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FLASH GENE

Symbol

NR5A2

contributors: mct - updated : 19-02-2018

HGNC name	nuclear receptor subfamily 5, group A, member 2
HGNC id	7984

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Rna function	mRNA is expressed at much higher levels than NR5A1 mRNA in the human gonad
Type	restricted

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 Digestive intestine       moderately Homo sapiens   liver       moderately Homo sapiens Fetal   pancreas exocrine       moderately Homo sapiens Endocrine pancreas         Homo sapiens Fetal Nervous brain diencephalon hypothalamus   highly Reproductive female system ovary     moderately Homo sapiens   male system testis     highly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose       Homo sapiens Epithelial secretory glandular exocrine   Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Reproductive granulosa cell Homo sapiens Reproductive Leydig cell Homo sapiens Reproductive spermatozoa Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text	yolk sac, liver

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminal modulator domain
	nuclear localization of the NR5A2 is mediated by two nuclear localization signals (NLSs) that are karyopherin/importin-dependent
	a central bipartite zinc finger
	calreticulin (CRT)-dependent NES (nuclear export signal) which is not only required for cytoplasmic trafficking, but also essential for correct protein folding to avoid misfolding-induced aggregation
	DNA binding domain
	one FTZ-F1 box
	a C terminal ligand domain

HOMOLOGY

interspecies

homolog to drosophila Ftz-f1

intraspecies

homolog to orphan receptor fushi tarazu factor 1 (FTZF1)

Homologene

FAMILY	nuclear receptor subfamily 5,group A
	fushi tarazu factor subfamily

CATEGORY

transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm

basic FUNCTION	contributing to the regulation of pancreas specific genes and to the embryonic development
	nuclear receptor, activating the alpha 1 fetoprotein gene in early differentiating hepatocytes
	activating the enhancer II of hepatitis B virus
	playing an important role in the regulation of gonadal function
	playing a role in the initiation of intestinal tumorigenesis both by affecting cell cycle control as well as through its impact on inflammatory pathways
	may be playing an essential role in embryogenesis and cholesterol homeostasis
	playing an important role in the development of breast carcinomas
	involved in intestinal lipid homeostasis and cell proliferation
	regulates intestinal immunity by triggering local glucocorticoid production
	playing an essential roles in cholesterol homeostasis
	could exert potential oncogenic effects during breast cancer formation
	indispensable to maintaining the pluripotent state of embryonic stem cells
	transcription factor that mainly participates in the homeostasis of bile acid production in the liver
	broad role in regulating bile acid homeostasis but is either not involved in the feedback regulation of bile acid synthesis or is compensated for by other factors
	implicated in the regulation of cholesterol, bile acid, and steroid hormone homeostasis
	could represent another key regulator of the steroidogenic lineage inmesenchymal stem cells and play a vital role in steroid hormone production in human Leydig cells
	shares many common gene targets with SOX2 and KLF4, which suggests that the transcription factor trio works in concert to mediate reprogramming
	activates NR0B2 gene promoter and transcription
	playing potentially an important role in the regulation of testicular aromatase expression
	NR5A2 and NR5A1, similarly induce changes to chromatin structure at the STAR gene promoter and the distal control region and suggesting that NR5A2 and NR5A1 work together in steroidogenic tissues, especially in the ovary, to regulate steroid hormone production
	controls cell differentiation in the developing pancreas and maintains cholesterol homeostasis in adults
	has a major role in development of pancreatic cancer
	NR5A2 is an essential regulator of gene transcription, critical for maintenance of cell pluripotency in early development and imperative for the proper functions of the liver, pancreas, and intestines during the adult life
	is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta, and has multiple, indispensible roles in establishing and sustaining pregnancy
	RARG and NR5A2 promote conversion of fibroblasts to functional neurons
	initiates a novel pathway of ER stress resolution that is independent of the unfolded protein response (UPR), yet equivalently required
	plays crucial regulatory roles during organogenesis
	controls several temporally distinct stages of pancreatic development that involve regulatory mechanisms relevant to pancreatic oncogenesis and the maintenance of the exocrine phenotype
	likely in spermatozoa the NR5A2 effects are closely integrated with the estrogen signaling, supporting NR5A2 as a downstream effector of the estradiol pathway on some sperm functions
	orphan nuclear receptor that has been shown to play a role in the transcriptional regulation of pathways involved in cancer
	may be important in the pathophysiology of Preterm birth (PTB)
	critical iterative and pleiotropic roles for Nr5a2 at distinct stages of pancreas and liver organogenesis
	could play a role in cancer stem cell (CSC) stemness and epithelial-mesenchymal transition (EMT) in pancreatic cancer, which may contribute to the worse clinical outcome
	is a transcription factor and either activates or inhibits transcription through actions at hundreds of enhancers
	is involved in the regulation of development, lipid metabolism and proliferation and is predominantly expressed in epithelial tissues
	is essential for granulosa cell proliferation, but its depletion does not alter the frequency of apoptosis nor autophagy
	participates in a wide variety of processes, including cholesterol and glucose metabolism in the liver, resolution of endoplasmic reticulum stress, intestinal glucocorticoid production, pancreatic development and acinar differentiation

