Full text data of SREBF1
SREBF1
(BHLHD1, SREBP1)
[Confidence: low (only semi-automatic identification from reviews)]
Sterol regulatory element-binding protein 1; SREBP-1 (Class D basic helix-loop-helix protein 1; bHLHd1; Sterol regulatory element-binding transcription factor 1; Processed sterol regulatory element-binding protein 1)
Sterol regulatory element-binding protein 1; SREBP-1 (Class D basic helix-loop-helix protein 1; bHLHd1; Sterol regulatory element-binding transcription factor 1; Processed sterol regulatory element-binding protein 1)
UniProt
P36956
ID SRBP1_HUMAN Reviewed; 1147 AA.
AC P36956; B0I4X3; B0I4X4; D3DXC4; Q16062; Q59F52; Q6P4R7; Q6PFW7;
read moreAC Q6PJ36; Q8TAK9;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 05-FEB-2008, sequence version 2.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Sterol regulatory element-binding protein 1;
DE Short=SREBP-1;
DE AltName: Full=Class D basic helix-loop-helix protein 1;
DE Short=bHLHd1;
DE AltName: Full=Sterol regulatory element-binding transcription factor 1;
DE Contains:
DE RecName: Full=Processed sterol regulatory element-binding protein 1;
GN Name=SREBF1; Synonyms=BHLHD1, SREBP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SREBP-1A), NUCLEOTIDE SEQUENCE
RP [MRNA] OF 1-29 (ISOFORM SREBP-1C), NUCLEOTIDE SEQUENCE [MRNA] OF
RP 1035-1147 (ISOFORMS SREBP-1B AND SREBP-1C), PARTIAL PROTEIN SEQUENCE,
RP AND VARIANT ALA-1000.
RC TISSUE=Cervix carcinoma;
RX PubMed=8402897; DOI=10.1016/0092-8674(93)90690-R;
RA Yokoyama C., Wang X., Briggs M.R., Admon A., Wu J., Hua X.,
RA Goldstein J.L., Brown M.S.;
RT "SREBP-1, a basic-helix-loop-helix-leucine zipper protein that
RT controls transcription of the low density lipoprotein receptor gene.";
RL Cell 75:187-197(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ALA-1000.
RC TISSUE=Fetal brain;
RX PubMed=7759101; DOI=10.1016/0888-7543(95)80009-B;
RA Hua X., Wu J., Goldstein J.L., Brown M.S., Hobbs H.H.;
RT "Structure of the human gene encoding sterol regulatory element
RT binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to
RT chromosomes 17p11.2 and 22q13.";
RL Genomics 25:667-673(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS SREBP-1ADELTA AND SREBP-1CDELTA),
RP AND SUBCELLULAR LOCATION (ISOFORMS SREBP-1ADELTA AND SREBP-1CDELTA).
RC TISSUE=Liver;
RX PubMed=18267114; DOI=10.1016/j.bbrc.2008.02.004;
RA Harada N., Yonemoto H., Yoshida M., Yamamoto H., Yin Y., Miyamoto A.,
RA Hattori A., Wu Q., Nakagawa T., Nakano M., Teshigawara K.,
RA Mawatari K., Hosaka T., Takahashi A., Nakaya Y.;
RT "Alternative splicing produces a constitutively active form of human
RT SREBP-1.";
RL Biochem. Biophys. Res. Commun. 368:820-826(2008).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ISOFORM SREBP-1A).
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS SREBP-1A AND 4), AND
RP VARIANTS SER-306 AND LEU-834.
RC TISSUE=Brain, Placenta, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 31-1147 (ISOFORM
RP SREBP-1A/4).
RC TISSUE=Spleen;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP CHARACTERIZATION, AND MUTAGENESIS.
RX PubMed=8626610; DOI=10.1074/jbc.271.17.10379;
RA Hua X., Sakai J., Brown M.S., Goldstein J.L.;
RT "Regulated cleavage of sterol regulatory element binding proteins
RT requires sequences on both sides of the endoplasmic reticulum
RT membrane.";
RL J. Biol. Chem. 271:10379-10384(1996).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-117, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 319-394.
RX PubMed=9634703; DOI=10.1016/S0969-2126(98)00067-7;
RA Parraga A., Bellsolell L., Ferre-D'Amare A.R., Burley S.K.;
RT "Co-crystal structure of sterol regulatory element binding protein 1a
RT at 2.3-A resolution.";
RL Structure 6:661-672(1998).
CC -!- FUNCTION: Transcriptional activator required for lipid
CC homeostasis. Regulates transcription of the LDL receptor gene as
CC well as the fatty acid and to a lesser degree the cholesterol
CC synthesis pathway (By similarity). Binds to the sterol regulatory
CC element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence
CC specificity binding to both an E-box motif (5'-ATCACGTGA-3') and
CC to SRE-1 (5'-ATCACCCCAC-3').
CC -!- SUBUNIT: Forms a tight complex with SCAP in the ER membrane.
CC Efficient DNA binding of the soluble transcription factor fragment
CC requires dimerization with another bHLH protein. Interacts with
CC LMNA.
CC -!- INTERACTION:
CC P45481:Crebbp (xeno); NbExp=2; IntAct=EBI-948328, EBI-296306;
CC Q96RN5:MED15; NbExp=6; IntAct=EBI-948328, EBI-394506;
CC Q96EB6:SIRT1; NbExp=2; IntAct=EBI-948338, EBI-1802965;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass
CC membrane protein. Golgi apparatus membrane; Multi-pass membrane
CC protein. Cytoplasmic vesicle, COPII-coated vesicle membrane;
CC Multi-pass membrane protein. Note=Moves from the endoplasmic
CC reticulum to the Golgi in the absence of sterols.
CC -!- SUBCELLULAR LOCATION: Processed sterol regulatory element-binding
CC protein 1: Nucleus.
CC -!- SUBCELLULAR LOCATION: Isoform SREBP-1aDelta: Nucleus.
CC -!- SUBCELLULAR LOCATION: Isoform SREBP-1cDelta: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Comment=Additional isoforms seem to exist;
CC Name=SREBP-1A;
CC IsoId=P36956-1; Sequence=Displayed;
CC Name=SREBP-1B;
CC IsoId=P36956-2; Sequence=VSP_002150;
CC Name=SREBP-1C;
CC IsoId=P36956-3; Sequence=VSP_002149, VSP_002150;
CC Note=Predominantly expressed in liver and adipose tissues;
CC Name=4;
CC IsoId=P36956-4; Sequence=VSP_030859;
CC Note=No experimental confirmation available;
CC Name=SREBP-1aDelta;
CC IsoId=P36956-5; Sequence=VSP_047598, VSP_047599;
CC Note=The absence of Golgi proteolytic processing requirement
CC makes this isoform constitutively active in transactivation of
CC lipogenic gene promoters;
CC Name=SREBP-1cDelta;
CC IsoId=P36956-6; Sequence=VSP_002149, VSP_047598, VSP_047599;
CC Note=The absence of Golgi proteolytic processing requirement
CC makes this isoform constitutively active in transactivation of
CC lipogenic gene promoters;
CC -!- TISSUE SPECIFICITY: Expressed in a wide variety of tissues, most
CC abundant in liver and adrenal gland. In fetal tissues lung and
CC liver shows highest expression. Isoform SREBP-1C predominates in
CC liver, adrenal gland and ovary, whereas isoform SREBP-1A
CC predominates in hepatoma cell lines. Isoform SREBP-1A and isoform
CC SREBP-1C are found in kidney, brain, white fat, and muscle.
CC -!- PTM: At low cholesterol the SCAP/SREBP complex is recruited into
CC COPII vesicles for export from the ER. In the Golgi complex SREBPs
CC are cleaved sequentially by site-1 and site-2 protease. The first
CC cleavage by site-1 protease occurs within the luminal loop, the
CC second cleavage by site-2 protease occurs within the first
CC transmembrane domain and releases the transcription factor from
CC the Golgi membrane. Apoptosis triggers cleavage by the cysteine
CC proteases caspase-3 and caspase-7.
CC -!- PTM: Phosphorylated by AMPK, leading to suppress protein
CC processing and nuclear translocation, and repress target gene
CC expression. Phosphorylation at Ser-402 by SIK1 represses activity
CC possibly by inhibiting DNA-binding (By similarity).
CC -!- SIMILARITY: Belongs to the SREBP family.
CC -!- SIMILARITY: Contains 1 bHLH (basic helix-loop-helix) domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB28522.2; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAD92846.1; Type=Miscellaneous discrepancy; Note=Intron retention;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Sterol regulatory element-
CC binding protein entry;
CC URL="http://en.wikipedia.org/wiki/Sterol_regulatory_element_binding_protein";
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DR EMBL; U00968; AAC50051.2; -; mRNA.
DR EMBL; S66167; AAB28522.2; ALT_INIT; mRNA.
DR EMBL; S66168; AAB28523.1; -; mRNA.
DR EMBL; AB373958; BAG06742.1; -; mRNA.
DR EMBL; AB373959; BAG06743.1; -; mRNA.
DR EMBL; AC122129; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471196; EAW55689.1; -; Genomic_DNA.
DR EMBL; CH471196; EAW55690.1; -; Genomic_DNA.
DR EMBL; BC023621; AAH23621.1; -; mRNA.
DR EMBL; BC026962; AAH26962.1; -; mRNA.
DR EMBL; BC057388; AAH57388.1; -; mRNA.
DR EMBL; BC063281; AAH63281.1; -; mRNA.
DR EMBL; AB209609; BAD92846.1; ALT_SEQ; mRNA.
DR PIR; A48845; A48845.
DR RefSeq; NP_001005291.1; NM_001005291.2.
DR RefSeq; NP_004167.3; NM_004176.4.
DR UniGene; Hs.592123; -.
DR UniGene; Hs.733635; -.
DR PDB; 1AM9; X-ray; 2.30 A; A/B/C/D=319-400.
DR PDBsum; 1AM9; -.
