NFE2L1: Difference between revisions

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{{Infobox_gene}}
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'''Nuclear factor erythroid 2-related factor 1''' (Nrf1) also known as '''nuclear factor erythroid-2-like 1''' (NFE2L1) is a [[protein]] that in humans is encoded by the ''NFE2L1'' [[gene]].<ref name="Chan_1993">{{cite journal | vauthors = Chan JY, Han XL, Kan YW | title = Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 23 | pages = 11371–5 | date = Dec 1993 | pmid = 8248256 | pmc = 47984 | doi = 10.1073/pnas.90.23.11371 }}</ref><ref name="Chan_1998">{{cite journal | vauthors = Chan JY, Kwong M, Lu R, Chang J, Wang B, Yen TS, Kan YW | title = Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice | journal = The EMBO Journal | volume = 17 | issue = 6 | pages = 1779–87 | date = Mar 1998 | pmid = 9501099 | pmc = 1170525 | doi = 10.1093/emboj/17.6.1779 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NFE2L1 nuclear factor (erythroid-derived 2)-like 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4779| accessdate = }}</ref> Since  NFE2L1 is referred to as Nrf1, it is often confused with nuclear respiratory factor 1 (Nrf1).
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
NFE2L1  is a cap ‘n’ collar, [[bZIP domain|basic-leucine zipper]] (bZIP) transcription factor. Several isoforms of NFE2L1 have been described for both human and mouse genes. NFE2L1 was first cloned in yeast using a genetic screening method. NFE2L1 is ubiquitously expressed, and high levels of transcript are detected in the heart, kidney, skeletal muscle, fat, and brain.<ref name="Chan_1993"/> Four separate regions — an asparagine/serine/threonine, acidic domains near the [[N-terminus]], and a serine-rich domain located near the CNC motif — are required for full transactivation function of NFE2L1.<ref>{{cite journal | vauthors = Husberg C, Murphy P, Martin E, Kolsto AB | title = Two domains of the human bZIP transcription factor TCF11 are necessary for transactivation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 21 | pages = 17641–52 | date = May 2001 | pmid = 11278371 | doi = 10.1074/jbc.M007951200 }}</ref><ref name = "Zhang_2009">{{cite journal | vauthors = Zhang Y, Lucocq JM, Hayes JD | title = The Nrf1 CNC/bZIP protein is a nuclear envelope-bound transcription factor that is activated by t-butyl hydroquinone but not by endoplasmic reticulum stressors | journal = The Biochemical Journal | volume = 418 | issue = 2 | pages = 293–310 | date = Mar 2009 | pmid = 18990090 | doi = 10.1042/BJ20081575 }}</ref><ref name = "Wang_2007">{{cite journal | vauthors = Wang W, Kwok AM, Chan JY | title = The p65 isoform of Nrf1 is a dominant negative inhibitor of ARE-mediated transcription | journal = The Journal of Biological Chemistry | volume = 282 | issue = 34 | pages = 24670–8 | date = Aug 2007 | pmid = 17609210 | doi = 10.1074/jbc.M700159200 }}</ref>  NFE2L1 is a key regulator of cellular functions including [[oxidative stress]] response, differentiation, inflammatory response, metabolism, cholesterol handling<ref name="Widenmaier_2017">{{cite journal | vauthors = Widenmaier SB, Snyder NA, Nguyen TB, Arduini A, Lee GY, Arruda AP, Saksi J, Bartelt A, Hotamisligil GS | title = NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis | journal = Cell | volume = 171 | issue = 5 | pages = 1094–1109.e15 | date = November 2017 | pmid = 29149604 | doi = 10.1016/j.cell.2017.10.003 }}</ref> and maintaining [[proteostasis]].
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Nuclear factor (erythroid-derived 2)-like 1
| HGNCid = 7781
| Symbol = NFE2L1
| AltSymbols =; FLJ00380; LCR-F1; NRF1; TCF11
| OMIM = 163260
| ECnumber = 
| Homologene = 20685
| MGIid = 99421
| GeneAtlas_image1 = PBB_GE_NFE2L1_214179_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_NFE2L1_200758_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_NFE2L1_200759_x_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003712 |text = transcription cofactor activity}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046983 |text = protein dimerization activity}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}  
| Process = {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006366 |text = transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0006783 |text = heme biosynthetic process}} {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0009653 |text = anatomical structure morphogenesis}}  
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4779
    | Hs_Ensembl = ENSG00000082641
    | Hs_RefseqProtein = NP_003195
    | Hs_RefseqmRNA = NM_003204
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 43480704
    | Hs_GenLoc_end = 43493840
    | Hs_Uniprot = Q14494
    | Mm_EntrezGene = 18023
    | Mm_Ensembl = ENSMUSG00000038615
    | Mm_RefseqmRNA = NM_008686
    | Mm_RefseqProtein = NP_032712
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 96633522
    | Mm_GenLoc_end = 96646020
    | Mm_Uniprot = Q3U4L3
  }}
}}
'''Nuclear factor (erythroid-derived 2)-like 1''', also known as '''NFE2L1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: NFE2L1 nuclear factor (erythroid-derived 2)-like 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4779| accessdate = }}</ref>


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== Interactions ==
{{PBB_Summary
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| summary_text =  
}}


==References==
NFE2L1 binds DNA as heterodimers with one of [[small Maf]] proteins ([[MAFF (gene)|MAFF]], [[MAFG]], [[MAFK]]).<ref>{{cite journal | vauthors = Marini MG, Chan K, Casula L, Kan YW, Cao A, Moi P | title = hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 26 | pages = 16490–7 | date = Jun 1997 | pmid = 9195958 | doi=10.1074/jbc.272.26.16490}}</ref><ref name = "Johnsen_1998">{{cite journal | vauthors = Johnsen O, Murphy P, Prydz H, Kolsto AB | title = Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription | journal = Nucleic Acids Research | volume = 26 | issue = 2 | pages = 512–20 | date = Jan 1998 | pmid = 9421508 | doi=10.1093/nar/26.2.512 | pmc=147270}}</ref><ref name = "Wang_2007"/> NFE2L1 has been shown to [[Protein-protein interaction|interact]] with [[C-jun]].<ref name=pmid9872330>{{cite journal | vauthors = Venugopal R, Jaiswal AK | title = Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes | journal = Oncogene | volume = 17 | issue = 24 | pages = 3145–56 | date = Dec 1998 | pmid = 9872330 | doi = 10.1038/sj.onc.1202237 }}</ref>
{{reflist|2}}
 
