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FLASH GENE
Symbol SREBF1 contributors: mct - updated : 30-03-2011
HGNC name sterol regulatory element binding transcription factor 1
HGNC id 11289
Location 17p11.2      Physical location : 17.714.664 - 17.740.325
Synonym name sterol regulatory element binding protein-1
Synonym symbol(s) SREBP1, SCREBP1, SREBP-1C, bHLHd1
DNA
TYPE functioning gene
STRUCTURE 25.66 kb     19 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
cytosine-phosphate-guanine/HTF
Binding site
text structure
  • upstream of the translation start site, a functional role for the 3 GC-boxes containing overlapping sites for the Sp1 and EGR-1 transcription factors
  • a PPRE element in the proximal promoter, and direct interaction of the PPAR receptor with this SREBF1 promoter
    • MAPPING cloned Y linked   status confirmed
    Map see SMCR (phenotype)
    Physical map
    LOC201164 17p11.2 similar to CG12314 gene product BHD MGC13008 17p11.2 hypothetical protein MGC13008 LOC390769 17 similar to actin 3 - fruit fly (Drosophila melanogaster) (fragments) COPS3 17p11.2 COP9 constitutive photomorphogenic homolog subunit 3 (Arabidopsis) NT5M 17p11.2 5',3'-nucleotidase, mitochondrial LOC388344 17 similar to ribosomal protein L13; 60S ribosomal protein L13; breast basic conserved protein 1 FLJ10193 RASD1 17p11.2 RAS, dexamethasone-induced 1 PEMT 17p11.2 phosphatidylethanolamine N-methyltransferase FLJ23022 17p11.2 hypothetical protein FLJ23022 RAI1 17p11.2 retinoic acid induced 1 SMCR5 17p11.2 Smith-Magenis syndrome chromosome region, candidate 5 SREBF1 17p11.2 sterol regulatory element binding transcription factor 1 TOM1L2 17p11.2 target of myb1-like 2 (chicken) DKFZP586M1120 17p11.2 hypothetical protein DKFZp586M1120 ATPAF2 17p11.2 ATP synthase mitochondrial F1 complex assembly factor 2 MGC3048 17p11.2 hypothetical protein MGC3048 DRG2 17p11.2 developmentally regulated GTP binding protein 2 MYO15A 17p11.2 myosin XVA FLJ20308 17p11.2 hypothetical protein FLJ20308 LLGL1 17p11.2 lethal giant larvae homolog 1 (Drosophila) FLII 17p11.2 flightless I homolog (Drosophila) SMCR7 17p12 Smith-Magenis syndrome chromosome region, candidate 7 TOP3A 17p11.2 topoisomerase (DNA) III alpha SMCR8 17p11.2 Smith-Magenis syndrome chromosome region, candidate 8 SHMT1 17p11.2 serine hydroxymethyltransferase 1 (soluble) LOC339237 17p11.2 similar to Envoplakin (210 kDa paraneoplastic pemphigus antigen) (p210) (210 kDa cornified envelope precursor) LOC339240 17p11.2 keratin pseudogene LOC339241 17p11.2 keratin pseudogene LOC339242 17p11.2 similar to Keratin, type I cytoskeletal 14 (Cytokeratin 14) (K14) (CK 14) LOC339243 17p11.2 similar to Keratin, type I cytoskeletal 16 (Cytokeratin 16) (K16) (CK 16)
    regionally located within the Smith-Magenis critical region
    RNA
    TRANSCRIPTS type messenger
    text three alternatively spliced isoforms, SREBF1a , SREBF1c, SREBF1b
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    20 splicing 5012 - 1177 hepatoma cell lines 2008 18267114
  • exon 1a and 2
  • inhibited the PEPCK promoter activity that was induced by HNF-4alpha
  • functional role of the three GC-boxes containing overlapping EGR-1/SP1 binding sites for promoter regulation
  • phosphorylation site in Ser-434, which regulates the FBXW7-dependent degradation of SREBP (Bengoechea-Alonso 2009)
    • - - - - 1177 liver, adrenal gland, ovary, glomerular, predominantly expressed in liver and adipose tissues 2008 18267114
  • exon 1c and 2
  • complexing with ADD1
  • inhibited the PEPCK promoter activity that was induced by HNF-4alpha
  • enhanced oxidative stress through NADPH oxidase, and contributed to formation of diabetic nephropathy without marked lipid accumulation in glomeruli
  • activation could contribute to emergence and/or progression of diabetic nephropathy
  • upregulatiing SLC2A4 transcription in adipose tissue
  • phosphorylation site in Ser-410, which regulates the FBXW7-dependent degradation of SREBP (Bengoechea-Alonso 2009)
    • 19 splicing 4922 - 1147 - 2008 18267114
    - - 1430 - 470 - 2008 18267114
  • contains a translational stop codon-encoding exon sequence between exons 7 and 8
  • lack transmembrane and C-terminal regulatory sequences necessary for localization of SREBP-1 to the endoplasmic reticulum
    • - - 1364 - 446 - 2008 18267114
  • contains a translational stop codon-encoding exon sequence between exons 7 and 8
  • lack transmembrane and C-terminal regulatory sequences necessary for localization of SREBP-1 to the endoplasmic reticulum
    		•
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly Homo sapiens
    Endocrineadrenal gland   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestivehepatocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal, pregnancy
