NFE2L3 explained

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.[1] [2]

Nrf3 is a basic leucine zipper (bZIP) transcription factor belonging to the Cap ‘n’ Collar (CNC) family of proteins.[3] 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.[4] These proteins are specifically encoded in the humans by Nfe2l1 and Nfe2l3 genes respectively.[5] [6]

Gene

The Nfe2l3 gene was mapped to the chromosomal location 7p15-p14 by fluorescence in situ hybridization (FISH).[5] 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.[3] [5] 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.[5]

The human Nfe2l3 gene encodes a 694 amino acid residue sequence.[3] [5] 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.[7]

Sub-cellular location

NRF3 is a membrane bound glycoprotein that can be targeted specifically to the endoplasmic reticulum (ER) and the nuclear membrane.[5] Biochemical studies have identified three migrating endogenous forms of NRF3 proteinA, B, and Cwhich are constitutively degraded by several proteolytic mechanisms.[5] [8] It is known that the "A" form is glycosylated, whereas "B" is unglycosylated, and "C" is generated by cleavage of "B."[3] [5] In total, seven potential sites of N-linked glycosylation [3] 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.[9] more specifically in the chorionic villi (at week 12 of gestation period) [10] 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.[11] Very low levels of expression were found in human megakaryocytes and erythrocytes, and NRF3 expression was not observed in reproductive organs of either sex.[5] [12]

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.[13]

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.[14] NRF3 expression is also elevated in human breast cancer cells and testicular carcinoma, implying that NRF3 may play a role in inducing carcinogenesis.[15]

Further reading

Notes and References

  1. Web site: Entrez Gene: nuclear factor (erythroid-derived 2)-like 3.
  2. Kobayashi A, Ito E, Toki T, Kogame K, Takahashi S, Igarashi K, Hayashi N, Yamamoto M . Molecular cloning and functional characterization of a new Cap'n' collar family transcription factor Nrf3 . The Journal of Biological Chemistry . 274 . 10 . 6443–52 . March 1999 . 10037736 . 10.1074/jbc.274.10.6443 . free .
  3. Landschulz WH, Johnson PF, McKnight SL . The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins . Science . 240 . 4860 . 1759–64 . June 1988 . 3289117 . 1701639 . 10.1126/science.3289117. 1988Sci...240.1759L .
  4. Derjuga A, Gourley TS, Holm TM, Heng HH, Shivdasani RA, Ahmed R, Andrews NC, Blank V . Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus . Molecular and Cellular Biology . 24 . 8 . 3286–94 . April 2004 . 15060151 . 381672 . 10.1128/mcb.24.8.3286-3294.2004.
  5. Chevillard G, Blank V . NFE2L3 (NRF3): the Cinderella of the Cap'n'Collar transcription factors . Cellular and Molecular Life Sciences . 68 . 20 . 3337–48 . October 2011 . 21687990 . 10.1007/s00018-011-0747-x . 25006101 . 11114735 .
  6. Caterina JJ, Donze D, Sun CW, Ciavatta DJ, Townes TM . 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 . June 1994 . 8036168 . 10.1093/nar/22.12.2383 . 523699.
  7. Xiao Q, Pepe AE, Wang G, Luo Z, Zhang L, Zeng L, Zhang Z, Hu Y, Ye S, Xu Q . Nrf3-Pla2g7 interaction plays an essential role in smooth muscle differentiation from stem cells . Arteriosclerosis, Thrombosis, and Vascular Biology . 32 . 3 . 730–44 . March 2012 . 22247257 . 10.1161/ATVBAHA.111.243188 . free .
  8. ((Chowdhury AMMA)), Katoh H, Hatanaka A, Iwanari H, Nakamura N, Hamakubo T, Natsume T, Waku T, Kobayashi A. Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control cancer cell proliferation. . Sci Rep . 2017 . 7 . 1 . 12494 . 28970512 . 10.1038/s41598-017-12675-y . 5624902. 2017NatSR...712494C .
  9. Chénais B, Derjuga A, Massrieh W, Red-Horse K, Bellingard V, Fisher SJ, Blank V . Functional and placental expression analysis of the human NRF3 transcription factor . Molecular Endocrinology . 19 . 1 . 125–37 . January 2005 . 15388789 . 10.1210/me.2003-0379. free .
  10. Chevillard G, Paquet M, Blank V . Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma . Blood . 117 . 6 . 2005–8 . February 2011 . 21148084 . 10.1182/blood-2010-02-271460 . free .
  11. Martín-Montalvo A, Villalba JM, Navas P, de Cabo R . NRF2, cancer and calorie restriction . Oncogene . 30 . 5 . 505–520 . February 2011 . 21057541 . 4684645 . 10.1038/onc.2010.492 .
  12. Venugopal R, Jaiswal AK . 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 . December 1998 . 9872330 . 10.1038/sj.onc.1202237 . free .
  13. Blank V, Andrews NC . The Maf transcription factors: regulators of differentiation . Trends in Biochemical Sciences . 22 . 11 . 437–41 . November 1997 . 9397686 . 10.1016/s0968-0004(97)01105-5.
  14. Willenbrock K, Küppers R, Renné C, Brune V, Eckerle S, Weidmann E, Bräuninger A, Hansmann ML . Common features and differences in the transcriptome of large cell anaplastic lymphoma and classical Hodgkin's lymphoma . Haematologica . 91 . 5 . 596–604 . May 2006 . 16670065 .
  15. Hayes JD, McMahon M . Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention . Cancer Letters . 174 . 2 . 103–13 . December 2001 . 11689285 . 10.1016/s0304-3835(01)00695-4.

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