==Further reading==
== Cellular homeostasis ==
{{refbegin | 2}}
 
{{PBB_Further_reading
NFE2L1 regulates a wide variety of cellular responses, several of which are related to important aspects of protection from stress stimuli. NFE2L1 is involved in providing cellular protection against oxidative stress through the induction of antioxidant genes. The [[glutathione]] synthesis pathway is catalyzed by [[glutamate-cysteine ligase]], which contains the catalytic [[GCLC]] and regulatory [[GCLM]], and [[glutathione synthetase]] (GSS).<ref>{{cite journal | vauthors = Lu SC | title = Regulation of glutathione synthesis | journal = Molecular Aspects of Medicine | volume = 30 | issue = 1-2 | pages = 42–59 | date = 2009 | pmid = 18601945 | doi = 10.1016/j.mam.2008.05.005 | pmc=2704241}}</ref> Nfe2l1 was found to regulate Gclm and Gss expression in mouse fibroblasts.<ref>{{cite journal | vauthors = Kwong M, Kan YW, Chan JY | title = The CNC basic leucine zipper factor, Nrf1, is essential for cell survival in response to oxidative stress-inducing agents. Role for Nrf1 in gamma-gcs(l) and gss expression in mouse fibroblasts | journal = The Journal of Biological Chemistry | volume = 274 | issue = 52 | pages = 37491–8 | date = Dec 1999 | pmid = 10601325 | doi=10.1074/jbc.274.52.37491}}</ref> Gclm was found to be a direct target of Nfe2l1, and Nfe2l1 also regulates Gclc expression through an indirect mechanism.<ref>{{cite journal | vauthors = Myhrstad MC, Husberg C, Murphy P, Nordström O, Blomhoff R, Moskaug JO, Kolstø AB | title = TCF11/Nrf1 overexpression increases the intracellular glutathione level and can transactivate the gamma-glutamylcysteine synthetase (GCS) heavy subunit promoter | journal = Biochimica et Biophysica Acta | volume = 1517 | issue = 2 | pages = 212–9 | date = Jan 2001 | pmid = 11342101 | doi=10.1016/s0167-4781(00)00276-1}}</ref><ref>{{cite journal | vauthors = Yang H, Magilnick N, Lee C, Kalmaz D, Ou X, Chan JY, Lu SC | title = Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1 | journal = Molecular and Cellular Biology | volume = 25 | issue = 14 | pages = 5933–46 | date = Jul 2005 | pmid = 15988009 | doi = 10.1128/MCB.25.14.5933-5946.2005 | pmc=1168815}}</ref> Nfe2l1 knockout mice also exhibit down-regulation of [[GPX1|Gpx1]] and [[HMOX1|Hmox1]], and Nfe2l1 (this gene)-deficient hepatocytes from liver-specific Nfe2l1 knockout mice showed decreased expression of various Gst genes.<ref name = "Chen_2003">{{cite journal | vauthors = Chen L, Kwong M, Lu R, Ginzinger D, Lee C, Leung L, Chan JY | title = Nrf1 is critical for redox balance and survival of liver cells during development | journal = Molecular and Cellular Biology | volume = 23 | issue = 13 | pages = 4673–86 | date = Jul 2003 | pmid = 12808106 | pmc=164851 | doi=10.1128/mcb.23.13.4673-4686.2003}}</ref><ref name = "Xu_2005">{{cite journal | vauthors = Xu Z, Chen L, Leung L, Yen TS, Lee C, Chan JY | title = Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 11 | pages = 4120–5 | date = Mar 2005 | pmid = 15738389 | doi = 10.1073/pnas.0500660102 | pmc=554825}}</ref> Metallothioenein-1 and Metallothioenein-2 genes, which protect cells against cytotoxicity induced by toxic metals, are also direct targets of Nfe2l1.<ref>{{cite journal | vauthors = Ohtsuji M, Katsuoka F, Kobayashi A, Aburatani H, Hayes JD, Yamamoto M | title = Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes | journal = The Journal of Biological Chemistry | volume = 283 | issue = 48 | pages = 33554–62 | date = Nov 2008 | pmid = 18826952 | doi = 10.1074/jbc.M804597200 | pmc=2662273}}</ref>
| citations =  
 
