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FLASH GENE

Symbol

SREBF2

contributors: mct/ - updated : 30-12-2015

HGNC name	sterol regulatory element binding transcription factor 2
HGNC id	11290

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	22q13.2      Physical location : 42.229.105 - 42.302.373
Synonym name	class D basic helix-loop-helix protein 2
Synonym symbol(s)	SREBP2, bHLHd2

DNA

TYPE	functioning gene
STRUCTURE	74.23 kb     19 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor
motif
text structure	SRE-1, NF-Y binding elements

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D22S276 - D22S1157 - SREBF2 - D22S1178 - D22S1041 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004599 19 - 4325 NP_004590 123.56 1141 - 1997 9070916 variant d - polyA site 5200 isoform d - 1141 pancreas Miserez variant a - - - isoform a - - - Hua (1996) form encoded by the "a" class exons (exons 18a and 19a) undergoing sterol-regulated cleavage variant c - - - isoform c - - - Hua (1996) form encoded by the "c" class exons (18c and 19c) is cleaved less efficiently and is not suppressed by sterols

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 Digestive pharynx       highly Lymphoid/Immune lymph node       highly Skin/Tegument skin       highly

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	NH2 terminal transcription domain
	a basic helix-loop-helix (bHLH), leucine zipper
	a middle hydrophobic region with two transmembrane segments (2TM)
	a site of sterol-regulated cleavage as the Leu522-Ser523 bond in the middle of the 31-AA hydrophilic loop that projects into the lumen of the endoplasmic reticulum and nuclear envelope
	a C terminal regulatory domain

mono polymer

dimer

HOMOLOGY

Homologene

FAMILY	basic helix loop helix (BHLH) trancription factors family
	SREBP family

CATEGORY

regulatory , transcription factor , protooncogene

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome
text	released from ER to Golgi when sterol levels are low
	attached to the endoplasmic reticulum (ER) and nuclear envelope by a hairpin domain consisting of two transmembrane regions connected by a short lumenal loop of approximately 30 hydrophilic AAs

basic FUNCTION	controlling cholesterol homeostasis, key protein regulating cholesterol synthesis and uptake
	transcriptional regulator, moving from the endoplasmic reticulum to the Golgi in the absence of sterols
	having a function in endothelial cells in addition to its role in cholesterol uptake and biosynthesis
	playing a role in the loss of sterol feedback regulation in cancer cells
	a crucial mediator of the effects of SIRT2 on metabolism)
	SREBF2 directly activates autophagy genes during cell-sterol depletion, conditions known to induce both autophagy and nuclear SREBF2 levels
	SREBF2, which can be modulated by the impairment of cerebral cholesterol homeostasis, has a direct role on BACE1 expression and may be involved in Alzheimer disease progression
	master transcriptional regulator of cholesterol synthesis, that diverts acetyl-CoA into cholesterol synthesis and may thus reduce respiration
	is a basic helix-loop-helix-leucine zipper transcription factor that positively regulates transcription of target genes involved in cholesterol metabolism
	enterocytes respond to the pharmacological blockade of cholesterol absorption by ramping up de novo sterol synthesis through activation of SREBF2
	is a key molecule in aggravating proinflammatory responses in endothelial cells and promoting atherosclerosis

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

hormonal

a component

complexing with SCAP, SREBF1 and importin beta (KPNB1) (forms a tight complex with SCAP in the ER membrane)

INTERACTION

DNA	binding to sterol regulatory element

RNA

small molecule

protein	cleaved by MBTPS1 in the ER luminal loop between the two membrane spanning regions, initiating the two-step proteolytic process by which the N terminal of SREBF is translocated to nucleus
	KPNB1
	down-regulating ABCA1 in vascular endothelial cells
	interacting with HNF4A (potentiates the SREBP functions and stimulates expression of SREBP-responsive genes in enterohepatic cells)
	RNF139 hinders SREBPF2 processing through interaction with SREBPF2 and SCAP, regulating its own turnover rate by means of its E3 ubiquitin ligase activity
	SREBF2, a key transcription factor of cholesterol synthesis, interacted with the AACS promoter was increased during neurite outgrowth
	sterol sensor SCAP is a key regulator of SREBF2, the major transcription factor controlling cholesterol synthesis
	SIRT6 is a critical factor for SREBF2 gene regulation
	multimeric ER proteins ERLIN1 and ERLIN2 are additional SREBF1, SREBF2 regulators
	SREBPF2 negatively regulates the FXR-mediated transcriptional activation of the FGF19 gene in human intestinal cells
	FOXO4 interacts with SREBF2 and EPAS1 to modulate CYP51A1 promoter activity
	SREBF1, SREBF2 actively prevents premature recycling of SCAP-SREBF until initiation of SREBF cleavage
	HMGCR is a target gene of SREBF2, and luteolin modulates HMGCR transcription by decreasing the expression and nuclear translocation of SREBF2
	MBTPS2 and SREBF1 and SREBF2 were known to be important players in the same pathway

cell & other

REGULATION

Other

regulated by thyroid hormone

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   in hypercholesterolemia

Susceptibility

to vascular dementia to osteoarthritis (OA)

Variant & Polymorphism SNP	SNP increasing the risk of vascular dementia
	association of SREBF2 with OA pathogenesis

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cardiovascular atheroma   targeting SREBF2-inflammasome pathways can be a therapeutic strategy for attenuating atherosclerosis

ANIMAL & CELL MODELS