SREBF1 (sterol regulatory element binding transcription factor 1)

2019-02-01   Seher Gök 

Scientific and Technological Research Council of Turkey; Ankara-TURKEY\\\/ seher.gok@tubitak.gov.tr

Identity

HGNC
LOCATION
Located on 17p11.2
IMAGE
Atlas Image
LEGEND
Figure 1. Gene neighbours of LIPE on chromosome 17p11.2 (Chromosome 17 - NC_000017.11 Reference: GRCh38.p12 current assembly, NCBI Annotation Release 109).
LOCUSID
ALIAS
HMD,IFAP2,SREBP1,bHLHd1

Abstract

Review on SREBF1, with data on DNA, on the protein encoded and where the gene is implicated.

DNA/RNA

Atlas Image
Figure 2. Genomic organization of the SREBF1 gene. Exons are numbered indicating the alternatively spliced a and c variants (adapted from Kedenko et al., 2012).

Description

Orientation: Minus strand; 25669 bp; Exon count: 22; intron count: 20

Transcription

SREBF1 gene has 23 transcripts (Table 1)
Table 1. Transcripts of human SREBF1 gene (Ensembl annotation Release 85).
Name  Transcript ID  bp  Protein   Biotype  
SREBF1-201  ENST00000261646.9  4178  1147  Protein coding  
SREBF1-202  ENST00000355815.8  4253  1177  Protein coding  
SREBF1-203  ENST00000395751.8  4653  216  Nonsense mediated decay  
SREBF1-204  ENST00000395756.5  3026  113  Nonsense mediated decay  
SREBF1-205  ENST00000395757.5  3696  893  Protein coding  
SREBF1-206  ENST00000423161.3  1058  325  Protein coding  
SREBF1-207  ENST00000447641.5  644  No protein  Retained intron   
SREBF1-208  ENST00000469356.3  1323  No protein  Retained intron   
SREBF1-209  ENST00000470247.1  374  No Protein  Retained intron   
SREBF1-210  ENST00000471445.5  936  No protein  Retained intron   
SREBF1-211  ENST00000476994.1  591  No protein  Retained intron   
SREBF1-212  ENST00000478616.1  882  163  Protein coding  
SREBF1-213  ENST00000485080.6  1230  110  Nonsense mediated decay  
SREBF1-214  ENST00000486311.5  473  157  Protein coding  
SREBF1-215  ENST00000487401.1  477  No protein  Retained intron   
SREBF1-216  ENST00000490796.1  698  No protein  Retained intron   
SREBF1-217  ENST00000577897.1  536  66  Protein coding  
SREBF1-218  ENST00000578469.1  588  31  Protein coding  
SREBF1-219  ENST00000580540.1  540  No protein  Retained intron   
SREBF1-220  ENST00000581707.1  695  No protein  Retained intron   
SREBF1-221  ENST00000583080.1  482  No protein  Retained intron   
SREBF1-222  ENST00000583732.1  580  No protein  Processed transcript  
SREBF1-223  ENST00000584760.1  564  No protein  Retained intron   

Proteins

Note

SREBF1 gene encodes 1147 amino acid sized protein which has 121675 Da molecular mass. SREBF1 is helix-loop-helix transcriptional activator required for lipid homeostasis (Figure 3). Regulates transcription of the LDL receptor gene as well as the fatty acid and cholesterol synthesis pathways. Binds to the sterol regulatory element 1 (SRE-1) (5-ATCACCCCAC-3). Has dual sequence specificity binding to both an E-box motif (5-ATCACGTGA-3) and to SRE-1 (5-ATCACCCCAC-3).
Atlas Image
Figure 3. Co-crystal structure of sterol regulatory element binding protein 1a bound to an LDL Receptor promoter at 2.3 A resolution (adapted from Párraga et al., 1998).

Description

The encoded protein is synthesized as a precursor that is initially attached to the nuclear membrane and endoplasmic reticulum. After cleavage, the mature protein translocates to the nucleus and activates transcription. This cleaveage is inhibited by sterols. Alternative promoter usage and splicing result in multiple transcript variants. 6 isoforms are described. Isoform 1A has been choosen as the canonical sequence (provided by RefSeq, Nov 2017). Quaternary structure of protein forms a tight complex with SCAP in the ER membrane. Efficient DNA binding of the soluble transcription factor fragment requires dimerization with another bHLH protein. Interacts with LMNA. Interacts with CEBPA, the interaction produces a transcriptional synergy (By similarity).
Post-translational modifications: 
At low cholesterol the SCAP/SREBP complex is recruited into COPII vesicles for export from the ER. In the Golgi complex SREBPs are cleaved sequentially by site-1 and site-2 protease. The first cleavage by site-1 protease occurs within the luminal loop, the second cleavage by site-2 protease occurs within the first transmembrane domain and releases the transcription factor from the Golgi membrane. Apoptosis triggers cleavage by the cysteine proteases CASP3 and CASP7 (caspase-3 and caspase-7).
Phosphorylated by AMPK (P
rotein kinase AMP-activated catalytic subunits), leading to suppress protein processing and nuclear translocation, and repress target gene expression. Phosphorylation at Ser-402 by SIK1 represses activity possibly by inhibiting DNA-binding.
Ubiquitinatylated at Lys347, Lys379, Lys587, Lys675, Lys934, Lys1070.