*{{cite journal  | author=Luna L, Skammelsrud N, Johnsen O, ''et al.'' |title=Structural organization and mapping of the human TCF11 gene. |journal=Genomics |volume=27 |issue= 2 |pages= 237-44 |year= 1995 |pmid= 7557987 |doi= 10.1006/geno.1995.1037 }}
Nfe2l1 is also involved in maintaining proteostasis. Brains of mice with [[conditional gene knockout|conditional knockout]] of Nfe2l1 in neuronal cells showed decreased proteasome activity and accumulation of [[ubiquitin]]-conjugated proteins, and down regulation of genes encoding the 20S core and 19S regulatory sub-complexes of the 26S [[proteasome]].<ref name = "Lee_2011">{{cite journal | vauthors = Lee CS, Lee C, Hu T, Nguyen JM, Zhang J, Martin MV, Vawter MP, Huang EJ, Chan JY | title = Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 20 | pages = 8408–13 | date = May 2011 | pmid = 21536885 | doi = 10.1073/pnas.1019209108 | pmc=3100960}}</ref> A similar effect on proteasome gene expression and function was observed in livers of mice with Nfe2l1 conditional knockout in hepatocytes.<ref>{{cite journal | vauthors = Lee CS, Ho DV, Chan JY | title = Nuclear factor-erythroid 2-related factor 1 regulates expression of proteasome genes in hepatocytes and protects against endoplasmic reticulum stress and steatosis in mice | journal = The FEBS Journal | volume = 280 | issue = 15 | pages = 3609–20 | date = Aug 2013 | pmid = 23702335 | doi = 10.1111/febs.12350 | pmc=3835180}}</ref> Induction of proteasome genes was also lost in brains and livers of Nfe2l1 conditional knockout mice. Re-establishment of Nfe2l1 function in Nfe2l1 null cells rescued proteasome expression and function, indicating Nfe2l1 was necessary for induction of proteasome genes (bounce-back response) in response to proteasome inhibition.<ref name = "Radhakrishnan_2010">{{cite journal | vauthors = Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ | title = Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells | journal = Molecular Cell | volume = 38 | issue = 1 | pages = 17–28 | date = Apr 2010 | pmid = 20385086 | doi = 10.1016/j.molcel.2010.02.029 | pmc=2874685}}</ref> This compensatory up-regulation of proteasome genes in response to proteasome inhibition has also been demonstrated to be Nfe2l1-dependent in various other cell types.<ref name = "Steffen_2010">{{cite journal | vauthors = Steffen J, Seeger M, Koch A, Krüger E | title = Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop | journal = Molecular Cell | volume = 40 | issue = 1 | pages = 147–58 | date = Oct 2010 | pmid = 20932482 | doi = 10.1016/j.molcel.2010.09.012 }}</ref><ref name = "Sha_2014">{{cite journal | vauthors = Sha Z, Goldberg AL | title = Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97 | journal = Current Biology | volume = 24 | issue = 14 | pages = 1573–83 | date = Jul 2014 | pmid = 24998528 | doi = 10.1016/j.cub.2014.06.004 | pmc=4108618}}</ref> NFE2L1 was shown to directly bind and activate expression of the [[PSMB6|PsmB6]] gene, which encodes a catalytic subunit of the 20S core.<ref name = "Lee_2011"/><ref name = "Radhakrishnan_2010"/> Nfe2l1 was also shown to regulate expression of Herpud1 and Vcp/p97, which are components of the ER-associated degradation pathway.<ref>{{cite journal | vauthors = Ho DV, Chan JY | title = Induction of Herpud1 expression by ER stress is regulated by Nrf1 | journal = FEBS Letters | volume = 589 | issue = 5 | pages = 615–20 | date = Feb 2015 | pmid = 25637874 | doi = 10.1016/j.febslet.2015.01.026 }}</ref><ref name = "Sha_2014"/>
*{{cite journal | author=Luna L, Johnsen O, Skartlien AH, ''et al.'' |title=Molecular cloning of a putative novel human bZIP transcription factor on chromosome 17q22. |journal=Genomics |volume=22 |issue= 3 |pages= 553-62 |year= 1995 |pmid= 8001966 |doi= 10.1006/geno.1994.1428 }}
 
*{{cite journal | author=Caterina JJ, Donze D, Sun CW, ''et al.'' |title=Cloning and functional characterization of LCR-F1: a bZIP transcription factor that activates erythroid-specific, human globin gene expression. |journal=Nucleic Acids Res. |volume=22 |issue= 12 |pages= 2383-91 |year= 1994 |pmid= 8036168 |doi= }}
Nfe2l1 also plays a role in metabolic processes. Loss of hepatic Nfe2l1 has been shown to result in lipid accumulation, hepatocellular damage, cysteine accumulation, and altered fatty acid composition.<ref name = "Xu_2005"/><ref>{{cite journal | vauthors = Tsujita T, Peirce V, Baird L, Matsuyama Y, Takaku M, Walsh SV, Griffin JL, Uruno A, Yamamoto M, Hayes JD | title = Transcription factor Nrf1 negatively regulates the cystine/glutamate transporter and lipid-metabolizing enzymes | journal = Molecular and Cellular Biology | volume = 34 | issue = 20 | pages = 3800–16 | date = Oct 2014 | pmid = 25092871 | doi = 10.1128/MCB.00110-14 | pmc=4187719}}</ref> Glucose homeostasis and insulin secretion have also been found to be under the control of Nfe2l1.<ref name = "Zheng_2015">{{cite journal | vauthors = Zheng H, Fu J, Xue P, Zhao R, Dong J, Liu D, Yamamoto M, Tong Q, Teng W, Qu W, Zhang Q, Andersen ME, Pi J | title = CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion | journal = Antioxidants & Redox Signaling | volume = 22 | issue = 10 | pages = 819–31 | date = Apr 2015 | pmid = 25556857 | doi = 10.1089/ars.2014.6017 | pmc=4367236}}</ref> Insulin-regulated glycolytic genes—[[Glucokinase|Gck]], [[Aldolase B|Aldob]], [[PGK1|Pgk1]], and [[PKLR|Pklr]], hepatic glucose transporter gene — [[GLUT2|SLC2A2]], and gluconeogenic genes — [[FBP1|Fbp1]] and [[PCK1|Pck1]] were repressed in livers of Nfe2l1 transgenic mice.<ref>{{cite journal | vauthors = Hirotsu Y, Higashi C, Fukutomi T, Katsuoka F, Tsujita T, Yagishita Y, Matsuyama Y, Motohashi H, Uruno A, Yamamoto M | title = Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice | journal = Genes to Cells | volume = 19 | issue = 8 | pages = 650–65 | date = Aug 2014 | pmid = 25041126 | doi = 10.1111/gtc.12165 }}</ref> Nfe2l1 may also play a role in maintaining chromosomal stability and genomic integrity by inducing expression of genes encoding components of the spindle assembly and kinetochore.<ref>{{cite journal | vauthors = Oh DH, Rigas D, Cho A, Chan JY | title = Deficiency in the nuclear-related factor erythroid 2 transcription factor (Nrf1) leads to genetic instability | journal = The FEBS Journal | volume = 279 | issue = 22 | pages = 4121–30 | date = Nov 2012 | pmid = 22971132 | doi = 10.1111/febs.12005 | pmc=3835192}}</ref> Nfe2l1 has also been shown to sense and respond to excess cholesterol in the [[Endoplasmic reticulum|ER]].<ref name="Widenmaier_2017" />
*{{cite journal  | author=Chan JY, Han XL, Kan YW |title=Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 23 |pages= 11371-5 |year= 1994 |pmid= 8248256 |doi= }}
 
*{{cite journal | author=Johnsen O, Skammelsrud N, Luna L, ''et al.'' |title=Small Maf proteins interact with the human transcription factor TCF11/Nrf1/LCR-F1. |journal=Nucleic Acids Res. |volume=24 |issue= 21 |pages= 4289-97 |year= 1996 |pmid= 8932385 |doi= }}
== Regulation ==
*{{cite journal | author=Toki T, Itoh J, Kitazawa J, ''et al.'' |title=Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif. |journal=Oncogene |volume=14 |issue= 16 |pages= 1901-10 |year= 1997 |pmid= 9150357 |doi= 10.1038/sj.onc.1201024 }}
 
