NFE2L3

Nuclear factor (erythroid 2)-like factor 3, also known as NFE2L3 or 'NRF3', is a transcription factor that in humans is encoded by the Nfe2l3 gene.[5][6]

NFE2L3
Identifiers
Aliases	NFE2L3, NRF3, nuclear factor, erythroid 2 like 3
External IDs	OMIM: 604135 MGI: 1339958 HomoloGene: 3168 GeneCards: NFE2L3
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7p15.2 Start 26,152,198 bp[1] End 26,187,137 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 B3|6 24.84 cM Start 51,432,670 bp[2] End 51,458,768 bp[2]
Gene ontology Molecular function • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • DNA binding • GO:0001105 transcription coactivator activity • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific • GO:0001948 protein binding • transcription regulatory region sequence-specific DNA binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • cytoplasm • cell nucleus Biological process • regulation of transcription from RNA polymerase II promoter • positive regulation of transcription, DNA-templated • regulation of transcription, DNA-templated • negative regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • transcription, DNA-templated Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9603	18025
Ensembl	ENSG00000050344	ENSMUSG00000029832
UniProt	Q9Y4A8	Q9WTM4
RefSeq (mRNA)	NM_004289	NM_010903
RefSeq (protein)	NP_004280	NP_035033
Location (UCSC)	Chr 7: 26.15 – 26.19 Mb	Chr 6: 51.43 – 51.46 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Nrf3 is a basic leucine zipper (bZIP) transcription factor belonging to the Cap ‘n’ Collar (CNC) family of proteins.[7] In 1989, the first CNC transcription factor NFE2L2 was identified. Subsequently, several related proteins were identified, including NFE2L1 and NFE2L3, in different organisms such as humans, mice, and zebrafish.[8] These proteins are specifically encoded in the humans by Nfe2l1 and Nfe2l3 genes respectively.[9][10]

Gene

The Nfe2l3 gene was mapped to the chromosomal location 7p15-p14 by fluorescence in situ hybridization (FISH).[9] It covers 34.93 kB from base 26191830 to 26226754 on the direct DNA strand with an exon count of 4. The gene is found near the HOXA gene cluster, similar to the clustering of p45 NF-E2, NFE2L1, and NFE2L2 near HOXC, HOXB, and HOXD genes respectively.[7][9] This implies that all four genes were likely derived from a single ancestral gene which was duplicated alongside the ancestral HOX cluster, diverging to give rise to four closely related transcription factors.[9]

The human Nfe2l3 gene encodes a 694 amino acid residue sequence.[7][9] From bioinformatic analysis, it has been observed that the NRF3 protein shows a high degree of conservation through its evolutionary pathway from zebrafish to humans. Key conserved domains such as N-terminal homology box 1 (NHB1), N-terminal homology box 2 (NHB2), and the CNC domain allude to the conserved functional properties of this transcription factor.[11]

Sub-cellular location

NRF3 is a membrane bound glycoprotein that can be targeted specifically to the endoplasmic reticulum (ER) and the nuclear membrane.[9] Biochemical studies have identified three migrating endogenous forms of NRF3 protein – A, B, and C – which are constitutively degraded by several proteolytic mechanisms.[9][12] It is known that the "A" form is glycosylated, whereas "B" is unglycosylated, and "C" is generated by cleavage of "B."[7][9] In total, seven potential sites of N-linked glycosylation [7] has been observed in the center portion of the NRF3 protein. However, further details of the three forms' location, regulation, and function in each cellular compartment remain unknown.

Protein expression levels

Expression levels of NRF3 proteins are highest in the placenta.[13] more specifically in the chorionic villi (at week 12 of gestation period) [14] Expression appears to be specific to primary placental cytotrophoblasts, not placental fibroblasts. Along with the placenta, the expression of this protein has also been observed in human choriocarcinoma cell lines which have been derived from trophoblastic tumours of the placenta. NFE2L2 has also been found in the heart, brain, lungs, kidney, pancreas, colon, thymus, leukocytes, and spleen.[15] Very low levels of expression were found in human megakaryocytes and erythrocytes, and NRF3 expression was not observed in reproductive organs of either sex.[9][16]

Function

The specific functions of the NRF3 protein are still unknown, but some putative functional properties have been inferred from those of NFE2L1 due to their structural similarity. It is known that NRF3 can heterodimerize with small musculo-aponeurotic fibro-sarcoma (MAF genes) factors to bind antioxidant response elements in target genes.[17]

Associated diseases

RNA microarray data has shown NRF3's involvement in various malignancies, with over-expression observed in Hodgkin's lymphoma, non-Hodgkin lymphoma, and mantle cell lymphoma.[18] NRF3 expression is also elevated in human breast cancer cells and testicular carcinoma, implying that NRF3 may play a role in inducing carcinogenesis.[19]

