||Chr 7: 26.15 – 26.19 Mb
||Chr 6: 51.43 – 51.46 Mb
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.
This protein is a basic leucine zipper transcription factor belonging to the Cap ‘n’ Collar (CNC) family of proteins. In 1989, the first CNC transcription factor was identified, namely NFE2L2. After that, several other protein members have also been identified over the years like NRF1 and NRF3 in different organisms like humans, mice and zebrafish. These proteins are specifically encoded in the humans by Nfe2l1 and Nfe2l3 genes respectively.
The mapping of Nfe2l3 gene by Fluorescence In-Situ Hybridisation (FISH) technique revealed its chromosomal location being 7p15-p14. It covers 34.93 kB from 26191830 to 26226754 on the direct DNA strand with an exon count of 4. The gene maps near the HOXA gene cluster which is similar to the genetic loci of p45 NFE2, NFE2L1 and NFE2L2 and are further clustered around HOXC, HOXB and HOXD genes respectively. This information tells us that all these genes have been derived from a single ancestral gene which is closely localised to HOX cluster and from there, these genes have diverged to four closely related transcription factors.
The human NFE2L3 encodes for a 694 base pairs amino acid protein. From Bioinformatics analysis, it has been observed that NFE2L3 protein shows a high degree of conservation through its evolutionary pathway from zebrafish to humans having key domains like N-terminal Homology Box 1 (NHB1), N-terminal Homology Box 2 (NHB2) and CNC domain. These conserved domains help to identify the functional properties of this protein.
NFE2L3 is a membrane bound glycoprotein that is targeted specifically to the endoplasmic reticulum (ER) and the nuclear membrane. From biochemical studies, it has been seen that there are three different migrating endogenous forms of NFE2L3 protein which are essentially short lived - the first one being migrating "A" form, the second one being an intermediate "B" form and the third one being a fast migrating "C" form. Using PNGase F and Endoglycosidase H enzymes, it was revealed that "A" form is glycosylated whereas "B" and "C" forms are unglycosylated. In total, seven potential sites of N-linked glycosylation  has been observed in the centre portion of this NFE2L3 protein, however the exact information on each of the forms are yet to be identified.
Protein Expression Levels
The expression levels of NFE2L3 proteins are found to be highest in placenta. more specifically in the chorionic villi (at week 12 of gestation period)  The expression levels are more common in primary placental cytotrophoblast, but not in 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 found in the placenta. Other variety of tissue regions that have experienced the expression of NFE2L3 protein has been Heart, Brain, Lungs, Kidney, Pancreas, Colon, Thymus, Leukocytes as well as Spleen. Very low levels of expression were found in case of Human Megakaryocytes and Erythrocytes whereas no expression was found in case of reproductive organs found in both the sexes.
The specific functions of NFE2L3 protein are still unknown, but since the structural information has been found to be similar to that of NFE2L1 protein, some functional properties can be deciphered from that.
This encoded protein NFE2L3 heterodimerizes with small musculo-aponeurotic fibro-sarcoma (MAF Genes) factors to bind antioxidant response elements in target genes. Several in vivo data has revealed that NFE2L3 is known to protect the body against carcinogen-induced lymphomagenesis. But, not enough information has been derived and researchers are still working on it.
Recently, a few reports have opened new avenues for NFE2L3 protein. But, all these proposals are still in its niche stage and needs concrete evidences to reveal its actual functionality.
A series of Gene chip analysis array data of NFE2L3 has shown its involvement in various malignancies with over-expressions like Hodgkin Lymphoma, Non-Hodgkin lymphoma cell lineages and Mantle cell lymphoma. Along with that, there has also been an up-regulation of mRNA levels in human breast cancer cells and testicular carcinoma tissues which reveals that NFE2L3 plays a role in inducing carcinogenesis.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.