*{{cite journal | author=Johnsen O, Murphy P, Prydz H, Kolsto AB |title=Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription. |journal=Nucleic Acids Res. |volume=26 |issue= 2 |pages= 512-20 |year= 1998 |pmid= 9421508 |doi= }}
NFE2L1 is an ER membrane protein. Its N-terminal domain (NTD) anchors the protein to the membrane. Specifically, amino acid residues 7 to 24 are known to be a hydrophobic domain that serves as a transmembrane region.<ref>{{cite journal | vauthors = Wang W, Chan JY | title = Nrf1 is targeted to the endoplasmic reticulum membrane by an N-terminal transmembrane domain. Inhibition of nuclear translocation and transacting function | journal = The Journal of Biological Chemistry | volume = 281 | issue = 28 | pages = 19676–87 | date = Jul 2006 | pmid = 16687406 | doi = 10.1074/jbc.M602802200 }}</ref> The concerted mechanism of HRD1, a member of E3-ubiquitin ligase family, and p97/VCP1 was found to play an important role in the degradation of NFE2L1 through the ER Associated Degradation (ERAD) pathway and the release of NFE2L1 from the ER membrane.<ref name = "Steffen_2010"/><ref name = "Tsuchiya_2011">{{cite journal | vauthors = Tsuchiya Y, Morita T, Kim M, Iemura S, Natsume T, Yamamoto M, Kobayashi A | title = Dual regulation of the transcriptional activity of Nrf1 by β-TrCP- and Hrd1-dependent degradation mechanisms | journal = Molecular and Cellular Biology | volume = 31 | issue = 22 | pages = 4500–12 | date = Nov 2011 | pmid = 21911472 | doi = 10.1128/MCB.05663-11 | pmc=3209242}}</ref><ref>{{cite journal | vauthors = Radhakrishnan SK, den Besten W, Deshaies RJ | title = p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition | journal = eLife | volume = 3 | pages = e01856 | date = 2014 | pmid = 24448410 | doi = 10.7554/eLife.01856 | pmc=3896944}}</ref> NFE2L1 is also regulated by other ubiquitin ligases and kinases. FBXW7, a member of the SCF ubiquitin ligase family, targets NFE2L1 for proteolytic degradation by the proteasome.<ref>{{cite journal | vauthors = Biswas M, Phan D, Watanabe M, Chan JY | title = The Fbw7 tumor suppressor regulates nuclear factor E2-related factor 1 transcription factor turnover through proteasome-mediated proteolysis | journal = The Journal of Biological Chemistry | volume = 286 | issue = 45 | pages = 39282–9 | date = Nov 2011 | pmid = 21953459 | doi = 10.1074/jbc.M111.253807 | pmc=3234752}}</ref> FBXW7 requires the Cdc4 phosphodegron domain within NFE2L1 to be phosphorylated via Glycogen Kinase 3.<ref>{{cite journal | vauthors = Biswas M, Kwong EK, Park E, Nagra P, Chan JY | title = Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) and inhibits pro-survival function of Nrf1 | journal = Experimental Cell Research | volume = 319 | issue = 13 | pages = 1922–31 | date = Aug 2013 | pmid = 23623971 | doi = 10.1016/j.yexcr.2013.04.013 | pmc=4186750}}</ref> Casein Kinase 2 was shown to phosphorylate Ser497 of NFE2L1, which attenuates the activity of NFE2L1 on proteasome gene expression.<ref>{{cite journal | vauthors = Tsuchiya Y, Taniguchi H, Ito Y, Morita T, Karim MR, Ohtake N, Fukagai K, Ito T, Okamuro S, Iemura S, Natsume T, Nishida E, Kobayashi A | title = The casein kinase 2-nrf1 axis controls the clearance of ubiquitinated proteins by regulating proteasome gene expression | journal = Molecular and Cellular Biology | volume = 33 | issue = 17 | pages = 3461–72 | date = Sep 2013 | pmid = 23816881 | doi = 10.1128/MCB.01271-12 | pmc=3753846}}</ref> NFE2L1 also interacts with another member of the SCF ligase ubiquitin family known as β-TrCP. β-TrCP also binds to the DSGLC motif, a highly conserved region of CNC-bZIP proteins, in order to poly-ubiquitinate NFE2L1 prior to its proteolytic degradation.<ref name = "Tsuchiya_2011"/> Phosphorylation of Ser599 by protein kinase A enables NFE2L1 and C/EBP-β to dimerize to repress DSPP expression during odontoblast differentiation.<ref>{{cite journal | vauthors = Narayanan K, Ramachandran A, Peterson MC, Hao J, Kolstø AB, Friedman AD, George A | title = The CCAAT enhancer-binding protein (C/EBP)beta and Nrf1 interact to regulate dentin sialophosphoprotein (DSPP) gene expression during odontoblast differentiation | journal = The Journal of Biological Chemistry | volume = 279 | issue = 44 | pages = 45423–32 | date = Oct 2004 | pmid = 15308669 | doi = 10.1074/jbc.M405031200 }}</ref> NFE2L1 expression and activation is also controlled by cellular stresses. Oxidative stress induced by arsenic and t-butyl hydroquinone leads to accumulation of NFE2L1 protein inside the nucleus as well as higher activation on antioxidant genes.<ref name = "Zhang_2009"/><ref>{{cite journal | vauthors = Zhao R, Hou Y, Xue P, Woods CG, Fu J, Feng B, Guan D, Sun G, Chan JY, Waalkes MP, Andersen ME, Pi J | title = Long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes | journal = Environmental Health Perspectives | volume = 119 | issue = 1 | pages = 56–62 | date = Jan 2011 | pmid = 20805060 | doi = 10.1289/ehp.1002304 | pmc=3018500}}</ref> Treatment with an ER stress inducer tunicamycin was shown to induce accumulation of NFE2L1 inside the nucleus; however, it was not associated with increased activity, suggesting further investigation is needed to elucidate the role of ER stress on NFE2L1.<ref>{{cite journal | vauthors = Zhang Y, Crouch DH, Yamamoto M, Hayes JD | title = Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum | journal = The Biochemical Journal | volume = 399 | issue = 3 | pages = 373–85 | date = Nov 2006 | pmid = 16872277 | doi = 10.1042/BJ20060725 | pmc=1615900}}</ref><ref name = "Zhang_2009"/> Hypoxia was also shown to increase the expression of NFE2L1 while attenuating expression of the p65 isoform of NFE2L1.<ref>{{cite journal | vauthors = Chepelev NL, Bennitz JD, Huang T, McBride S, Willmore WG | title = The Nrf1 CNC-bZIP protein is regulated by the proteasome and activated by hypoxia | journal = PLoS One | volume = 6 | issue = 12 | pages = e29167 | date = 2011 | pmid = 22216197 | doi = 10.1371/journal.pone.0029167 | pmc=3244438}}</ref> Growth factors affect expression of NFE2L1 through a mTORC and SREBP-1 mediated pathway. Growth factors induce higher activity of mTORC, which then promotes activity of its downstream protein SREBP-1, a transcription factor for NFE2L1.<ref>{{cite journal | vauthors = Zhang Y, Manning BD | title = mTORC1 signaling activates NRF1 to increase cellular proteasome levels | journal = Cell Cycle | volume = 14 | issue = 13 | pages = 2011–7 | date = 2015 | pmid = 26017155 | doi = 10.1080/15384101.2015.1044188 | pmc=4613906}}</ref><ref>{{cite journal | vauthors = Zhang Y, Nicholatos J, Dreier JR, Ricoult SJ, Widenmaier SB, Hotamisligil GS, Kwiatkowski DJ, Manning BD | title = Coordinated regulation of protein synthesis and degradation by mTORC1 | journal = Nature | volume = 513 | issue = 7518 | pages = 440–3 | date = Sep 2014 | pmid = 25043031 | doi = 10.1038/nature13492 | pmc=4402229}}</ref>
*{{cite journal  | author=Chan JY, Kwong M, Lu R, ''et al.'' |title=Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice. |journal=EMBO J. |volume=17 |issue= 6 |pages= 1779-87 |year= 1998 |pmid= 9501099 |doi= 10.1093/emboj/17.6.1779 }}
 
