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FLASH GENE

Symbol

NFE2L1

contributors: mct/shn - updated : 07-03-2015

HGNC name	nuclear factor (erythroid-derived 2)-like 1
HGNC id	7781

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	17q21.32      Physical location : 46.125.685 - 46.138.906
Synonym name	NF-E2-related factor 1
	NFE2-related factor 1
	TCF-11
	locus control region-factor 1
	nuclear factor erythroid 2-related factor 1
	nuclear factor, erythroid derived 2, like 1
	transcription factor 11 (basic leucine zipper type)
	transcription factor HBZ17; transcription factor LCR-F1
Synonym symbol(s)	TCF11, BRF1, LCR-F1, HBZ17, FLJ00380, NRF-1, NRF1

DNA

TYPE	functioning gene
STRUCTURE	13.22 kb     6 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	cen - D17S1859 - D17S1785 - NFE2L1 - D17S958 - D17S1150 - qter

regionally located

physically linked to BTR (PMID: 7557987)

RNA

TRANSCRIPTS	type	messenger

text	several mRNA isoforms generated by alternative splicing (Luna), at least six variants (PMID: 9826775)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003204 6 - 4891 NP_003195 84.7 772 - 2007 16806233

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Homo sapiens Digestive mouth tongue     highly Endocrine thyroid       highly Nervous brain       highly Homo sapiens Urinary kidney       highly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal   highly Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES		basic
STRUCTURE

motifs/domains	NTD (N-terminal domain), AAs 1–124, with a leucine-rich sequence, called NHB1 (N-terminal homology box 1, which tethers NFE2L1 to the ER (endoplasmic reticulum , and an NHB2 (N-terminal
	homology box 2; AAs 82–106), and region located between NHB1 and NHB2 includes the SAS and CRACs motifs (SAS, CRACs and NHB2 subdomains are transiently translocated into the ER lumen)
	basic leucine zipper (bZIP) motif
	two putative Cdc4 CPD motifs
	two separate domain, N terminal acidic domain and a serine-rich stretch adjacent to the CNC bZIP domain required for transactivation
	a nuclear export signal (NES) localised in the N-terminus responsible for the active nuclear export of the protein
	a large C-terminal portion is dynamically retrotranslocated from
	the ER lumen to the cytoplasmic and/or nucleoplasmic sides

conjugated

ubiquitinated

HOMOLOGY

interspecies	ortholog to Nfe2l1, Mus musculus
	ortholog to Nfe2l1, Rattus nrvegicus
	ortholog to NFE2L1, Pan troglodytes
	ortholog to nfe2l1, Danio rerio

intraspecies

paralog to NEF2

Homologene

FAMILY	Cap'n'collar (CNC) family of transcription factor
	BZIP family

CATEGORY

immunity/defense , regulatory , transcription factor , transport

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,nucleus
	intracellular,nuclear envelope
text	NHB1 (N-terminal homology box 1) sequence is required to anchor it to the endoplasmic reticulum
	an integral membrane protein which can be sorted from the ER to the nuclear envelope
	tethered to ER (endoplasmic reticulum) and nuclear envelope membranes

basic FUNCTION	activating erythroid specific, globin gene expression
	regulating expression of ferritin genes and heme synthesis
	may be playing a distinct functional role in regulating antioxidant response element (ARE)-driven genes
	playing an essential role during fetal liver hematopoiesis
	a novel transcriptional inhibitor of the human ACCbeta gene promoter in the mammalian heart
	a pivotal transcriptional modulator controlling gene expression of mitochondrial proteins
	CNC (cap'n'collar) bZIP (basic-region leucine zipper) transcription factor that is tethered to ER (endoplasmic reticulum) and nuclear envelope membranes through its N-terminal signal peptide
	can adopt several topologies within membranes that are determined by its NTD (N-terminal domain)
	plays a critical role in regulating the expression of many antioxidant response element (ARE)-dependent genes
	in response to proteasome inhibition, plays a central role in upregulating the proteasome system via an ERAD-dependent feedback loop
	up-regulation of NFE2L1, together with other FBXW7 substrates, such as JUN, MYC, and cyclin E, promotes tumorigenesis
	role of NFE2L1 in UVB-induced DNA damage repair, suggesting that NFE2L1 is a tumor suppressor in the skin
	is a novel regulator of the LPIN1 and PPPARGC1B genes, providing new insights into the NFE2L1 function in hepatic lipid metabolism
	may play a role in maintaining genomic integrity, and NFE2L1 dysregulation may induce tumorigenesis
	plays an integral role in the maintenance of proteasome function in hepatocytes and in the prevention of liver steatosis development
	promotes glial fate under direct SOX9 regulatory control

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development , cell to cell transport

text	circulation, intercellular transport

PATHWAY

metabolism

porphyrin/heme

signaling

a component	forming a transcription factor complex with several AP1 binding proteins
	forms a ternary complex containing both KEAP1 and NFE2L2, in which the dimeric KEAP1 protein simultaneously binds both PGAM5 and NFE2L2 through their conserved E(S/T)GE motifs

INTERACTION

DNA

RNA

small molecule

protein	p45 NF-E2, ECH and Fos
	v-maf musculoaponeurotic fibrosarcoma oncogene homolog G (avian), MafG
	c-Jun, Jun-B and Jun-D proteins
	FBXW7 is a regulator of NFE2L1 expression, suggesting a novel function of FBXW7 in cellular stress response (FBXW7 regulates NFE2L1 via a CPD motif)
	NFE2L1 binds to the antioxidant response elements (AREs) in regulatory regions of the LPIN1 and PPARGC1B genes
	GSK3B interacts with NFE2L1 and phosphorylates the CDC4 phosphodegron domain (CPD) in NFE2L1 , and regulates NFE2L1 expression and cell survival function in response to stress activation
	proteasome-mediated processing of NFE2L1 is essential for coordinate induction of all proteasome subunits and VCP

cell & other

REGULATION

inhibited by

negatively controlled by its NTD (N-terminal domain) that lies between amino acids 1 and 124

Other	glycosylated through its Asn/Ser/Thr-rich domain, between AAs 296 and 403 (glycosylation not necessary to retain it in the ER)
	ubiquitinated and stabilized by proteasomal inhibition, and proteasome pathway plays a role in regulating its stability in the cell

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       loss of function NFE2L1 deficiency leads to the reduced expression of the transcriptional coactivator genes LPIN1 and PPARGC1B

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     NFE2L1-mediated proteasome homeostasis could be an attractive target for therapeutic intervention in cancer

ANIMAL & CELL MODELS

	disruption of the transcription factor Nrf-1 results in anemia and embryonic lethality in mice
	mice with somatic inactivation of nrf1 in the liver develop hepatic cancer whose livers exhibit steatosis, apoptosis, necrosis, inflammation, and fibrosis