DR ProteinModelPortal; P36956; -.
DR SMR; P36956; 319-400.
DR DIP; DIP-331N; -.
DR IntAct; P36956; 13.
DR MINT; MINT-2803077; -.
DR STRING; 9606.ENSP00000348069; -.
DR PhosphoSite; P36956; -.
DR DMDM; 166897633; -.
DR PaxDb; P36956; -.
DR PRIDE; P36956; -.
DR Ensembl; ENST00000261646; ENSP00000261646; ENSG00000072310.
DR Ensembl; ENST00000338854; ENSP00000345822; ENSG00000072310.
DR Ensembl; ENST00000355815; ENSP00000348069; ENSG00000072310.
DR Ensembl; ENST00000435530; ENSP00000413389; ENSG00000072310.
DR GeneID; 6720; -.
DR KEGG; hsa:6720; -.
DR UCSC; uc010cpq.1; human.
DR CTD; 6720; -.
DR GeneCards; GC17M017714; -.
DR HGNC; HGNC:11289; SREBF1.
DR HPA; CAB005406; -.
DR MIM; 184756; gene.
DR neXtProt; NX_P36956; -.
DR PharmGKB; PA335; -.
DR eggNOG; NOG242942; -.
DR HOVERGEN; HBG061592; -.
DR KO; K07197; -.
DR OMA; FDPPYAG; -.
DR PhylomeDB; P36956; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_147840; SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG.
DR Reactome; REACT_24941; Circadian Clock.
DR SignaLink; P36956; -.
DR ChiTaRS; SREBF1; human.
DR EvolutionaryTrace; P36956; -.
DR GeneWiki; SREBF1; -.
DR GenomeRNAi; 6720; -.
DR NextBio; 26212; -.
DR PMAP-CutDB; P36956; -.
DR PRO; PR:P36956; -.
DR ArrayExpress; P36956; -.
DR Bgee; P36956; -.
DR CleanEx; HS_SREBF1; -.
DR Genevestigator; P36956; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0012507; C:ER to Golgi transport vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005635; C:nuclear envelope; TAS:ProtInc.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR GO; GO:0043565; F:sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; IDA:HGNC.
DR GO; GO:0032810; F:sterol response element binding; IDA:HGNC.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0009267; P:cellular response to starvation; ISS:HGNC.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0008610; P:lipid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0046676; P:negative regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0045542; P:positive regulation of cholesterol biosynthetic process; IEA:Ensembl.
DR GO; GO:0031065; P:positive regulation of histone deacetylation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:0010867; P:positive regulation of triglyceride biosynthetic process; ISS:UniProtKB.
DR GO; GO:0019217; P:regulation of fatty acid metabolic process; IEA:Ensembl.
DR GO; GO:0003062; P:regulation of heart rate by chemical signal; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription from RNA polymerase II promoter; TAS:ProtInc.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0070542; P:response to fatty acid; IEA:Ensembl.
DR GO; GO:0032094; P:response to food; IEA:Ensembl.
DR GO; GO:0033762; P:response to glucagon stimulus; IEA:Ensembl.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0032570; P:response to progesterone stimulus; IEA:Ensembl.
DR GO; GO:0032526; P:response to retinoic acid; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR Pfam; PF00010; HLH; 1.
DR SMART; SM00353; HLH; 1.
DR SUPFAM; SSF47459; SSF47459; 1.
DR PROSITE; PS50888; BHLH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Cholesterol metabolism;
KW Complete proteome; Cytoplasmic vesicle; Direct protein sequencing;
KW DNA-binding; Endoplasmic reticulum; Golgi apparatus; Lipid metabolism;
KW Membrane; Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Steroid metabolism; Sterol metabolism; Transcription;
KW Transcription regulation; Transmembrane; Transmembrane helix.
FT CHAIN 1 1147 Sterol regulatory element-binding protein
FT 1.
FT /FTId=PRO_0000127447.
FT CHAIN 1 490 Processed sterol regulatory element-
FT binding protein 1.
FT /FTId=PRO_0000314029.
FT TOPO_DOM 1 487 Cytoplasmic (Potential).
FT TRANSMEM 488 508 Helical; (Potential).
FT TOPO_DOM 509 547 Lumenal (Potential).
FT TRANSMEM 548 568 Helical; (Potential).
FT TOPO_DOM 569 1147 Cytoplasmic (Potential).
FT DOMAIN 323 373 bHLH.
FT REGION 1 60 Transcriptional activation (acidic).
FT REGION 234 497 Interaction with LMNA (By similarity).
FT REGION 373 394 Leucine-zipper.
FT COMPBIAS 61 178 Pro/Ser-rich.
FT COMPBIAS 427 462 Gly/Pro/Ser-rich.
FT SITE 460 461 Cleavage; by caspase-3 and caspase-7 (By
FT similarity).
FT SITE 490 491 Cleavage; by S2P (By similarity).
FT SITE 530 531 Cleavage; by S1P (Probable).
FT MOD_RES 117 117 Phosphoserine.
FT MOD_RES 337 337 Phosphoserine; by SIK1 (By similarity).
FT MOD_RES 338 338 Phosphoserine; by SIK1 (By similarity).
FT MOD_RES 396 396 Phosphoserine; by AMPK (By similarity).
FT MOD_RES 402 402 Phosphoserine; by SIK1 (By similarity).
FT VAR_SEQ 1 29 MDEPPFSEAALEQALGEPCDLDAALLTDI -> MDCTF
FT (in isoform SREBP-1C and isoform SREBP-
FT 1cDelta).
FT /FTId=VSP_002149.
FT VAR_SEQ 30 30 E -> EGEVGAGRGRANGLDAPRAGADRGAMDCTFE (in
FT isoform 4).
FT /FTId=VSP_030859.
FT VAR_SEQ 469 470 AK -> TE (in isoform SREBP-1aDelta and
FT isoform SREBP-1cDelta).
FT /FTId=VSP_047598.
FT VAR_SEQ 471 1147 Missing (in isoform SREBP-1aDelta and
FT isoform SREBP-1cDelta).
FT /FTId=VSP_047599.
FT VAR_SEQ 1035 1147 VFLHEATARLMAGASPTRTHQLLDRSLRRRAGPGGKGGAVA
FT ELEPRPTRREHAEALLLASCYLPPGFLSAPGQRVGMLAEAA
FT RTLEKLGDRRLLHDCQQMLMRLGGGTTVTSS -> LMDVLT
FT SESAWALPQHLGKGFPSPSGHKVPGWHGRMD (in
FT isoform SREBP-1B and isoform SREBP-1C).
FT /FTId=VSP_002150.
FT VARIANT 306 306 N -> S (in dbSNP:rs17855793).
FT /FTId=VAR_038468.
FT VARIANT 309 309 A -> T (in dbSNP:rs35188700).
FT /FTId=VAR_038469.
FT VARIANT 417 417 V -> M (in dbSNP:rs2229590).
FT /FTId=VAR_038470.
FT VARIANT 580 580 V -> M (in dbSNP:rs36215896).
FT /FTId=VAR_038471.
FT VARIANT 746 746 R -> H (in dbSNP:rs2228461).
FT /FTId=VAR_038472.
FT VARIANT 834 834 S -> L (in dbSNP:rs17855792).
FT /FTId=VAR_038473.
FT VARIANT 1000 1000 T -> A (in dbSNP:rs1042017).
FT /FTId=VAR_038474.
FT VARIANT 1008 1008 A -> P (in dbSNP:rs35014224).
FT /FTId=VAR_038475.
FT MUTAGEN 455 455 S->A: No effect on proteolytic
FT processing.
FT MUTAGEN 456 456 D->A: No effect on proteolytic
FT processing.
FT MUTAGEN 457 457 S->A: No effect on proteolytic
FT processing.
FT MUTAGEN 460 460 D->A: No effect on proteolytic
FT processing.
FT MUTAGEN 466 466 D->A: No effect on proteolytic
FT processing.
FT MUTAGEN 481 481 G->A: No effect on proteolytic
FT processing.
FT MUTAGEN 482 482 M->A: No effect on proteolytic
FT processing.
FT MUTAGEN 483 483 L->A: No effect on proteolytic
FT processing.
FT MUTAGEN 484 487 DRSR->AS: Strong reduction of proteolytic
FT processing in response to low sterol.
FT MUTAGEN 484 484 D->A: Loss of proteolytic processing in
FT response to low sterol.
FT MUTAGEN 485 485 R->A: No effect on proteolytic
FT processing.
FT MUTAGEN 527 527 R->A: Loss of proteolytic processing in
FT response to low sterol.