*{{cite journal | author=Novotny V, Prieschl EE, Csonga R, ''et al.'' |title=Nrf1 in a complex with fosB, c-jun, junD and ATF2 forms the AP1 component at the TNF alpha promoter in stimulated mast cells. |journal=Nucleic Acids Res. |volume=26 |issue= 23 |pages= 5480-5 |year= 1999 |pmid= 9826775 |doi= }}
== Animal studies ==
*{{cite journal | author=Venugopal R, Jaiswal AK |title=Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. |journal=Oncogene |volume=17 |issue= 24 |pages= 3145-56 |year= 1999 |pmid= 9872330 |doi= 10.1038/sj.onc.1202237 }}
 
*{{cite journal  | author=Murphy P, Kolstø A |title=Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development. |journal=Mech. Dev. |volume=97 |issue= 1-2 |pages= 141-8 |year= 2001 |pmid= 11025215 |doi= }}
Loss and gain of function studies in mice showed that dysregulation of Nfe2l1 leads to pathological states that could have relevance in human diseases. Nfe2l1 is crucial for embryonic development and survival of hepatocytes during development.<ref name="Chan_1998"/><ref name = "Chen_2003"/> Loss of Nfe2l1 in mouse hepatocytes leads to steatosis, inflammation, and tumorigenesis.<ref name = "Xu_2005"/> Nfe2l1 is also necessary for neuronal homeostasis.<ref name = "Lee_2011"/> Loss of Nfe2l1 function is also associated with insulin resistance. Mice with conditional deletion of Nfe2l1 in pancreatic β-cells exhibited severe fasting hyperinsulinemia and glucose intolerance, suggesting that Nfe2l1 may play a role in the development of type-2 diabetes<ref name = "Zheng_2015"/> Future studies may provide therapeutic efforts involving Nfe2l1 for cancer, neurodegeneration, and metabolic diseases.
*{{cite journal | author=Jiang LQ, Wen SJ, Wang HY, Chen LY |title=Screening the proteins that interact with calpain in a human heart cDNA library using a yeast two-hybrid system. |journal=Hypertens. Res. |volume=25 |issue= 4 |pages= 647-52 |year= 2003 |pmid= 12358155 |doi= }}
 
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
== References ==
*{{cite journal | author=Husberg C, Murphy P, Bjørgo E, ''et al.'' |title=Cellular localisation and nuclear export of the human bZIP transcription factor TCF11. |journal=Biochim. Biophys. Acta |volume=1640 |issue= 2-3 |pages= 143-51 |year= 2003 |pmid= 12729924 |doi= }}
{{reflist|32em}}
*{{cite journal | author=Newman JR, Keating AE |title=Comprehensive identification of human bZIP interactions with coiled-coil arrays. |journal=Science |volume=300 |issue= 5628 |pages= 2097-101 |year= 2003 |pmid= 12805554 |doi= 10.1126/science.1084648 }}
 