References

1. GRCh38: Ensembl release 89: ENSG00000050344 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029832 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: nuclear factor (erythroid-derived 2)-like 3".
6. Kobayashi A, Ito E, Toki T, Kogame K, Takahashi S, Igarashi K, Hayashi N, Yamamoto M (March 1999). "Molecular cloning and functional characterization of a new Cap'n' collar family transcription factor Nrf3". The Journal of Biological Chemistry. 274 (10): 6443–52. doi:10.1074/jbc.274.10.6443. PMID 10037736.
7. Landschulz WH, Johnson PF, McKnight SL (June 1988). "The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins". Science. 240 (4860): 1759–64. doi:10.1126/science.3289117. JSTOR 1701639. PMID 3289117.
8. Derjuga A, Gourley TS, Holm TM, Heng HH, Shivdasani RA, Ahmed R, Andrews NC, Blank V (April 2004). "Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus". Molecular and Cellular Biology. 24 (8): 3286–94. doi:10.1128/mcb.24.8.3286-3294.2004. PMC 381672. PMID 15060151.
9. Chevillard G, Blank V (October 2011). "NFE2L3 (NRF3): the Cinderella of the Cap'n'Collar transcription factors". Cellular and Molecular Life Sciences. 68 (20): 3337–48. doi:10.1007/s00018-011-0747-x. PMID 21687990.
10. Caterina JJ, Donze D, Sun CW, Ciavatta DJ, Townes TM (June 1994). "Cloning and functional characterization of LCR-F1: a bZIP transcription factor that activates erythroid-specific, human globin gene expression". Nucleic Acids Research. 22 (12): 2383–91. doi:10.1093/nar/22.12.2383. PMC 523699. PMID 8036168.
11. Xiao Q, Pepe AE, Wang G, Luo Z, Zhang L, Zeng L, Zhang Z, Hu Y, Ye S, Xu Q (March 2012). "Nrf3-Pla2g7 interaction plays an essential role in smooth muscle differentiation from stem cells". Arteriosclerosis, Thrombosis, and Vascular Biology. 32 (3): 730–44. doi:10.1161/ATVBAHA.111.243188. PMID 22247257.
12. Chowdhury AMMA, Katoh H, Hatanaka A, Iwanari H, Nakamura N, Hamakubo T, Natsume T, Waku T, Kobayashi A (2017). "Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control cancer cell proliferation". Sci Rep. 7 (1): 12494. doi:10.1038/s41598-017-12675-y. PMC 5624902. PMID 28970512.CS1 maint: multiple names: authors list (link)
13. Chénais B, Derjuga A, Massrieh W, Red-Horse K, Bellingard V, Fisher SJ, Blank V (January 2005). "Functional and placental expression analysis of the human NRF3 transcription factor". Molecular Endocrinology. 19 (1): 125–37. doi:10.1210/me.2003-0379. PMID 15388789.
14. Chevillard G, Paquet M, Blank V (February 2011). "Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma". Blood. 117 (6): 2005–8. doi:10.1182/blood-2010-02-271460. PMID 21148084.
15. Martín-Montalvo, A.; Villalba, J. M.; Navas, P.; de Cabo, R. (3 February 2011). "NRF2, cancer and calorie restriction" (PDF). Oncogene. 30 (5): 505–520. doi:10.1038/onc.2010.492. ISSN 1476-5594. PMC 4684645. PMID 21057541.
16. Venugopal R, Jaiswal AK (December 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.
17. Blank V, Andrews NC (November 1997). "The Maf transcription factors: regulators of differentiation". Trends in Biochemical Sciences. 22 (11): 437–41. doi:10.1016/s0968-0004(97)01105-5. PMID 9397686.
18. Willenbrock K, Küppers R, Renné C, Brune V, Eckerle S, Weidmann E, Bräuninger A, Hansmann ML (May 2006). "Common features and differences in the transcriptome of large cell anaplastic lymphoma and classical Hodgkin's lymphoma". Haematologica. 91 (5): 596–604. PMID 16670065.
19. Hayes JD, McMahon M (December 2001). "Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention". Cancer Letters. 174 (2): 103–13. doi:10.1016/s0304-3835(01)00695-4. PMID 11689285.

Further reading

• Davila S, Froeling FE, Tan A, Bonnard C, Boland GJ, Snippe H, Hibberd ML, Seielstad M (April 2010). "New genetic associations detected in a host response study to hepatitis B vaccine". Genes and Immunity. 11 (3): 232–8. doi:10.1038/gene.2010.1. PMID 20237496.
• Sankaranarayanan K, Jaiswal AK (December 2004). "Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene". The Journal of Biological Chemistry. 279 (49): 50810–7. doi:10.1074/jbc.M404984200. PMID 15385560.
• Chénais B, Derjuga A, Massrieh W, Red-Horse K, Bellingard V, Fisher SJ, Blank V (January 2005). "Functional and placental expression analysis of the human NRF3 transcription factor". Molecular Endocrinology. 19 (1): 125–37. doi:10.1210/me.2003-0379. PMID 15388789.
• Nouhi Z, Chevillard G, Derjuga A, Blank V (November 2007). "Endoplasmic reticulum association and N-linked glycosylation of the human Nrf3 transcription factor". FEBS Letters. 581 (28): 5401–6. doi:10.1016/j.febslet.2007.10.041. PMID 17976382.
• Terui K, Takahashi Y, Kitazawa J, Toki T, Yokoyama M, Ito E (December 2000). "Expression of transcription factors during megakaryocytic differentiation of CD34+ cells from human cord blood induced by thrombopoietin". The Tohoku Journal of Experimental Medicine. 192 (4): 259–73. doi:10.1620/tjem.192.259. PMID 11286316.
• "Toward a complete human genome sequence". Genome Research. 8 (11): 1097–108. November 1998. doi:10.1101/gr.8.11.1097. PMID 9847074.
• Zhang Y, Kobayashi A, Yamamoto M, Hayes JD (January 2009). "The Nrf3 transcription factor is a membrane-bound glycoprotein targeted to the endoplasmic reticulum through its N-terminal homology box 1 sequence". The Journal of Biological Chemistry. 284 (5): 3195–210. doi:10.1074/jbc.M805337200. PMID 19047052.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.