Expression

Expressed in a wide variety of tissues, most abundant in fat and adrenal gland. In fetal tissues, lung and liver shows highest expression. Isoform SREBF-1C predominates in liver, adrenal gland and ovary, whereas isoform SREBF-1A predominates in hepatoma cell lines. Isoform SREBF-1A and isoform SREBF-1C are found in kidney, brain, white fat, and muscle.

Localisation

Endoplasmic reticulum membrane, golgi membrane, nuclear envelope, nucleoplasm, nucleus, COPII - coated vesicle membrane.

Function

SREBF1 Transcription factor binds to the sterol regulatory element-1 (SRE1) (5-ATCACCCCAC-3) which is a motif found in the promoter of the low density lipoprotein receptor genes and other genes that involved in sterol biosynthesis. Depletion of cholesterol leads to intra-membrane proteolysis, releasing the active portion of SREBF1 containing the basic DNA-binding region from the endoplasmic reticulum membrane. After translocation to the nucleus and binding to its specific DNA sequences, SREBF1 dimers induce the expression of target genes involved in adipogenesis and membrane biogenesis (Nohturfft and Zhang, 2009).

Homology

SREBF1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito and frog (Table 2).
Table 2. Pairwise alignment of SREBF1 gene and protein sequences (in distance from human).
GeneIdentity %&
Species  Symbol   Protein  DNA  
H. Sapiens  SREBF1      
vs. P.troglodytes  SREBF1  98.7  99.0  
vs. M.mulatta   SREBF1  97.5  97.1  
vs. C.lupus  SREBF1  87.9  87.2  
vs. B.taurus  SREBF1  84.5  85.8  
vs. M.musculus  Srebf1  81.2  80.9  
vs. R.norvegicus  Srebf1  81.6  82.0  
vs.  G.gallus   SREBF1  65.8  69.5  
vs. X.tropicalis   srebf1  67.0  65.9  
vs D.reriro  srebf1  61.3  62.4  
vs D.melanogaster  HLH106  37.5  48.4  
vs. A.gambiae  AgaP_AGAP000076  39.2  49.7  

Mutations

Note

304 missense, 36 truncating and 3 inframe and 7 other mutations of SREBF1 was identified in 74247 samples from 240 studies (cBioPortal) (Figure 4).
Atlas Image
Figure 4. Mutation types observed in SREBF1 expression in literature and corresponding color codes are as follows: Green: Missense Mutations ; Black: Truncating Mutations: Nonsense, Nonstop, Frameshift deletion, Frameshift insertion, Splice site; Beige: In-frame Mutations: In-frame deletion, In-frame insertion ; Purple: Other Mutations: All other types of mutations.

Somatic

4 SNPs were registered for SREBF1 (according to SNPedia and Human Gene Mutation Database).

Implicated in

Entity name
Endometrial Cancer (EC)
Note
Higher level of SREBF1 has been detected in EC cells compared to the normal endometrium, and which was more prominent in higher-grade EC. NP (rs2297508) of SREBF-1 may serve as a genetic predisposition factor for the development of EC Qui et al., 2014).
Entity name
Pancreatic Cancer
Note
SREBF1 is highly expressed in pancreatic ductal cancer. The expression of SREBF1 is an independent risk factor affecting the overall survival of patients with pancreatic cancer (Sun et al., 2015.
Entity name
Hepatocellular Carcinoma (HCC)
Note
SREBF1 expression is activated in HCC. Suppression of SREBF1 induced growth arrest and apoptosis whereas overexpression of SREBF1 enhanced cell proliferation in human HCC cell lines. There are a significant relationship between poor survival and high SREBF1 protein expression and correlation between high SREBF1 protein expression and high risk of mortality with statistical significance (Yamashita et al., 2008).
Entity name
Ovarian Cancer
Note
SREBF1 protein expression was significantly higher in human ovarian cancer compared to benign and borderline ovarian tumors (Nie et al., 2013).
Entity name
Breast cancer
Note
mRNA levels for SREBF-1c increase in a panel of primary human breast cancer samples (Yang et al., 2003).
Entity name
Colorectal Carcinoma
Note
SREBF1 and FAS expression upregulated in colorectal carcinoma cells. It was hypothesized that, tumor cells recognize and respond to a deficiency in endogenous fatty acid synthesis by upregulating both SREBF1 and FAS expression and these findings support the model that SREBF1 participates in the transcriptional regulation of lipogenic genes in colorectal neoplasia (Li et al., 2000).
Entity name
Obesity and Obesity-related metabolic traits; Type 2 diabetes and Dyslipidemia
Note
The SREBF1 molecular screening of 40 unrelated obese patients revealed 19 single nucleotide polymorphisms (SNPs). SNP17 (54G/C, exon 18c) is associated with morbid obesity. SNP3 (-150G/A, exon 1a), SNP5 (-36delG, exon 1a), and SNP17 are found in high linkage disequilibrium (D > 0.8). The haplotype including wild-type alleles of these SNPs (C/G/G/T/C/G, HAP2) is identified as a risk factor for morbid obesity (P = 0.003). In the obese group, SNP3, SNP5, and SNP17 are associated with male-specific hypertriglyceridemia (P = 0.07, P = 0.01, and P = 0.05, respectively). SNP17 is also associated with type 2 diabetes (P = 0.03) (Eberlé et al., 2004).
In addition, it was shown that insulin induces SREBF1 gene expression in isolated human adipocytes and skeletal muscle and also promotes SREBF1 cleavage in human isolated adipocytes. Common insulin-resistant states, such as obesity and type 2 diabetes, are characterized by decreased expression of SREBP1c mRNA (Sewter et al., 2002).