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
== Further reading ==
*{{cite journal  | author=Rual JF, Venkatesan K, Hao T, ''et al.'' |title=Towards a proteome-scale map of the human protein-protein interaction network. |journal=Nature |volume=437 |issue= 7062 |pages= 1173-8 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209 }}
{{refbegin|33em}}
*{{cite journal  | author=Ma J, Dempsey AA, Stamatiou D, ''et al.'' |title=Identifying leukocyte gene expression patterns associated with plasma lipid levels in human subjects. |journal=Atherosclerosis |volume=191 |issue= 1 |pages= 63-72 |year= 2007 |pmid= 16806233 |doi= 10.1016/j.atherosclerosis.2006.05.032 }}
* {{cite journal | vauthors = Zhang Y, Xiang Y | title = Molecular and cellular basis for the unique functioning of Nrf1, an indispensable transcription factor for maintaining cell homoeostasis and organ integrity | journal = The Biochemical Journal | volume = 473 | issue = 8 | pages = 961–1000 | date = April 2016 | pmid = 27060105 | doi = 10.1042/BJ20151182 }}
}}
* {{cite journal | vauthors = Yuan J, Zhang S, Zhang Y | title = Nrf1 is paved as a new strategic avenue to prevent and treat cancer, neurodegenerative and other diseases | journal = Toxicology and Applied Pharmacology | volume = 360 | pages = 273–283 | date = September 2018 | pmid = 30267745 | doi = 10.1016/j.taap.2018.09.037 }}
* {{cite journal | vauthors = Luna L, Skammelsrud N, Johnsen O, Abel KJ, Weber BL, Prydz H, Kolstø AB | title = Structural organization and mapping of the human TCF11 gene | journal = Genomics | volume = 27 | issue = 2 | pages = 237–44 | date = May 1995 | pmid = 7557987 | doi = 10.1006/geno.1995.1037 }}
* {{cite journal | vauthors = Luna L, Johnsen O, Skartlien AH, Pedeutour F, Turc-Carel C, Prydz H, Kolstø AB | title = Molecular cloning of a putative novel human bZIP transcription factor on chromosome 17q22 | journal = Genomics | volume = 22 | issue = 3 | pages = 553–62 | date = Aug 1994 | pmid = 8001966 | doi = 10.1006/geno.1994.1428 }}
* {{cite journal | vauthors = Caterina JJ, Donze D, Sun CW, Ciavatta DJ, Townes TM | title = Cloning and functional characterization of LCR-F1: a bZIP transcription factor that activates erythroid-specific, human globin gene expression | journal = Nucleic Acids Research | volume = 22 | issue = 12 | pages = 2383–91 | date = Jun 1994 | pmid = 8036168 | pmc = 523699 | doi = 10.1093/nar/22.12.2383 }}
* {{cite journal | vauthors = Johnsen O, Skammelsrud N, Luna L, Nishizawa M, Prydz H, Kolstø AB | title = Small Maf proteins interact with the human transcription factor TCF11/Nrf1/LCR-F1 | journal = Nucleic Acids Research | volume = 24 | issue = 21 | pages = 4289–97 | date = Nov 1996 | pmid = 8932385 | pmc = 146217 | doi = 10.1093/nar/24.21.4289 }}
* {{cite journal | vauthors = Toki T, Itoh J, Kitazawa J, Arai K, Hatakeyama K, Akasaka J, Igarashi K, Nomura N, Yokoyama M, Yamamoto M, Ito E | title = Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif | journal = Oncogene | volume = 14 | issue = 16 | pages = 1901–10 | date = Apr 1997 | pmid = 9150357 | doi = 10.1038/sj.onc.1201024 }}
* {{cite journal | vauthors = Novotny V, Prieschl EE, Csonga R, Fabjani G, Baumruker T | title = Nrf1 in a complex with fosB, c-jun, junD and ATF2 forms the AP1 component at the TNF alpha promoter in stimulated mast cells | journal = Nucleic Acids Research | volume = 26 | issue = 23 | pages = 5480–5 | date = Dec 1998 | pmid = 9826775 | pmc = 147998 | doi = 10.1093/nar/26.23.5480 }}
* {{cite journal | vauthors = Murphy P, Kolstø A | title = Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development | journal = Mechanisms of Development | volume = 97 | issue = 1-2 | pages = 141–8 | date = Oct 2000 | pmid = 11025215 | doi = 10.1016/S0925-4773(00)00413-5 }}
* {{cite journal | vauthors = Jiang LQ, Wen SJ, Wang HY, Chen LY | title = Screening the proteins that interact with calpain in a human heart cDNA library using a yeast two-hybrid system | journal = Hypertension Research | volume = 25 | issue = 4 | pages = 647–52 | date = Jul 2002 | pmid = 12358155 | doi = 10.1291/hypres.25.647 }}
* {{cite journal | vauthors = Husberg C, Murphy P, Bjørgo E, Kalland KH, Kolstø AB | title = Cellular localisation and nuclear export of the human bZIP transcription factor TCF11 | journal = Biochimica et Biophysica Acta | volume = 1640 | issue = 2-3 | pages = 143–51 | date = May 2003 | pmid = 12729924 | doi = 10.1016/S0167-4889(03)00041-7 }}
* {{cite journal | vauthors = Newman JR, Keating AE | title = Comprehensive identification of human bZIP interactions with coiled-coil arrays | journal = Science | volume = 300 | issue = 5628 | pages = 2097–101 | date = Jun 2003 | pmid = 12805554 | doi = 10.1126/science.1084648 }}
* {{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = Oct 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}
* {{cite journal | vauthors = Ma J, Dempsey AA, Stamatiou D, Marshall KW, Liew CC | title = Identifying leukocyte gene expression patterns associated with plasma lipid levels in human subjects | journal = Atherosclerosis | volume = 191 | issue = 1 | pages = 63–72 | date = Mar 2007 | pmid = 16806233 | doi = 10.1016/j.atherosclerosis.2006.05.032 }}
{{refend}}
{{refend}}


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Latest revision as of 17:21, 27 October 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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View/Edit Human

Nuclear factor erythroid 2-related factor 1 (Nrf1) also known as nuclear factor erythroid-2-like 1 (NFE2L1) is a protein that in humans is encoded by the NFE2L1 gene.[1][2][3] Since NFE2L1 is referred to as Nrf1, it is often confused with nuclear respiratory factor 1 (Nrf1).

NFE2L1 is a cap ‘n’ collar, basic-leucine zipper (bZIP) transcription factor. Several isoforms of NFE2L1 have been described for both human and mouse genes. NFE2L1 was first cloned in yeast using a genetic screening method. NFE2L1 is ubiquitously expressed, and high levels of transcript are detected in the heart, kidney, skeletal muscle, fat, and brain.[1] Four separate regions — an asparagine/serine/threonine, acidic domains near the N-terminus, and a serine-rich domain located near the CNC motif — are required for full transactivation function of NFE2L1.[4][5][6] NFE2L1 is a key regulator of cellular functions including oxidative stress response, differentiation, inflammatory response, metabolism, cholesterol handling[7] and maintaining proteostasis.