FT HELIX 321 350
FT HELIX 359 396
SQ SEQUENCE 1147 AA; 121675 MW; 58F28870739FF259 CRC64;
MDEPPFSEAA LEQALGEPCD LDAALLTDIE DMLQLINNQD SDFPGLFDPP YAGSGAGGTD
PASPDTSSPG SLSPPPATLS SSLEAFLSGP QAAPSPLSPP QPAPTPLKMY PSMPAFSPGP
GIKEESVPLS ILQTPTPQPL PGALLPQSFP APAPPQFSST PVLGYPSPPG GFSTGSPPGN
TQQPLPGLPL ASPPGVPPVS LHTQVQSVVP QQLLTVTAAP TAAPVTTTVT SQIQQVPVLL
QPHFIKADSL LLTAMKTDGA TVKAAGLSPL VSGTTVQTGP LPTLVSGGTI LATVPLVVDA
EKLPINRLAA GSKAPASAQS RGEKRTAHNA IEKRYRSSIN DKIIELKDLV VGTEAKLNKS
AVLRKAIDYI RFLQHSNQKL KQENLSLRTA VHKSKSLKDL VSACGSGGNT DVLMEGVKTE
VEDTLTPPPS DAGSPFQSSP LSLGSRGSGS GGSGSDSEPD SPVFEDSKAK PEQRPSLHSR
GMLDRSRLAL CTLVFLCLSC NPLASLLGAR GLPSPSDTTS VYHSPGRNVL GTESRDGPGW
AQWLLPPVVW LLNGLLVLVS LVLLFVYGEP VTRPHSGPAV YFWRHRKQAD LDLARGDFAQ
AAQQLWLALR ALGRPLPTSH LDLACSLLWN LIRHLLQRLW VGRWLAGRAG GLQQDCALRV
DASASARDAA LVYHKLHQLH TMGKHTGGHL TATNLALSAL NLAECAGDAV SVATLAEIYV
AAALRVKTSL PRALHFLTRF FLSSARQACL AQSGSVPPAM QWLCHPVGHR FFVDGDWSVL
STPWESLYSL AGNPVDPLAQ VTQLFREHLL ERALNCVTQP NPSPGSADGD KEFSDALGYL
QLLNSCSDAA GAPAYSFSIS SSMATTTGVD PVAKWWASLT AVVIHWLRRD EEAAERLCPL
VEHLPRVLQE SERPLPRAAL HSFKAARALL GCAKAESGPA SLTICEKASG YLQDSLATTP
ASSSIDKAVQ LFLCDLLLVV RTSLWRQQQP PAPAPAAQGT SSRPQASALE LRGFQRDLSS
LRRLAQSFRP AMRRVFLHEA TARLMAGASP TRTHQLLDRS LRRRAGPGGK GGAVAELEPR
PTRREHAEAL LLASCYLPPG FLSAPGQRVG MLAEAARTLE KLGDRRLLHD CQQMLMRLGG
GTTVTSS
//
ID SRBP1_HUMAN Reviewed; 1147 AA.
AC P36956; B0I4X3; B0I4X4; D3DXC4; Q16062; Q59F52; Q6P4R7; Q6PFW7;
read moreAC Q6PJ36; Q8TAK9;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 05-FEB-2008, sequence version 2.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Sterol regulatory element-binding protein 1;
DE Short=SREBP-1;
DE AltName: Full=Class D basic helix-loop-helix protein 1;
DE Short=bHLHd1;
DE AltName: Full=Sterol regulatory element-binding transcription factor 1;
DE Contains:
DE RecName: Full=Processed sterol regulatory element-binding protein 1;
GN Name=SREBF1; Synonyms=BHLHD1, SREBP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SREBP-1A), NUCLEOTIDE SEQUENCE
RP [MRNA] OF 1-29 (ISOFORM SREBP-1C), NUCLEOTIDE SEQUENCE [MRNA] OF
RP 1035-1147 (ISOFORMS SREBP-1B AND SREBP-1C), PARTIAL PROTEIN SEQUENCE,
RP AND VARIANT ALA-1000.
RC TISSUE=Cervix carcinoma;
RX PubMed=8402897; DOI=10.1016/0092-8674(93)90690-R;
RA Yokoyama C., Wang X., Briggs M.R., Admon A., Wu J., Hua X.,
RA Goldstein J.L., Brown M.S.;
RT "SREBP-1, a basic-helix-loop-helix-leucine zipper protein that
RT controls transcription of the low density lipoprotein receptor gene.";
RL Cell 75:187-197(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ALA-1000.
RC TISSUE=Fetal brain;
RX PubMed=7759101; DOI=10.1016/0888-7543(95)80009-B;
RA Hua X., Wu J., Goldstein J.L., Brown M.S., Hobbs H.H.;
RT "Structure of the human gene encoding sterol regulatory element
RT binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to
RT chromosomes 17p11.2 and 22q13.";
RL Genomics 25:667-673(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS SREBP-1ADELTA AND SREBP-1CDELTA),
RP AND SUBCELLULAR LOCATION (ISOFORMS SREBP-1ADELTA AND SREBP-1CDELTA).
RC TISSUE=Liver;
RX PubMed=18267114; DOI=10.1016/j.bbrc.2008.02.004;
RA Harada N., Yonemoto H., Yoshida M., Yamamoto H., Yin Y., Miyamoto A.,
RA Hattori A., Wu Q., Nakagawa T., Nakano M., Teshigawara K.,
RA Mawatari K., Hosaka T., Takahashi A., Nakaya Y.;
RT "Alternative splicing produces a constitutively active form of human
RT SREBP-1.";
RL Biochem. Biophys. Res. Commun. 368:820-826(2008).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ISOFORM SREBP-1A).
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS SREBP-1A AND 4), AND
RP VARIANTS SER-306 AND LEU-834.
RC TISSUE=Brain, Placenta, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 31-1147 (ISOFORM
RP SREBP-1A/4).
RC TISSUE=Spleen;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP CHARACTERIZATION, AND MUTAGENESIS.
RX PubMed=8626610; DOI=10.1074/jbc.271.17.10379;
RA Hua X., Sakai J., Brown M.S., Goldstein J.L.;
RT "Regulated cleavage of sterol regulatory element binding proteins
RT requires sequences on both sides of the endoplasmic reticulum
RT membrane.";
RL J. Biol. Chem. 271:10379-10384(1996).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-117, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 319-394.
RX PubMed=9634703; DOI=10.1016/S0969-2126(98)00067-7;
RA Parraga A., Bellsolell L., Ferre-D'Amare A.R., Burley S.K.;
RT "Co-crystal structure of sterol regulatory element binding protein 1a
RT at 2.3-A resolution.";
RL Structure 6:661-672(1998).
CC -!- FUNCTION: Transcriptional activator required for lipid
CC homeostasis. Regulates transcription of the LDL receptor gene as
CC well as the fatty acid and to a lesser degree the cholesterol
CC synthesis pathway (By similarity). Binds to the sterol regulatory
CC element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence
CC specificity binding to both an E-box motif (5'-ATCACGTGA-3') and
CC to SRE-1 (5'-ATCACCCCAC-3').
CC -!- SUBUNIT: Forms a tight complex with SCAP in the ER membrane.
CC Efficient DNA binding of the soluble transcription factor fragment
CC requires dimerization with another bHLH protein. Interacts with
CC LMNA.
CC -!- INTERACTION:
CC P45481:Crebbp (xeno); NbExp=2; IntAct=EBI-948328, EBI-296306;
CC Q96RN5:MED15; NbExp=6; IntAct=EBI-948328, EBI-394506;
CC Q96EB6:SIRT1; NbExp=2; IntAct=EBI-948338, EBI-1802965;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass
CC membrane protein. Golgi apparatus membrane; Multi-pass membrane
CC protein. Cytoplasmic vesicle, COPII-coated vesicle membrane;
CC Multi-pass membrane protein. Note=Moves from the endoplasmic
CC reticulum to the Golgi in the absence of sterols.
CC -!- SUBCELLULAR LOCATION: Processed sterol regulatory element-binding
CC protein 1: Nucleus.
CC -!- SUBCELLULAR LOCATION: Isoform SREBP-1aDelta: Nucleus.
CC -!- SUBCELLULAR LOCATION: Isoform SREBP-1cDelta: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Comment=Additional isoforms seem to exist;
CC Name=SREBP-1A;
CC IsoId=P36956-1; Sequence=Displayed;
CC Name=SREBP-1B;
CC IsoId=P36956-2; Sequence=VSP_002150;
CC Name=SREBP-1C;
CC IsoId=P36956-3; Sequence=VSP_002149, VSP_002150;
CC Note=Predominantly expressed in liver and adipose tissues;
CC Name=4;
CC IsoId=P36956-4; Sequence=VSP_030859;
CC Note=No experimental confirmation available;
CC Name=SREBP-1aDelta;
CC IsoId=P36956-5; Sequence=VSP_047598, VSP_047599;
CC Note=The absence of Golgi proteolytic processing requirement
CC makes this isoform constitutively active in transactivation of
CC lipogenic gene promoters;
CC Name=SREBP-1cDelta;
CC IsoId=P36956-6; Sequence=VSP_002149, VSP_047598, VSP_047599;
CC Note=The absence of Golgi proteolytic processing requirement
CC makes this isoform constitutively active in transactivation of
CC lipogenic gene promoters;
CC -!- TISSUE SPECIFICITY: Expressed in a wide variety of tissues, most
CC abundant in liver and adrenal gland. In fetal tissues lung and
CC liver shows highest expression. Isoform SREBP-1C predominates in
CC liver, adrenal gland and ovary, whereas isoform SREBP-1A
CC predominates in hepatoma cell lines. Isoform SREBP-1A and isoform
CC SREBP-1C are found in kidney, brain, white fat, and muscle.
CC -!- PTM: At low cholesterol the SCAP/SREBP complex is recruited into
CC COPII vesicles for export from the ER. In the Golgi complex SREBPs
CC are cleaved sequentially by site-1 and site-2 protease. The first
CC cleavage by site-1 protease occurs within the luminal loop, the
CC second cleavage by site-2 protease occurs within the first
CC transmembrane domain and releases the transcription factor from
CC the Golgi membrane. Apoptosis triggers cleavage by the cysteine
CC proteases caspase-3 and caspase-7.
CC -!- PTM: Phosphorylated by AMPK, leading to suppress protein
CC processing and nuclear translocation, and repress target gene
CC expression. Phosphorylation at Ser-402 by SIK1 represses activity
CC possibly by inhibiting DNA-binding (By similarity).
CC -!- SIMILARITY: Belongs to the SREBP family.
CC -!- SIMILARITY: Contains 1 bHLH (basic helix-loop-helix) domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB28522.2; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAD92846.1; Type=Miscellaneous discrepancy; Note=Intron retention;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Sterol regulatory element-
CC binding protein entry;
CC URL="http://en.wikipedia.org/wiki/Sterol_regulatory_element_binding_protein";
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DR EMBL; U00968; AAC50051.2; -; mRNA.
DR EMBL; S66167; AAB28522.2; ALT_INIT; mRNA.
DR EMBL; S66168; AAB28523.1; -; mRNA.
DR EMBL; AB373958; BAG06742.1; -; mRNA.
DR EMBL; AB373959; BAG06743.1; -; mRNA.