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

a component

NR5A2/NR0B1 complex provides the molecular mechanism for the function of NR0B1 as a potent transcriptional repressor

INTERACTION

DNA

RNA

small molecule

protein	expression in human granulosa cells is regulated by CYP11A1
	may be involved both in stimulating basal CYP7A1 and CYP8B1 transcription and in repressing their expression as part of the nuclear bile acid receptor [farnesoid X receptor (FXR)]-small heterodimer partner signaling cascade
	bound to the distal control region and promoter of STAR
	NR5A2 controls CYP7A1 expression from two distinct sites, i.e., liver and ileum, in the enterohepatic circulation
	in breast cancer cells, NR5A2 promotes cell proliferation by enhancing ESR1 mediated transcription of target genes such as GREB1
	NR5A2 acts as a transcriptional activator in the regulation of POU5F1 gene expression through the cooperative interaction with three binding sites directly or/and indirectly
	binds directly to the kisspeptin (KISS1) promoter and stimulates KISS1 transcription
	NR5A2 cooperates with FOXA1 and binds directly to CDKN1A promoter and a distal regulatory region found at -62&
	8201;kb from its transcriptional start sites, allowing repression of CDKN1A transcription
	SERBP1 and ILF3 were identified as NR5A2 interacting partners
	directly binds to its binding sites in the FASLG promoter, and thereby drives FASLG promoter activity
	NR5A2 regulates FASLG transcription and associated T-cell effector functions
	interaction between Clock NR5A1/NR5A2 and BMP15 is likely to be involved in the fine-tuning of steroidogenesis by ovarian granulosa cells

cell & other

REGULATION

activated by

HNF1 and HNF3B

repressed by

NR0B2 (NR0B2 recruits SIRT1 deacetylase to inhibit NR5A2-mediated target gene activation)

Other	regulated by a DR4 element
	activation of NR5A2 produced a reduction in the oxidation of fatty acids, an effect which disappeared in low-glucose conditions

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in breast cancer cell lines expressing ESR1 tumoral       gain of function in pancreatic cancer cells compared to normal pancreatic ductal epithelium tumoral     --over   in pancreatic tumors

Susceptibility

to inflammatory bowel disease (IBD)

Variant & Polymorphism	protective role against the onset of IBD, intimately linked with its commanding role on glucocorticoid synthesis in the intestinal epithelium

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer endocrine pancreas might be a plausible therapeutic target for treatment of pancreatic cancer cancer     targeting NR5A2 may provide an attractive prospect for treatment of tumors that are resistant to hormonal and targeted therapy

ANIMAL & CELL MODELS