Interactions

NFE2L1 binds DNA as heterodimers with one of small Maf proteins (MAFF, MAFG, MAFK).[8][9][6] NFE2L1 has been shown to interact with C-jun.[10]

Cellular homeostasis

NFE2L1 regulates a wide variety of cellular responses, several of which are related to important aspects of protection from stress stimuli. NFE2L1 is involved in providing cellular protection against oxidative stress through the induction of antioxidant genes. The glutathione synthesis pathway is catalyzed by glutamate-cysteine ligase, which contains the catalytic GCLC and regulatory GCLM, and glutathione synthetase (GSS).[11] Nfe2l1 was found to regulate Gclm and Gss expression in mouse fibroblasts.[12] Gclm was found to be a direct target of Nfe2l1, and Nfe2l1 also regulates Gclc expression through an indirect mechanism.[13][14] Nfe2l1 knockout mice also exhibit down-regulation of Gpx1 and Hmox1, and Nfe2l1 (this gene)-deficient hepatocytes from liver-specific Nfe2l1 knockout mice showed decreased expression of various Gst genes.[15][16] Metallothioenein-1 and Metallothioenein-2 genes, which protect cells against cytotoxicity induced by toxic metals, are also direct targets of Nfe2l1.[17]

Nfe2l1 is also involved in maintaining proteostasis. Brains of mice with conditional knockout of Nfe2l1 in neuronal cells showed decreased proteasome activity and accumulation of ubiquitin-conjugated proteins, and down regulation of genes encoding the 20S core and 19S regulatory sub-complexes of the 26S proteasome.[18] A similar effect on proteasome gene expression and function was observed in livers of mice with Nfe2l1 conditional knockout in hepatocytes.[19] Induction of proteasome genes was also lost in brains and livers of Nfe2l1 conditional knockout mice. Re-establishment of Nfe2l1 function in Nfe2l1 null cells rescued proteasome expression and function, indicating Nfe2l1 was necessary for induction of proteasome genes (bounce-back response) in response to proteasome inhibition.[20] This compensatory up-regulation of proteasome genes in response to proteasome inhibition has also been demonstrated to be Nfe2l1-dependent in various other cell types.[21][22] NFE2L1 was shown to directly bind and activate expression of the PsmB6 gene, which encodes a catalytic subunit of the 20S core.[18][20] Nfe2l1 was also shown to regulate expression of Herpud1 and Vcp/p97, which are components of the ER-associated degradation pathway.[23][22]

Nfe2l1 also plays a role in metabolic processes. Loss of hepatic Nfe2l1 has been shown to result in lipid accumulation, hepatocellular damage, cysteine accumulation, and altered fatty acid composition.[16][24] Glucose homeostasis and insulin secretion have also been found to be under the control of Nfe2l1.[25] Insulin-regulated glycolytic genes—Gck, Aldob, Pgk1, and Pklr, hepatic glucose transporter gene — SLC2A2, and gluconeogenic genes — Fbp1 and Pck1 were repressed in livers of Nfe2l1 transgenic mice.[26] Nfe2l1 may also play a role in maintaining chromosomal stability and genomic integrity by inducing expression of genes encoding components of the spindle assembly and kinetochore.[27] Nfe2l1 has also been shown to sense and respond to excess cholesterol in the ER.[7]

Regulation

NFE2L1 is an ER membrane protein. Its N-terminal domain (NTD) anchors the protein to the membrane. Specifically, amino acid residues 7 to 24 are known to be a hydrophobic domain that serves as a transmembrane region.[28] The concerted mechanism of HRD1, a member of E3-ubiquitin ligase family, and p97/VCP1 was found to play an important role in the degradation of NFE2L1 through the ER Associated Degradation (ERAD) pathway and the release of NFE2L1 from the ER membrane.[21][29][30] NFE2L1 is also regulated by other ubiquitin ligases and kinases. FBXW7, a member of the SCF ubiquitin ligase family, targets NFE2L1 for proteolytic degradation by the proteasome.[31] FBXW7 requires the Cdc4 phosphodegron domain within NFE2L1 to be phosphorylated via Glycogen Kinase 3.[32] Casein Kinase 2 was shown to phosphorylate Ser497 of NFE2L1, which attenuates the activity of NFE2L1 on proteasome gene expression.[33] NFE2L1 also interacts with another member of the SCF ligase ubiquitin family known as β-TrCP. β-TrCP also binds to the DSGLC motif, a highly conserved region of CNC-bZIP proteins, in order to poly-ubiquitinate NFE2L1 prior to its proteolytic degradation.[29] Phosphorylation of Ser599 by protein kinase A enables NFE2L1 and C/EBP-β to dimerize to repress DSPP expression during odontoblast differentiation.[34] NFE2L1 expression and activation is also controlled by cellular stresses. Oxidative stress induced by arsenic and t-butyl hydroquinone leads to accumulation of NFE2L1 protein inside the nucleus as well as higher activation on antioxidant genes.[5][35] Treatment with an ER stress inducer tunicamycin was shown to induce accumulation of NFE2L1 inside the nucleus; however, it was not associated with increased activity, suggesting further investigation is needed to elucidate the role of ER stress on NFE2L1.[36][5] Hypoxia was also shown to increase the expression of NFE2L1 while attenuating expression of the p65 isoform of NFE2L1.[37] Growth factors affect expression of NFE2L1 through a mTORC and SREBP-1 mediated pathway. Growth factors induce higher activity of mTORC, which then promotes activity of its downstream protein SREBP-1, a transcription factor for NFE2L1.[38][39]

Animal studies

Loss and gain of function studies in mice showed that dysregulation of Nfe2l1 leads to pathological states that could have relevance in human diseases. Nfe2l1 is crucial for embryonic development and survival of hepatocytes during development.[2][15] Loss of Nfe2l1 in mouse hepatocytes leads to steatosis, inflammation, and tumorigenesis.[16] Nfe2l1 is also necessary for neuronal homeostasis.[18] Loss of Nfe2l1 function is also associated with insulin resistance. Mice with conditional deletion of Nfe2l1 in pancreatic β-cells exhibited severe fasting hyperinsulinemia and glucose intolerance, suggesting that Nfe2l1 may play a role in the development of type-2 diabetes[25] Future studies may provide therapeutic efforts involving Nfe2l1 for cancer, neurodegeneration, and metabolic diseases.