DR EMBL; AC122129; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471196; EAW55689.1; -; Genomic_DNA.
DR EMBL; CH471196; EAW55690.1; -; Genomic_DNA.
DR EMBL; BC023621; AAH23621.1; -; mRNA.
DR EMBL; BC026962; AAH26962.1; -; mRNA.
DR EMBL; BC057388; AAH57388.1; -; mRNA.
DR EMBL; BC063281; AAH63281.1; -; mRNA.
DR EMBL; AB209609; BAD92846.1; ALT_SEQ; mRNA.
DR PIR; A48845; A48845.
DR RefSeq; NP_001005291.1; NM_001005291.2.
DR RefSeq; NP_004167.3; NM_004176.4.
DR UniGene; Hs.592123; -.
DR UniGene; Hs.733635; -.
DR PDB; 1AM9; X-ray; 2.30 A; A/B/C/D=319-400.
DR PDBsum; 1AM9; -.
DR ProteinModelPortal; P36956; -.
DR SMR; P36956; 319-400.
DR DIP; DIP-331N; -.
DR IntAct; P36956; 13.
DR MINT; MINT-2803077; -.
DR STRING; 9606.ENSP00000348069; -.
DR PhosphoSite; P36956; -.
DR DMDM; 166897633; -.
DR PaxDb; P36956; -.
DR PRIDE; P36956; -.
DR Ensembl; ENST00000261646; ENSP00000261646; ENSG00000072310.
DR Ensembl; ENST00000338854; ENSP00000345822; ENSG00000072310.
DR Ensembl; ENST00000355815; ENSP00000348069; ENSG00000072310.
DR Ensembl; ENST00000435530; ENSP00000413389; ENSG00000072310.
DR GeneID; 6720; -.
DR KEGG; hsa:6720; -.
DR UCSC; uc010cpq.1; human.
DR CTD; 6720; -.
DR GeneCards; GC17M017714; -.
DR HGNC; HGNC:11289; SREBF1.
DR HPA; CAB005406; -.
DR MIM; 184756; gene.
DR neXtProt; NX_P36956; -.
DR PharmGKB; PA335; -.
DR eggNOG; NOG242942; -.
DR HOVERGEN; HBG061592; -.
DR KO; K07197; -.
DR OMA; FDPPYAG; -.
DR PhylomeDB; P36956; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_147840; SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG.
DR Reactome; REACT_24941; Circadian Clock.
DR SignaLink; P36956; -.
DR ChiTaRS; SREBF1; human.
DR EvolutionaryTrace; P36956; -.
DR GeneWiki; SREBF1; -.
DR GenomeRNAi; 6720; -.
DR NextBio; 26212; -.
DR PMAP-CutDB; P36956; -.
DR PRO; PR:P36956; -.
DR ArrayExpress; P36956; -.
DR Bgee; P36956; -.
DR CleanEx; HS_SREBF1; -.
DR Genevestigator; P36956; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0012507; C:ER to Golgi transport vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005635; C:nuclear envelope; TAS:ProtInc.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR GO; GO:0043565; F:sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; IDA:HGNC.
DR GO; GO:0032810; F:sterol response element binding; IDA:HGNC.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0009267; P:cellular response to starvation; ISS:HGNC.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0008610; P:lipid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0046676; P:negative regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0045542; P:positive regulation of cholesterol biosynthetic process; IEA:Ensembl.
DR GO; GO:0031065; P:positive regulation of histone deacetylation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:0010867; P:positive regulation of triglyceride biosynthetic process; ISS:UniProtKB.
DR GO; GO:0019217; P:regulation of fatty acid metabolic process; IEA:Ensembl.
DR GO; GO:0003062; P:regulation of heart rate by chemical signal; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription from RNA polymerase II promoter; TAS:ProtInc.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0070542; P:response to fatty acid; IEA:Ensembl.
DR GO; GO:0032094; P:response to food; IEA:Ensembl.
DR GO; GO:0033762; P:response to glucagon stimulus; IEA:Ensembl.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0032570; P:response to progesterone stimulus; IEA:Ensembl.
DR GO; GO:0032526; P:response to retinoic acid; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR Pfam; PF00010; HLH; 1.
DR SMART; SM00353; HLH; 1.
DR SUPFAM; SSF47459; SSF47459; 1.
DR PROSITE; PS50888; BHLH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Cholesterol metabolism;
KW Complete proteome; Cytoplasmic vesicle; Direct protein sequencing;
KW DNA-binding; Endoplasmic reticulum; Golgi apparatus; Lipid metabolism;
KW Membrane; Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Steroid metabolism; Sterol metabolism; Transcription;
KW Transcription regulation; Transmembrane; Transmembrane helix.
FT CHAIN 1 1147 Sterol regulatory element-binding protein
FT 1.
FT /FTId=PRO_0000127447.
FT CHAIN 1 490 Processed sterol regulatory element-
FT binding protein 1.
FT /FTId=PRO_0000314029.
FT TOPO_DOM 1 487 Cytoplasmic (Potential).
FT TRANSMEM 488 508 Helical; (Potential).
FT TOPO_DOM 509 547 Lumenal (Potential).
FT TRANSMEM 548 568 Helical; (Potential).
FT TOPO_DOM 569 1147 Cytoplasmic (Potential).
FT DOMAIN 323 373 bHLH.
FT REGION 1 60 Transcriptional activation (acidic).
FT REGION 234 497 Interaction with LMNA (By similarity).
FT REGION 373 394 Leucine-zipper.
FT COMPBIAS 61 178 Pro/Ser-rich.
FT COMPBIAS 427 462 Gly/Pro/Ser-rich.
FT SITE 460 461 Cleavage; by caspase-3 and caspase-7 (By
FT similarity).
FT SITE 490 491 Cleavage; by S2P (By similarity).
FT SITE 530 531 Cleavage; by S1P (Probable).
FT MOD_RES 117 117 Phosphoserine.
FT MOD_RES 337 337 Phosphoserine; by SIK1 (By similarity).
FT MOD_RES 338 338 Phosphoserine; by SIK1 (By similarity).
FT MOD_RES 396 396 Phosphoserine; by AMPK (By similarity).
FT MOD_RES 402 402 Phosphoserine; by SIK1 (By similarity).
FT VAR_SEQ 1 29 MDEPPFSEAALEQALGEPCDLDAALLTDI -> MDCTF
FT (in isoform SREBP-1C and isoform SREBP-
FT 1cDelta).
FT /FTId=VSP_002149.
FT VAR_SEQ 30 30 E -> EGEVGAGRGRANGLDAPRAGADRGAMDCTFE (in
FT isoform 4).
FT /FTId=VSP_030859.
FT VAR_SEQ 469 470 AK -> TE (in isoform SREBP-1aDelta and
FT isoform SREBP-1cDelta).
FT /FTId=VSP_047598.
FT VAR_SEQ 471 1147 Missing (in isoform SREBP-1aDelta and
FT isoform SREBP-1cDelta).
FT /FTId=VSP_047599.
FT VAR_SEQ 1035 1147 VFLHEATARLMAGASPTRTHQLLDRSLRRRAGPGGKGGAVA
FT ELEPRPTRREHAEALLLASCYLPPGFLSAPGQRVGMLAEAA
FT RTLEKLGDRRLLHDCQQMLMRLGGGTTVTSS -> LMDVLT
FT SESAWALPQHLGKGFPSPSGHKVPGWHGRMD (in
FT isoform SREBP-1B and isoform SREBP-1C).
FT /FTId=VSP_002150.
FT VARIANT 306 306 N -> S (in dbSNP:rs17855793).
FT /FTId=VAR_038468.
FT VARIANT 309 309 A -> T (in dbSNP:rs35188700).
FT /FTId=VAR_038469.
FT VARIANT 417 417 V -> M (in dbSNP:rs2229590).
FT /FTId=VAR_038470.
FT VARIANT 580 580 V -> M (in dbSNP:rs36215896).
FT /FTId=VAR_038471.
FT VARIANT 746 746 R -> H (in dbSNP:rs2228461).
FT /FTId=VAR_038472.
FT VARIANT 834 834 S -> L (in dbSNP:rs17855792).
FT /FTId=VAR_038473.
FT VARIANT 1000 1000 T -> A (in dbSNP:rs1042017).
FT /FTId=VAR_038474.
FT VARIANT 1008 1008 A -> P (in dbSNP:rs35014224).
FT /FTId=VAR_038475.
FT MUTAGEN 455 455 S->A: No effect on proteolytic
FT processing.
FT MUTAGEN 456 456 D->A: No effect on proteolytic
FT processing.
FT MUTAGEN 457 457 S->A: No effect on proteolytic
FT processing.
FT MUTAGEN 460 460 D->A: No effect on proteolytic
FT processing.
FT MUTAGEN 466 466 D->A: No effect on proteolytic
FT processing.
FT MUTAGEN 481 481 G->A: No effect on proteolytic
FT processing.
FT MUTAGEN 482 482 M->A: No effect on proteolytic
FT processing.
FT MUTAGEN 483 483 L->A: No effect on proteolytic
FT processing.
FT MUTAGEN 484 487 DRSR->AS: Strong reduction of proteolytic
FT processing in response to low sterol.
FT MUTAGEN 484 484 D->A: Loss of proteolytic processing in
FT response to low sterol.
FT MUTAGEN 485 485 R->A: No effect on proteolytic
FT processing.
FT MUTAGEN 527 527 R->A: Loss of proteolytic processing in
FT response to low sterol.