    Text placenta, lung, liver
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • NH2 terminal transcription domain including a lamin A/C binding site
  • a basic helix-loop-helix, leucine zipper
  • a middle hydrophobic region with two transmembrane segments (2TM)
  • a C terminal regulatory domain
    • HOMOLOGY
    interspecies homolog to murine Srebf1
    Homologene
    FAMILY
    Sterol regulatory element-binding proteins family
    CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,nucleus
    intracellular,nuclear envelope
    text
  • released from ER to Golgi when sterol levels are low
  • in ER membrane, immature SREBF complex is retained by another ER membrane resident protein called INSIG1
    • basic FUNCTION
  • controlling cholesterol homeostasis
  • having a novel role as negative regulator of gluconeogenic genes through a cross-talk with HNF4A interference with PPARGC1B recruitment
  • playing a central role in energy homeostasis by promoting glycolysis, lipogenesis, and adipogenesis
  • involvd in suppression of VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in vascular smooth muscle cells
  • preferentially activate transcription of lipogenic genes including fatty acid synthase (FAS) and glycerol-3-phosphate acyltransferase (GPAT)
  • plays a role in suppression of hepatic bile acid biosynthesis in response to insulin under feeding conditions by inhibiting transcription of CYP7A1
  • bHLH transcription factor that controls lipogenesis and is induced during overnutrition to facilitate the conversion of glucose to fatty acids and triglycerides for the storage of the excess energy (Shimano 2007)
  • regulator of lipogenesis by activating number of enzyme genes, such as FASN or ACACA, that are involved in this pathway at the transcriptional level
  • mediating SIK1-dependent regulation of hepatic lipogenesis
  • key lipogenic activator, and its expression is dynamically regulated in response to nutritional and hormonal cues
    • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling hormonal
  • activation of the SREBF1/SYTL4 pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity
    • a component
  • complexing with SCAP and SREBF2
    • INTERACTION
    DNA
    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 after a secund cleavage by MBTPS2
  • LMNA (retention of SREBF by LMNA, causing down-regulation of PPARG expression and reducing the rate of preadipocytes differentiation)
  • target of SIRT1 (SIRT1 interaction with SREBPF1 was increased during fasting and decreased upon feeding)
  • PPARA is a novel regulatory factor in SREBF1 regulation which plays a relevant role in the interplay between lipids and insulin metabolic regulation
  • FGFR3 signaling promotes the cleavage and activation of the master transcriptional regulator of lipogenesis, SREBF1, that in turn regulates the expression of SCD
    • cell & other
    REGULATION
    activated by NR1H2 and NR1H3 (resulting in activation of the gene for fatty acid synthase)
    liver X receptor-netinoid X receptor
    HMG-CoA reductase inhibitors (statins)
    repressed by FOXO1 (FOXO1-mediated suppression of SREBF1 promoter activity could be partially alleviated by insulin)
    Other regulated by phosphorylation during the cell cycle
    degradation controlled by cross-talk between multiple phosphorylated residues in its C-terminal domain, and the phosphorylation of Ser-434 could function as a molecular switch to control these processes (Bengoechea-Alonso 2009)
    regulation of the stability of active SREBP1 by FKBW7
    regulation of SREBPF1 expression by MTOR signaling in hepatocytes
    regulated by MTOR (its activity is regulated by MTOR which contributes to Akt-dependent cell growth) (
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       gain of function
    significantly activated spinal cord tissue of both familial or sporadic ALS individuals, and this activation requires degradation of ER membrane resident protein INSIG1
    Susceptibility to obesity and type 2 diabetes
    Variant & Polymorphism other polymorphisms are associated with obesity and type 2 diabetes
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    digestivelivercirrhosis
    modulation of SREBF1 activity by SIK proteins would provide an attractive means for the regulation of nonalcoholic fatty liver
    diabetemetabolic syndrom 
    reducing acetylation of SREBPF1 by targeting SIRT1 may be useful for treating metabolic disorders, including fatty liver, obesity, and type II diabetes
    neurologyneurodegenerative 
    suppressing SREBP1 activation may have a therapeutic value in Amyotrophic lateral sclerosis
    ANIMAL & CELL MODELS
  • Srebf1 acetylation levels were highly elevated in diet-induced obese mice