam, a DNA binding stimulatory factor that is required for mtDNA maintenance. Recently, mitochondrial transcription specificity factors (TFB1M and TFB2M), which markedly enhance mtDNA transcription in the presence of Tfam and mitochondrial RNA polymerase, have been identified in mammalian cells. This study establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC. The physiological induction of these coactivators has been associated with the integration of NRFs and other transcription factors in a program of mitochondrial biogenesis. Finally, the TFB genes are up-regulated along with Tfam and either PGC-1alpha or PRC in cellular systems where mitochondrial biogenesis is induced. Moreover, ectopic expression of PGC-1alpha is sufficient to induce the coordinate expression of all three nucleus-encoded mitochondrial transcription factors along with nuclear and mitochondrial respiratory subunits. These results support the conclusion that the coordinate regulation of nucleus-encoded mitochondrial transcription factors by NRFs and PGC-1 family coactivators is essential to the control of mitochondrial biogenesis (Gleyzer, 2005).

Glutamate-cysteine ligase catalytic subunit (GCLC) is regulated transcriptionally by Nrf1 and Nrf2. tert-Butylhydroquinone (TBH) induces human GCLC via Nrf2-mediated trans activation of the antioxidant-responsive element (ARE). Interestingly, TBH also induces rat GCLC, but the rat GCLC promoter lacks ARE. This study examined the role of Nrf1 and Nrf2 in the transcriptional regulation of rat GCLC. The baseline and TBH-mediated increase in GCLC mRNA levels and rat GCLC promoter activity were lower in Nrf1 and Nrf2 null fibroblasts than in wild-type cells. The basal protein and mRNA levels and nuclear binding activities of c-Jun, c-Fos, p50, and p65 were lower in these null cells and exhibited a blunted response to TBH. Lower c-Jun and p65 expression also occurs in Nrf2 null livers. Levels of other AP-1 and NF-kappaB family members were either unaffected (i.e., JunB) or increased (i.e., Fra-1). Overexpression of Nrf1 and Nrf2 in respective cells restored the rat GCLC promoter activity and response to TBH but not if the AP-1 and NF-kappaB binding sites were mutated. Fra-1 overexpression lowered endogenous GCLC expression and rat GCLC promoter activity, while Fra-1 antisense had the opposite effects. In conclusion, Nrf1 and Nrf2 regulate rat GCLC promoter by modulating the expression of key AP-1 and NF-kappaB family members (Yang, 2005).

Post-translational modification of Erect wing homologs

Cyclin D1 promotes nuclear DNA synthesis through phosphorylation and inactivation of the pRb tumor suppressor. This study shows that cyclin D1 deficiency increases mitochondrial size and activity that is rescued by cyclin D1 in a Cdk-dependent manner. Nuclear respiratory factor 1 (NRF-1), which induces nuclear-encoded mitochondrial genes, is repressed in expression and activity by cyclin D1. Cyclin D1-dependent kinase phosphorylates NRF-1 at S47. Cyclin D1 abundance thus coordinates nuclear DNA synthesis and mitochondrial function (C. Wang, 2006).

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