FT HELIX 321 350
FT HELIX 359 396
SQ SEQUENCE 1147 AA; 121675 MW; 58F28870739FF259 CRC64;
MDEPPFSEAA LEQALGEPCD LDAALLTDIE DMLQLINNQD SDFPGLFDPP YAGSGAGGTD
PASPDTSSPG SLSPPPATLS SSLEAFLSGP QAAPSPLSPP QPAPTPLKMY PSMPAFSPGP
GIKEESVPLS ILQTPTPQPL PGALLPQSFP APAPPQFSST PVLGYPSPPG GFSTGSPPGN
TQQPLPGLPL ASPPGVPPVS LHTQVQSVVP QQLLTVTAAP TAAPVTTTVT SQIQQVPVLL
QPHFIKADSL LLTAMKTDGA TVKAAGLSPL VSGTTVQTGP LPTLVSGGTI LATVPLVVDA
EKLPINRLAA GSKAPASAQS RGEKRTAHNA IEKRYRSSIN DKIIELKDLV VGTEAKLNKS
AVLRKAIDYI RFLQHSNQKL KQENLSLRTA VHKSKSLKDL VSACGSGGNT DVLMEGVKTE
VEDTLTPPPS DAGSPFQSSP LSLGSRGSGS GGSGSDSEPD SPVFEDSKAK PEQRPSLHSR
GMLDRSRLAL CTLVFLCLSC NPLASLLGAR GLPSPSDTTS VYHSPGRNVL GTESRDGPGW
AQWLLPPVVW LLNGLLVLVS LVLLFVYGEP VTRPHSGPAV YFWRHRKQAD LDLARGDFAQ
AAQQLWLALR ALGRPLPTSH LDLACSLLWN LIRHLLQRLW VGRWLAGRAG GLQQDCALRV
DASASARDAA LVYHKLHQLH TMGKHTGGHL TATNLALSAL NLAECAGDAV SVATLAEIYV
AAALRVKTSL PRALHFLTRF FLSSARQACL AQSGSVPPAM QWLCHPVGHR FFVDGDWSVL
STPWESLYSL AGNPVDPLAQ VTQLFREHLL ERALNCVTQP NPSPGSADGD KEFSDALGYL
QLLNSCSDAA GAPAYSFSIS SSMATTTGVD PVAKWWASLT AVVIHWLRRD EEAAERLCPL
VEHLPRVLQE SERPLPRAAL HSFKAARALL GCAKAESGPA SLTICEKASG YLQDSLATTP
ASSSIDKAVQ LFLCDLLLVV RTSLWRQQQP PAPAPAAQGT SSRPQASALE LRGFQRDLSS
LRRLAQSFRP AMRRVFLHEA TARLMAGASP TRTHQLLDRS LRRRAGPGGK GGAVAELEPR
PTRREHAEAL LLASCYLPPG FLSAPGQRVG MLAEAARTLE KLGDRRLLHD CQQMLMRLGG
GTTVTSS
//
MIM
184756
*RECORD*
*FIELD* NO
184756
*FIELD* TI
*184756 STEROL REGULATORY ELEMENT-BINDING TRANSCRIPTION FACTOR 1; SREBF1
;;STEROL REGULATORY ELEMENT-BINDING PROTEIN 1; SREBP1
read more*FIELD* TX
DESCRIPTION
Sterol regulatory element-binding protein-1 (SREBP1) and SREBP2 (600481)
are structurally related proteins that control cholesterol homeostasis
by stimulating transcription of sterol-regulated genes (summary by
Osborne, 2001).
CLONING
Sterol regulatory element-1 (SRE1), a decamer
(5-prime-ATC-ACCCCAC-3-prime) flanking the low density lipoprotein
receptor gene (LDLR; 606945), activates transcription in sterol-depleted
cells and is silenced by sterols. Yokoyama et al. (1993) cloned the cDNA
corresponding to human SREBP1, a protein that binds SRE1, activates
transcription, and thereby mediates the final regulatory step in LDL
metabolism. SREBP1 contains a basic helix-loop-helix leucine zipper
(bHLH-ZIP) motif, but it differs from other bHLH-ZIP proteins in its
larger size (1,147 amino acids) and target sequence. Instead of an
inverted repeat (CANNTG), the target for all known bHLH-ZIP proteins,
SRE1 contains a direct repeat of CAC.
Hua et al. (1995) described the cloning and characterization of SREBP1
from a human cosmid DNA library. Alternative splicing at both the
5-prime and 3-prime ends of the mRNA results in several forms of the
protein whose functional differences were unknown.
Shimomura et al. (1997) noted that the 5-prime end of SREBP1 exists in 2
forms, designated 1a and 1c, resulting from the use of 2 transcription
start sites that produce 2 separate 5-prime exons, each of which is
spliced to a common exon 2. Among organs in adult mice, the authors
found that expression of the 1a and 1c transcripts varied; the 1a exon
predominated in cells that differentiated into adipocytes and in the
spleen, whereas the 1c exon predominated in liver cells, white and brown
adipose tissue, adrenal gland, and several other tissues of the adult
mouse. The findings suggested that the 2 transcripts are controlled
independently in specific organs in response to metabolic factors.
GENE FUNCTION
Yokoyama et al. (1993) found that overexpression of SREBP1 activates
transcription of reporter genes containing SRE1 in the absence (15-fold)
and presence (90-fold) of sterols, abolishing sterol regulation.
SREBP1 is synthesized as a 125-kD precursor that is attached to the
nuclear membrane and endoplasmic reticulum (ER). Wang et al. (1994)
found that in sterol-depleted cells, the membrane-bound precursor is
cleaved to generate a soluble N-terminal fragment (apparent molecular
mass, 68 kD) that translocates to the nucleus. This fragment, which
includes the bHLH-ZIP domain, activates transcription of the genes for
the LDL receptor and HMG-CoA synthase (142940). Sterols inhibit the
cleavage of SREBP1, and the 68-kD nuclear form is rapidly catabolized,
thereby reducing transcription. N-acetyl-leucyl-leucyl-norleucinal
(ALLN), an inhibitor of neutral cysteine proteases, blocked the
breakdown of the 68-kD form and superinduced sterol-regulated genes.
Sterol-regulated proteolysis of a membrane-bound transcription factor is
a novel mechanism by which transcription can be regulated by membrane
lipids.
Cholesterol homeostasis in animal cells is achieved by regulated
cleavage of SREBPs, membrane-bound transcription factors. Proteolytic
release of the active domains of SREBPs from membranes requires a
sterol-sensing protein called SCAP (601510), which forms a complex with
SREBPs. In sterol-depleted cells, DeBose-Boyd et al. (1999) found that
SCAP escorts SREBPs from the ER to the Golgi, where SREBPs are cleaved
by site-1 protease (S1P; 603355). The authors showed that sterols block
this transport and abolish cleavage. Relocating active S1P from Golgi to
ER by treating cells with brefeldin A or by fusing the ER retention
signal KDEL to S1P obviated the SCAP requirement and rendered cleavage
insensitive to sterols. DeBose-Boyd et al. (1999) concluded that
transport-dependent proteolysis may be a common mechanism to regulate
the processing of membrane proteins.
See review by Osborne (2001).
The gene encoding nuclear lamin A/C (LMNA; 150330) is mutated in at
least 3 inherited disorders. Two of these, Emery-Dreifuss muscular
dystrophy (EDMD; 310300) and a form of dilated cardiomyopathy (CMD1A;
115200), involve muscle defects, and the other, familial partial
lipodystrophy (FPLD; 151660), involves loss of subcutaneous adipose
tissue. Lloyd et al. (2002) identified proteins interacting with the
C-terminal domain of lamin A by screening a mouse 3T3-L1 adipocyte
library in a yeast 2-hybrid interaction screen. Using this approach,
SREBP1 was identified as a novel lamin A interactor. A binding site for
lamin A was identified in the N-terminal transcription factor domain of
SREBP1, between residues 227 and 487. The binding of lamin A to SREBP1
was noticeably reduced by FPLD mutations; one EDMD mutation also
interfered with the interaction between lamin A and SREBP1. The authors
speculated that fat loss seen in laminopathies may be caused in part by
reduced binding of the adipocyte differentiation factor SREBP1 to lamin
A.
Lin et al. (2005) found that high-fat feeding stimulated expression of
both Pgc1-beta (PPARGC1B; 608886) and Srebp1a/1c in mouse liver.
Pgc1-beta coactivated the Srebp transcription factor family and
stimulated lipogenic gene expression. Furthermore, Pgc1-beta was
required for Srebp-mediated lipogenic gene expression. However, unlike
Srebp itself, Pgc1-beta reduced fat accumulation in liver while greatly
increasing circulating triglycerides and cholesterol in very low density
lipoprotein particles. Lin et al. (2005) determined that the stimulation
of lipoprotein transport upon Pgc1-beta expression was likely due to the
simultaneous coactivation of the liver nuclear hormone receptor,
Lxr-alpha (NR1H3; 602423). These data suggested a mechanism through
which dietary saturated fats can stimulate hyperlipidemia and
atherogenesis.
Synthesis of membrane lipids is critical for cell growth and
proliferation. Bengoechea-Alonso et al. (2005) found that G2/M arrest in
human cell lines induced expression of a number of SREBP-responsive
promoter reporter genes in an SREBP-dependent manner. In addition, the
mature forms of SREBP1a and SREBP1c were hyperphosphorylated on
C-terminal residues in mitotic cells, whereas mature SREBP2 was not. The
transcriptional potency of mature SREBP1 was enhanced in cells arrested
in G2/M, and this effect depended on the C-terminal domain of the
protein. In agreement with these observations, synthesis of cholesterol
was enhanced in G2/M-arrested cells. Bengoechea-Alonso et al. (2005)
concluded that the activity of mature SREBP1 is regulated by
phosphorylation during the cell cycle, and that SREBP1 provides a link
between lipid synthesis, proliferation, and cell growth.
Yang et al. (2006) showed that SREBPs use the evolutionarily conserved
ARC105 (607372), also called MED15, subunit to activate target genes.