Bibliography

Pubmed IDLast YearTitleAuthors
152774002004SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts.Eberlé D et al
232850672012Genetic polymorphisms of the main transcription factors for adiponectin gene promoter in regulation of adiponectin levels: association analysis in three European cohorts.Kedenko L et al
110822862000Sterol regulatory element-binding protein-1 participates in the regulation of fatty acid synthase expression in colorectal neoplasia.Li JN et al
238180992013Sterol regulatory element-binding protein 1 is required for ovarian tumor growth.Nie LY et al
195756372009Coordination of lipid metabolism in membrane biogenesis.Nohturfft A et al
96347031998Co-crystal structure of sterol regulatory element binding protein 1a at 2.3 A resolution.Párraga A et al
246140762014Single nucleotide polymorphism of SREBF-1 gene associated with an increased risk of endometrial cancer in Chinese women.Qiu CP et al
119169232002Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha.Sewter C et al
255894632015SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting lipid metabolism.Sun Y et al
190080112009Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma.Yamashita T et al
125316992003Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c.Yang Yu et al

Other Information

Locus ID:

NCBI: 6720
MIM: 184756
HGNC: 11289
Ensembl: ENSG00000072310

Variants:

dbSNP: 6720
ClinVar: 6720
TCGA: ENSG00000072310
COSMIC: SREBF1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000072310ENST00000261646P36956
ENSG00000072310ENST00000355815P36956
ENSG00000072310ENST00000395756S4R3B4
ENSG00000072310ENST00000395757P36956
ENSG00000072310ENST00000395757B5MD58
ENSG00000072310ENST00000423161F6V242
ENSG00000072310ENST00000478616K7EIW8
ENSG00000072310ENST00000485080K7EMT8
ENSG00000072310ENST00000486311K7EMD1
ENSG00000072310ENST00000577897J3QLB6
ENSG00000072310ENST00000578469K7EKR7

Expression (GTEx)

0
50
100
150
200
250
300

Pathways

PathwaySourceExternal ID
Insulin signaling pathwayKEGGko04910
Insulin signaling pathwayKEGGhsa04910
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Circadian ClockREACTOMER-HSA-400253
RORA activates gene expressionREACTOMER-HSA-1368082
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Fatty acid, triacylglycerol, and ketone body metabolismREACTOMER-HSA-535734
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)REACTOMER-HSA-400206
PPARA activates gene expressionREACTOMER-HSA-1989781
Regulation of cholesterol biosynthesis by SREBP (SREBF)REACTOMER-HSA-1655829
Activation of gene expression by SREBF (SREBP)REACTOMER-HSA-2426168
Developmental BiologyREACTOMER-HSA-1266738
Transcriptional regulation of white adipocyte differentiationREACTOMER-HSA-381340
Insulin resistanceKEGGhsa04931

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA133950441hmg coa reductase inhibitorsChemicalClinicalAnnotationassociatedPD24329191
PA33744PRKAA1GenePathwayassociated22722338
PA33745PRKAA2GenePathwayassociated22722338
PA33746PRKAB1GenePathwayassociated22722338
PA33747PRKAB2GenePathwayassociated22722338
PA33751PRKAG1GenePathwayassociated22722338
PA33752PRKAG2GenePathwayassociated22722338
PA33753PRKAG3GenePathwayassociated22722338
PA37935SIRT1GenePathwayassociated22722338
PA447216SchizophreniaDiseaseClinicalAnnotationassociatedPD24329191
PA449688fluvastatinChemicalClinicalAnnotationassociatedPD

References

Pubmed IDYearTitleCitations
204668822010MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis.345
208177292010SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism.163
160071822005PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP.125
220359582011A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans.124
182814742008Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1.122
220591522011An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway.108
183606972008SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease.99
150263652004Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen independence.97
186546402008Genome-wide occupancy of SREBP1 and its partners NFY and SP1 reveals novel functional roles and combinatorial regulation of distinct classes of genes.95
150851962004Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis.93

Citation

Seher Gök

SREBF1 (sterol regulatory element binding transcription factor 1)

Atlas Genet Cytogenet Oncol Haematol. 2019-02-01

Online version: http://atlasgeneticsoncology.org/gene/42386/srebf1