References

  1. ↑ 1.0 1.1 Chan JY, Han XL, Kan YW (Dec 1993). "Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast". Proceedings of the National Academy of Sciences of the United States of America. 90 (23): 11371–5. doi:10.1073/pnas.90.23.11371. PMC 47984. PMID 8248256.
  2. ↑ 2.0 2.1 Chan JY, Kwong M, Lu R, Chang J, Wang B, Yen TS, Kan YW (Mar 1998). "Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice". The EMBO Journal. 17 (6): 1779–87. doi:10.1093/emboj/17.6.1779. PMC 1170525. PMID 9501099.
  3. ↑ "Entrez Gene: NFE2L1 nuclear factor (erythroid-derived 2)-like 1".
  4. ↑ Husberg C, Murphy P, Martin E, Kolsto AB (May 2001). "Two domains of the human bZIP transcription factor TCF11 are necessary for transactivation". The Journal of Biological Chemistry. 276 (21): 17641–52. doi:10.1074/jbc.M007951200. PMID 11278371.
  5. ↑ 5.0 5.1 5.2 Zhang Y, Lucocq JM, Hayes JD (Mar 2009). "The Nrf1 CNC/bZIP protein is a nuclear envelope-bound transcription factor that is activated by t-butyl hydroquinone but not by endoplasmic reticulum stressors". The Biochemical Journal. 418 (2): 293–310. doi:10.1042/BJ20081575. PMID 18990090.
  6. ↑ 6.0 6.1 Wang W, Kwok AM, Chan JY (Aug 2007). "The p65 isoform of Nrf1 is a dominant negative inhibitor of ARE-mediated transcription". The Journal of Biological Chemistry. 282 (34): 24670–8. doi:10.1074/jbc.M700159200. PMID 17609210.
  7. ↑ 7.0 7.1 Widenmaier SB, Snyder NA, Nguyen TB, Arduini A, Lee GY, Arruda AP, Saksi J, Bartelt A, Hotamisligil GS (November 2017). "NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis". Cell. 171 (5): 1094–1109.e15. doi:10.1016/j.cell.2017.10.003. PMID 29149604.
  8. ↑ Marini MG, Chan K, Casula L, Kan YW, Cao A, Moi P (Jun 1997). "hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2". The Journal of Biological Chemistry. 272 (26): 16490–7. doi:10.1074/jbc.272.26.16490. PMID 9195958.
  9. ↑ Johnsen O, Murphy P, Prydz H, Kolsto AB (Jan 1998). "Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription". Nucleic Acids Research. 26 (2): 512–20. doi:10.1093/nar/26.2.512. PMC 147270. PMID 9421508.
  10. ↑ Venugopal R, Jaiswal AK (Dec 1998). "Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes". Oncogene. 17 (24): 3145–56. doi:10.1038/sj.onc.1202237. PMID 9872330.
  11. ↑ Lu SC (2009). "Regulation of glutathione synthesis". Molecular Aspects of Medicine. 30 (1–2): 42–59. doi:10.1016/j.mam.2008.05.005. PMC 2704241. PMID 18601945.
  12. ↑ Kwong M, Kan YW, Chan JY (Dec 1999). "The CNC basic leucine zipper factor, Nrf1, is essential for cell survival in response to oxidative stress-inducing agents. Role for Nrf1 in gamma-gcs(l) and gss expression in mouse fibroblasts". The Journal of Biological Chemistry. 274 (52): 37491–8. doi:10.1074/jbc.274.52.37491. PMID 10601325.
  13. ↑ Myhrstad MC, Husberg C, Murphy P, Nordström O, Blomhoff R, Moskaug JO, Kolstø AB (Jan 2001). "TCF11/Nrf1 overexpression increases the intracellular glutathione level and can transactivate the gamma-glutamylcysteine synthetase (GCS) heavy subunit promoter". Biochimica et Biophysica Acta. 1517 (2): 212–9. doi:10.1016/s0167-4781(00)00276-1. PMID 11342101.
  14. ↑ Yang H, Magilnick N, Lee C, Kalmaz D, Ou X, Chan JY, Lu SC (Jul 2005). "Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1". Molecular and Cellular Biology. 25 (14): 5933–46. doi:10.1128/MCB.25.14.5933-5946.2005. PMC 1168815. PMID 15988009.
  15. ↑ 15.0 15.1 Chen L, Kwong M, Lu R, Ginzinger D, Lee C, Leung L, Chan JY (Jul 2003). "Nrf1 is critical for redox balance and survival of liver cells during development". Molecular and Cellular Biology. 23 (13): 4673–86. doi:10.1128/mcb.23.13.4673-4686.2003. PMC 164851. PMID 12808106.
  16. ↑ 16.0 16.1 16.2 Xu Z, Chen L, Leung L, Yen TS, Lee C, Chan JY (Mar 2005). "Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia". Proceedings of the National Academy of Sciences of the United States of America. 102 (11): 4120–5. doi:10.1073/pnas.0500660102. PMC 554825. PMID 15738389.
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  18. ↑ 18.0 18.1 18.2 Lee CS, Lee C, Hu T, Nguyen JM, Zhang J, Martin MV, Vawter MP, Huang EJ, Chan JY (May 2011). "Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration". Proceedings of the National Academy of Sciences of the United States of America. 108 (20): 8408–13. doi:10.1073/pnas.1019209108. PMC 3100960. PMID 21536885.
  19. ↑ Lee CS, Ho DV, Chan JY (Aug 2013). "Nuclear factor-erythroid 2-related factor 1 regulates expression of proteasome genes in hepatocytes and protects against endoplasmic reticulum stress and steatosis in mice". The FEBS Journal. 280 (15): 3609–20. doi:10.1111/febs.12350. PMC 3835180. PMID 23702335.
  20. ↑ 20.0 20.1 Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ (Apr 2010). "Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells". Molecular Cell. 38 (1): 17–28. doi:10.1016/j.molcel.2010.02.029. PMC 2874685. PMID 20385086.
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  22. ↑ 22.0 22.1 Sha Z, Goldberg AL (Jul 2014). "Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97". Current Biology. 24 (14): 1573–83. doi:10.1016/j.cub.2014.06.004. PMC 4108618. PMID 24998528.
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  24. ↑ Tsujita T, Peirce V, Baird L, Matsuyama Y, Takaku M, Walsh SV, Griffin JL, Uruno A, Yamamoto M, Hayes JD (Oct 2014). "Transcription factor Nrf1 negatively regulates the cystine/glutamate transporter and lipid-metabolizing enzymes". Molecular and Cellular Biology. 34 (20): 3800–16. doi:10.1128/MCB.00110-14. PMC 4187719. PMID 25092871.
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  32. ↑ Biswas M, Kwong EK, Park E, Nagra P, Chan JY (Aug 2013). "Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) and inhibits pro-survival function of Nrf1". Experimental Cell Research. 319 (13): 1922–31. doi:10.1016/j.yexcr.2013.04.013. PMC 4186750. PMID 23623971.
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