Structural analysis of the SREBP-binding domain in ARC105 by nuclear
magnetic resonance (NMR) revealed a 3-helix bundle with marked
similarity to the CBP/p300 (see 600140) KIX domain. In contrast to
SREBPs, the CREB (123810) and c-MYB (189990) activators do not bind the
ARC105 KIX domain, although they interact with the CBP KIX domain,
revealing a surprising specificity among structurally related
activator-binding domains. The C. elegans SREBP homolog Sbp1 promotes
fatty acid homeostasis by regulating the expression of lipogenic
enzymes. Yang et al. (2006) found that, like Sbp1, the C. elegans ARC105
homolog Mdt15 is required for fatty acid homeostasis, and showed that
both Sbp1 and Mdt15 control transcription of genes governing
desaturation of stearic acid to oleic acid. Dietary addition of oleic
acid significantly rescued various defects of nematodes targeted with
RNA interference against Sbp1 and Mdt15, including impaired intestinal
fat storage, infertility, decreased size, and slow locomotion,
suggesting that regulation of oleic acid levels represents a
physiologically critical function of Sbp1 and Mdt15. Yang et al. (2006)
concluded that ARC105 is a key effector of SREBP-dependent gene
regulation and control of lipid homeostasis in metazoans.
Najafi-Shoushtari et al. (2010) demonstrated that the microRNA miR33B
(613486) embedded within an intron of the SREBP1 gene targets the
adenosine triphosphate-binding cassette transporter A1 (ABCA1; 600046),
an important regulator of high density lipoprotein (HDL) synthesis and
reverse cholesterol transport, for posttranscriptional repression. The
mature form of miR33B appeared to be coexpressed with SREBP1 in a number
of human tissues examined.
GENE STRUCTURE
Hua et al. (1995) determined that the SREBF1 gene is 26 kb long and has
22 exons and 20 introns.
Najafi-Shoushtari et al. (2010) identified the miR33B gene in intron 17
of the SREBP1 gene. The presence of this microRNA in SREBP1 is not
conserved in mice.
MAPPING
By analysis of human/rodent somatic cell hybrids and fluorescence in
situ hybridization, Hua et al. (1995) mapped the SREBF1 gene to 17p11.2.
ANIMAL MODEL
The synthesis of cholesterol and its uptake from plasma LDL are
regulated by 2 membrane-bound transcription factors, SREBP1 and SREBP2.
Shimano et al. (1997) used homologous recombination to generate mice
with disruptions in the gene coding the 2 isoforms of SREBP1, which they
termed SREBP1a and SREBP1c. Heterozygous gene-disrupted mice were
phenotypically normal, but 50 to 85% of the homozygous -/- mice died in
utero at embryonic day 11. The surviving -/- mice appeared normal at
birth and throughout life. Their livers expressed no functional SREBP1,
but there was a 1.5-fold upregulation of SREBP2 at the level of mRNA and
a 2- to 3-fold increase in the amount of mature SREBP2 in liver nuclei.
Previous studies had shown that SREBP2 is much more potent than SREBP1c,
the predominant hepatic isoform of SREBP1, in activating transcription
of genes encoding enzymes of cholesterol synthesis. Elevated levels of
mRNAs for 4 enzymes of cholesterol synthesis were observed. Cholesterol
synthesis, as measured by the incorporation of tritium-labeled water,
was elevated 3-fold in the livers of the -/- mice, and hepatic
cholesterol content was increased by 50%. Thus, Shimano et al. (1997)
concluded that SREBP2 can replace SREBP1 in regulating cholesterol
synthesis in livers of mice and that the higher potency of SREBP2 leads
to excessive hepatic cholesterol synthesis in these animals.
Shimomura et al. (1998) produced transgenic mice that overexpressed
nuclear SREBP1C in adipose tissue under the control of the
adipocyte-specific aP2 (600434) enhancer/promoter. These mice exhibited
many of the features of congenital generalized lipodystrophy (BSCL;
269700). White fat failed to differentiate fully, and the size of the
white fat deposits was markedly decreased. Brown fat was hypertrophic
and contained fat-laden cells resembling immature white fat. Levels of
mRNA encoding adipocyte differentiation markers, including leptin
(164160), were reduced, but levels of PREF1 (176290) and TNF-alpha
(191160) were increased. Marked insulin resistance with 60-fold
elevation in plasma insulin was observed. Diabetes mellitus with
elevated blood glucose of greater than 300 mg/dl that failed to decline
when insulin was injected was also seen. The transgenic mice had fatty
liver from birth and developed elevated plasma triglyceride levels later
in life.
By studying lipodystrophic and obese (ob/ob) mice, Shimomura et al.
(2000) showed that chronic hyperinsulinemia downregulates the mRNA for
IRS2 (600797), an essential component of the insulin-signaling pathway
in liver, thereby producing insulin resistance. Despite IRS2 deficiency,
insulin continues to stimulate production of SREBP1c. The combination of
insulin resistance (inappropriate gluconeogenesis) and insulin
sensitivity (elevated lipogenesis) establishes a vicious cycle that
aggravates hyperinsulinemia and insulin resistance in lipodystrophic and
ob/ob mice.
Using oligonucleotide microarray and Northern blot analyses to analyze
gene expression, Tobe et al. (2001) detected increased expression of
SREBP1 in insulin-resistant Irs2-deficient mouse liver. Tobe et al.
(2001) also detected an increase in the expression of several SREBP1
downstream genes involved in fatty acid synthesis. Tobe et al. (2001)
showed that leptin resistance contributes to the upregulation of the
SREBP1 gene by demonstrating that high dose leptin administration
reduced food intake and body weight, and ameliorated SREBP1
overexpression in Irs2-deficient mice.
Nagata et al. (2004) noted that a high-fructose diet in rats induces
metabolic derangements similar to those found in the metabolic syndrome,
which is a constellation of features including hyperlipidemia, visceral
obesity, impaired glucose tolerance, and hyperinsulinemia. In a group of
10 strains of inbred mice, which could be separated into those that
developed the metabolic syndrome in response to a high-fructose diet
(CBA) and those that did not develop the syndrome (DBA), the authors
found that hepatic mRNA expression of the SREBP1 protein was enhanced in
CBA mice, but not in DBA mice. Sequence analysis showed that the
nucleotide sequence at -468 bp in the SREBP1 promoter was guanine in the
CBA group and adenine in the DBA group. In cultured hepatocytes from CBA
mice, the activity of the SREBP1 promoter was significantly increased by
2.4- and 2.2-fold in response to fructose or insulin, respectively,
whereas the activity of the DBA SREBP1 promoter responded to insulin but
not to fructose. The authors concluded that genetic alterations of
transcriptional regulation at the SREBP1 promoter explain the different
responses to a high-fructose diet in these 2 strains.
In cortical neuron culture, Taghibiglou et al. (2009) found that
activation of NMDA receptors resulted in increased activation and
nuclear accumulation of SREBP1. The activation was primarily mediated by
the NR2B (138252) subunit-containing receptor. Inhibition of
NMDAR-dependent SREBP1 activation by cholesterol decreased NMDA-induced
excitotoxic cell death. Similarly, shRNA against SREBP1 also resulted in
decreased cell death in culture. These findings implicated SREBP1 as a
mediator of NMDA-induced excitotoxicity. NMDAR-mediated activation of
SREBP1 was shown to result from increased INSIG1 (602055) degradation,
which could be inhibited with an interference peptide. In a rat model of
focal ischemic stroke, systemic administration of the INSIG1
interference peptide prevented SREBP1 activation, substantially reduced
neuronal damage, and improved behavioral outcome.
*FIELD* RF
1. Bengoechea-Alonso, M. T.; Punga, T.; Ericsson, J.: Hyperphosphorylation
regulates the activity of SREBP1 during mitosis. Proc. Nat. Acad.
Sci. 102: 11681-11686, 2005.
2. DeBose-Boyd, R. A.; Brown, M. S.; Li, W.-P.; Nohturfft, A.; Goldstein,
J. L.; Espenshade, P. J.: Transport-dependent proteolysis of SREBP:
relocation of Site-1 protease from Golgi to ER obviates the need for
SREBP transport to Golgi. Cell 99: 703-712, 1999.
3. Hua, X.; Wu, J.; Goldstein, J. L.; Brown, M. S.; Hobbs, H. H.:
Structure of the human gene encoding sterol regulatory element binding
protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes
17p11.2 and 22q13. Genomics 25: 667-673, 1995.
4. Lin, J.; Yang, R.; Tarr, P. T.; Wu, P.-H.; Handschin, C.; Li, S.;
Yang, W.; Pei, L.; Uldry, M.; Tontonoz, P.; Newgard, C. B.; Spiegelman,
B. M.: Hyperlipidemic effects of dietary saturated fats mediated
through PGC-1-beta coactivation of SREBP. Cell 120: 261-273, 2005.
5. Lloyd, D. J.; Trembath, R. C.; Shackleton, S.: A novel interaction
between lamin A and SREBP1: implications for partial lipodystrophy
and other laminopathies. Hum. Molec. Genet. 11: 769-777, 2002.
6. Nagata, R.; Nishio, Y.; Sekine, O.; Nagai, Y.; Maeno, Y.; Ugi,
S.; Maegawa, H.; Kashiwagi, A.: Single nucleotide polymorphism (-468
G to A) at the promoter region of SREBP-1c associates with genetic
defect of fructose-induced hepatic lipogenesis. J. Biol. Chem. 279:
29031-29042, 2004. Note: Erratum: J. Biol. Chem. 279: 37210 only,
2004.
7. Najafi-Shoushtari, S. H.; Kristo, F.; Li, Y.; Shioda, T.; Cohen,
D. E.; Gerszten, R. E.; Naar, A. M.: MicroRNA-33 and the SREBP host
genes cooperate to control cholesterol homeostasis. Science 328:
1566-1569, 2010.
8. Osborne, T. F.: CREating a SCAP-less liver keeps SREBPs pinned
in the ER membrane and prevents increased lipid synthesis in response
to low cholesterol and high insulin. Genes Dev. 15: 1873-1878, 2001.
9. Shimano, H.; Shimomura, I.; Hammer, R. E.; Herz, J.; Goldstein,
J. L.; Brown, M. S.; Horton, J. D.: Elevated levels of SREBP-2 and
cholesterol synthesis in livers of mice homozygous for a targeted
disruption of the SREBP-1 gene. J. Clin. Invest. 100: 2115-2124,
1997.
10. Shimomura, I.; Hammer, R. E.; Richardson, J. A.; Ikemoto, S.;
Bashmakov, Y.; Goldstein, J. L.; Brown, M. S.: Insulin resistance
and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c
in adipose tissue: model for congenital generalized lipodystrophy. Genes
Dev. 12: 3182-3194, 1998.
11. Shimomura, I.; Matsuda, M.; Hammer, R. E.; Bashmakov, Y.; Brown,
M. S.; Goldstein, J. L.: Decreased IRS-2 and increased SREBP-1c lead
to mixed insulin resistance and sensitivity in livers of lipodystrophic
and ob/ob mice. Molec. Cell 6: 77-86, 2000.
12. Shimomura, I.; Shimano, H.; Horton, J. D.; Goldstein, J. L.; Brown,
M. S.: Differential expression of exons 1a and 1c in mRNAs for sterol
regulatory element binding protein-1 in human and mouse organs and
cultured cells. J. Clin. Invest. 99: 838-845, 1997.
13. Taghibiglou, C.; Martin, H. G. S.; Lai, T. W.; Cho, T.; Prasad,
S.; Kojic, L.; Lu, J.; Liu, Y.; Lo, E.; Zhang, S.; Wu, J. Z. Z.; Li,
Y. P.; Wen, Y. H.; Imm, J.-H.; Cynader, M. S.; Wang, Y. T.: Role
of NMDA receptor-dependent activation of SREBP1 in excitotoxic and
ischemic neuronal injuries. Nature Med. 15: 1399-1406, 2009.
14. Tobe, K.; Suzuki, R.; Aoyama, M.; Yamauchi, T.; Kamon, J.; Kubota,
N.; Terauchi, Y.; Matsui, J.; Akanuma, Y.; Kimura, S.; Tanaka, J.;
Abe, M.; Ohsumi, J.; Nagai, R.; Kadowaki, T.: Increased expression
of the sterol regulatory element-binding protein-1 gene in insulin
receptor substrate-2 -/- mouse liver. J. Biol. Chem. 276: 38337-38340,
2001.
15. Wang, X.; Sato, R.; Brown, M. S.; Hua, X.; Goldstein, J. L.:
SREBP-1, a membrane-bound transcription factor released by sterol-regulated
proteolysis. Cell 77: 53-62, 1994.
16. Yang, F.; Vought, B. W.; Satterlee, J. S.; Walker, A. K.; Sun,
Z.-Y. J.; Watts, J. L.; DeBeaumont, R.; Saito, R. M.; Hyberts, S.
G.; Yang, S.; Macol, C.; Iyer, L.; Tjian, R.; van den Heuvel, S.;
Hart, A. C.; Wagner, G.; Naar, A. M.: An ARC/mediator subunit required
for SREBP control of cholesterol and lipid homeostasis. Nature 442:
700-704, 2006.
17. Yokoyama, C.; Wang, X.; Briggs, M. R.; Admon, A.; Wu, J.; Hua,
X.; Goldstein, J. L.; Brown, M. S.: SREBP-1, a basic-helix-loop-helix-leucine
zipper protein that controls transcription of the low density lipoprotein
receptor gene. Cell 75: 187-197, 1993.
*FIELD* CN
Ada Hamosh - updated: 7/12/2010
Cassandra L. Kniffin - updated: 12/17/2009
Patricia A. Hartz - updated: 11/1/2006
Ada Hamosh - updated: 9/8/2006
Stylianos E. Antonarakis - updated: 2/16/2005
Cassandra L. Kniffin - updated: 7/16/2004
George E. Tiller - updated: 10/28/2002
Dawn Watkins-Chow - updated: 6/13/2002
Patricia A. Hartz - updated: 4/18/2002
Stylianos E. Antonarakis - updated: 9/11/2000
Stylianos E. Antonarakis - updated: 1/19/2000
Ada Hamosh - updated: 9/3/1999
Victor A. McKusick - updated: 11/7/1997
*FIELD* CD
Victor A. McKusick: 2/4/1994
*FIELD* ED
terry: 06/07/2012
alopez: 3/7/2012
alopez: 7/16/2010
alopez: 7/14/2010
terry: 7/12/2010
wwang: 1/6/2010
ckniffin: 12/17/2009
mgross: 11/3/2006
terry: 11/1/2006
alopez: 9/19/2006
terry: 9/8/2006
mgross: 2/16/2005
terry: 8/17/2004
tkritzer: 7/26/2004
ckniffin: 7/16/2004
tkritzer: 2/28/2003
cwells: 10/28/2002
cwells: 6/13/2002
ckniffin: 6/5/2002
carol: 4/18/2002
mgross: 9/11/2000
mgross: 1/19/2000
alopez: 9/3/1999
terry: 9/3/1999
dkim: 12/10/1998
jenny: 11/12/1997
terry: 11/7/1997
mark: 4/7/1995
jason: 7/13/1994
carol: 2/4/1994
*RECORD*
*FIELD* NO
184756
*FIELD* TI
*184756 STEROL REGULATORY ELEMENT-BINDING TRANSCRIPTION FACTOR 1; SREBF1
;;STEROL REGULATORY ELEMENT-BINDING PROTEIN 1; SREBP1
read more*FIELD* TX
DESCRIPTION
Sterol regulatory element-binding protein-1 (SREBP1) and SREBP2 (600481)
are structurally related proteins that control cholesterol homeostasis
by stimulating transcription of sterol-regulated genes (summary by
Osborne, 2001).
CLONING
Sterol regulatory element-1 (SRE1), a decamer
(5-prime-ATC-ACCCCAC-3-prime) flanking the low density lipoprotein
receptor gene (LDLR; 606945), activates transcription in sterol-depleted
cells and is silenced by sterols. Yokoyama et al. (1993) cloned the cDNA
corresponding to human SREBP1, a protein that binds SRE1, activates
transcription, and thereby mediates the final regulatory step in LDL
metabolism. SREBP1 contains a basic helix-loop-helix leucine zipper
(bHLH-ZIP) motif, but it differs from other bHLH-ZIP proteins in its
larger size (1,147 amino acids) and target sequence. Instead of an
inverted repeat (CANNTG), the target for all known bHLH-ZIP proteins,
SRE1 contains a direct repeat of CAC.
Hua et al. (1995) described the cloning and characterization of SREBP1
from a human cosmid DNA library. Alternative splicing at both the
5-prime and 3-prime ends of the mRNA results in several forms of the
protein whose functional differences were unknown.
Shimomura et al. (1997) noted that the 5-prime end of SREBP1 exists in 2
forms, designated 1a and 1c, resulting from the use of 2 transcription
start sites that produce 2 separate 5-prime exons, each of which is
spliced to a common exon 2. Among organs in adult mice, the authors
found that expression of the 1a and 1c transcripts varied; the 1a exon
predominated in cells that differentiated into adipocytes and in the
spleen, whereas the 1c exon predominated in liver cells, white and brown
adipose tissue, adrenal gland, and several other tissues of the adult
mouse. The findings suggested that the 2 transcripts are controlled
independently in specific organs in response to metabolic factors.
GENE FUNCTION
Yokoyama et al. (1993) found that overexpression of SREBP1 activates
transcription of reporter genes containing SRE1 in the absence (15-fold)
and presence (90-fold) of sterols, abolishing sterol regulation.
SREBP1 is synthesized as a 125-kD precursor that is attached to the
nuclear membrane and endoplasmic reticulum (ER). Wang et al. (1994)
found that in sterol-depleted cells, the membrane-bound precursor is
cleaved to generate a soluble N-terminal fragment (apparent molecular
mass, 68 kD) that translocates to the nucleus. This fragment, which
includes the bHLH-ZIP domain, activates transcription of the genes for
the LDL receptor and HMG-CoA synthase (142940). Sterols inhibit the
cleavage of SREBP1, and the 68-kD nuclear form is rapidly catabolized,
thereby reducing transcription. N-acetyl-leucyl-leucyl-norleucinal
(ALLN), an inhibitor of neutral cysteine proteases, blocked the
breakdown of the 68-kD form and superinduced sterol-regulated genes.
Sterol-regulated proteolysis of a membrane-bound transcription factor is
a novel mechanism by which transcription can be regulated by membrane
lipids.
Cholesterol homeostasis in animal cells is achieved by regulated
cleavage of SREBPs, membrane-bound transcription factors. Proteolytic
release of the active domains of SREBPs from membranes requires a
sterol-sensing protein called SCAP (601510), which forms a complex with
SREBPs. In sterol-depleted cells, DeBose-Boyd et al. (1999) found that
SCAP escorts SREBPs from the ER to the Golgi, where SREBPs are cleaved
by site-1 protease (S1P; 603355). The authors showed that sterols block
this transport and abolish cleavage. Relocating active S1P from Golgi to
ER by treating cells with brefeldin A or by fusing the ER retention
signal KDEL to S1P obviated the SCAP requirement and rendered cleavage
insensitive to sterols. DeBose-Boyd et al. (1999) concluded that
transport-dependent proteolysis may be a common mechanism to regulate
the processing of membrane proteins.
See review by Osborne (2001).
The gene encoding nuclear lamin A/C (LMNA; 150330) is mutated in at
least 3 inherited disorders. Two of these, Emery-Dreifuss muscular
dystrophy (EDMD; 310300) and a form of dilated cardiomyopathy (CMD1A;
115200), involve muscle defects, and the other, familial partial
lipodystrophy (FPLD; 151660), involves loss of subcutaneous adipose
tissue. Lloyd et al. (2002) identified proteins interacting with the
C-terminal domain of lamin A by screening a mouse 3T3-L1 adipocyte
library in a yeast 2-hybrid interaction screen. Using this approach,
SREBP1 was identified as a novel lamin A interactor. A binding site for
lamin A was identified in the N-terminal transcription factor domain of
SREBP1, between residues 227 and 487. The binding of lamin A to SREBP1
was noticeably reduced by FPLD mutations; one EDMD mutation also
interfered with the interaction between lamin A and SREBP1. The authors
speculated that fat loss seen in laminopathies may be caused in part by
reduced binding of the adipocyte differentiation factor SREBP1 to lamin
A.
Lin et al. (2005) found that high-fat feeding stimulated expression of
both Pgc1-beta (PPARGC1B; 608886) and Srebp1a/1c in mouse liver.
Pgc1-beta coactivated the Srebp transcription factor family and
stimulated lipogenic gene expression. Furthermore, Pgc1-beta was
required for Srebp-mediated lipogenic gene expression. However, unlike
Srebp itself, Pgc1-beta reduced fat accumulation in liver while greatly
increasing circulating triglycerides and cholesterol in very low density
lipoprotein particles. Lin et al. (2005) determined that the stimulation
of lipoprotein transport upon Pgc1-beta expression was likely due to the
simultaneous coactivation of the liver nuclear hormone receptor,
Lxr-alpha (NR1H3; 602423). These data suggested a mechanism through
which dietary saturated fats can stimulate hyperlipidemia and
atherogenesis.
Synthesis of membrane lipids is critical for cell growth and
proliferation. Bengoechea-Alonso et al. (2005) found that G2/M arrest in
human cell lines induced expression of a number of SREBP-responsive
promoter reporter genes in an SREBP-dependent manner. In addition, the
mature forms of SREBP1a and SREBP1c were hyperphosphorylated on
C-terminal residues in mitotic cells, whereas mature SREBP2 was not. The
transcriptional potency of mature SREBP1 was enhanced in cells arrested
in G2/M, and this effect depended on the C-terminal domain of the
protein. In agreement with these observations, synthesis of cholesterol
was enhanced in G2/M-arrested cells. Bengoechea-Alonso et al. (2005)
concluded that the activity of mature SREBP1 is regulated by
phosphorylation during the cell cycle, and that SREBP1 provides a link
between lipid synthesis, proliferation, and cell growth.
Yang et al. (2006) showed that SREBPs use the evolutionarily conserved
ARC105 (607372), also called MED15, subunit to activate target genes.
Structural analysis of the SREBP-binding domain in ARC105 by nuclear
magnetic resonance (NMR) revealed a 3-helix bundle with marked
similarity to the CBP/p300 (see 600140) KIX domain. In contrast to
SREBPs, the CREB (123810) and c-MYB (189990) activators do not bind the
ARC105 KIX domain, although they interact with the CBP KIX domain,
revealing a surprising specificity among structurally related
activator-binding domains. The C. elegans SREBP homolog Sbp1 promotes
fatty acid homeostasis by regulating the expression of lipogenic
enzymes. Yang et al. (2006) found that, like Sbp1, the C. elegans ARC105
homolog Mdt15 is required for fatty acid homeostasis, and showed that
both Sbp1 and Mdt15 control transcription of genes governing
desaturation of stearic acid to oleic acid. Dietary addition of oleic
acid significantly rescued various defects of nematodes targeted with
RNA interference against Sbp1 and Mdt15, including impaired intestinal
fat storage, infertility, decreased size, and slow locomotion,
suggesting that regulation of oleic acid levels represents a
physiologically critical function of Sbp1 and Mdt15. Yang et al. (2006)
concluded that ARC105 is a key effector of SREBP-dependent gene
regulation and control of lipid homeostasis in metazoans.
Najafi-Shoushtari et al. (2010) demonstrated that the microRNA miR33B
(613486) embedded within an intron of the SREBP1 gene targets the
adenosine triphosphate-binding cassette transporter A1 (ABCA1; 600046),
an important regulator of high density lipoprotein (HDL) synthesis and
reverse cholesterol transport, for posttranscriptional repression. The
mature form of miR33B appeared to be coexpressed with SREBP1 in a number
of human tissues examined.
GENE STRUCTURE
Hua et al. (1995) determined that the SREBF1 gene is 26 kb long and has
22 exons and 20 introns.
Najafi-Shoushtari et al. (2010) identified the miR33B gene in intron 17
of the SREBP1 gene. The presence of this microRNA in SREBP1 is not
conserved in mice.
MAPPING
By analysis of human/rodent somatic cell hybrids and fluorescence in
situ hybridization, Hua et al. (1995) mapped the SREBF1 gene to 17p11.2.
ANIMAL MODEL
The synthesis of cholesterol and its uptake from plasma LDL are
regulated by 2 membrane-bound transcription factors, SREBP1 and SREBP2.
Shimano et al. (1997) used homologous recombination to generate mice
with disruptions in the gene coding the 2 isoforms of SREBP1, which they
termed SREBP1a and SREBP1c. Heterozygous gene-disrupted mice were
phenotypically normal, but 50 to 85% of the homozygous -/- mice died in
utero at embryonic day 11. The surviving -/- mice appeared normal at
birth and throughout life. Their livers expressed no functional SREBP1,
but there was a 1.5-fold upregulation of SREBP2 at the level of mRNA and
a 2- to 3-fold increase in the amount of mature SREBP2 in liver nuclei.
Previous studies had shown that SREBP2 is much more potent than SREBP1c,
the predominant hepatic isoform of SREBP1, in activating transcription
of genes encoding enzymes of cholesterol synthesis. Elevated levels of
mRNAs for 4 enzymes of cholesterol synthesis were observed. Cholesterol
synthesis, as measured by the incorporation of tritium-labeled water,
was elevated 3-fold in the livers of the -/- mice, and hepatic
cholesterol content was increased by 50%. Thus, Shimano et al. (1997)
concluded that SREBP2 can replace SREBP1 in regulating cholesterol
synthesis in livers of mice and that the higher potency of SREBP2 leads
to excessive hepatic cholesterol synthesis in these animals.
Shimomura et al. (1998) produced transgenic mice that overexpressed
nuclear SREBP1C in adipose tissue under the control of the
adipocyte-specific aP2 (600434) enhancer/promoter. These mice exhibited
many of the features of congenital generalized lipodystrophy (BSCL;
269700). White fat failed to differentiate fully, and the size of the
white fat deposits was markedly decreased. Brown fat was hypertrophic
and contained fat-laden cells resembling immature white fat. Levels of
mRNA encoding adipocyte differentiation markers, including leptin
(164160), were reduced, but levels of PREF1 (176290) and TNF-alpha
(191160) were increased. Marked insulin resistance with 60-fold
elevation in plasma insulin was observed. Diabetes mellitus with
elevated blood glucose of greater than 300 mg/dl that failed to decline
when insulin was injected was also seen. The transgenic mice had fatty
liver from birth and developed elevated plasma triglyceride levels later
in life.
By studying lipodystrophic and obese (ob/ob) mice, Shimomura et al.
(2000) showed that chronic hyperinsulinemia downregulates the mRNA for
IRS2 (600797), an essential component of the insulin-signaling pathway
in liver, thereby producing insulin resistance. Despite IRS2 deficiency,
insulin continues to stimulate production of SREBP1c. The combination of
insulin resistance (inappropriate gluconeogenesis) and insulin
sensitivity (elevated lipogenesis) establishes a vicious cycle that
aggravates hyperinsulinemia and insulin resistance in lipodystrophic and
ob/ob mice.
Using oligonucleotide microarray and Northern blot analyses to analyze
gene expression, Tobe et al. (2001) detected increased expression of
SREBP1 in insulin-resistant Irs2-deficient mouse liver. Tobe et al.
(2001) also detected an increase in the expression of several SREBP1
downstream genes involved in fatty acid synthesis. Tobe et al. (2001)
showed that leptin resistance contributes to the upregulation of the
SREBP1 gene by demonstrating that high dose leptin administration
reduced food intake and body weight, and ameliorated SREBP1
overexpression in Irs2-deficient mice.
Nagata et al. (2004) noted that a high-fructose diet in rats induces
metabolic derangements similar to those found in the metabolic syndrome,
which is a constellation of features including hyperlipidemia, visceral
obesity, impaired glucose tolerance, and hyperinsulinemia. In a group of
10 strains of inbred mice, which could be separated into those that
developed the metabolic syndrome in response to a high-fructose diet
(CBA) and those that did not develop the syndrome (DBA), the authors
found that hepatic mRNA expression of the SREBP1 protein was enhanced in
CBA mice, but not in DBA mice. Sequence analysis showed that the
nucleotide sequence at -468 bp in the SREBP1 promoter was guanine in the
CBA group and adenine in the DBA group. In cultured hepatocytes from CBA
mice, the activity of the SREBP1 promoter was significantly increased by
2.4- and 2.2-fold in response to fructose or insulin, respectively,
whereas the activity of the DBA SREBP1 promoter responded to insulin but
not to fructose. The authors concluded that genetic alterations of
transcriptional regulation at the SREBP1 promoter explain the different
responses to a high-fructose diet in these 2 strains.
In cortical neuron culture, Taghibiglou et al. (2009) found that
activation of NMDA receptors resulted in increased activation and
nuclear accumulation of SREBP1. The activation was primarily mediated by
the NR2B (138252) subunit-containing receptor. Inhibition of
NMDAR-dependent SREBP1 activation by cholesterol decreased NMDA-induced
excitotoxic cell death. Similarly, shRNA against SREBP1 also resulted in
decreased cell death in culture. These findings implicated SREBP1 as a
mediator of NMDA-induced excitotoxicity. NMDAR-mediated activation of
SREBP1 was shown to result from increased INSIG1 (602055) degradation,
which could be inhibited with an interference peptide. In a rat model of
focal ischemic stroke, systemic administration of the INSIG1
interference peptide prevented SREBP1 activation, substantially reduced
neuronal damage, and improved behavioral outcome.
*FIELD* RF
1. Bengoechea-Alonso, M. T.; Punga, T.; Ericsson, J.: Hyperphosphorylation
regulates the activity of SREBP1 during mitosis. Proc. Nat. Acad.
Sci. 102: 11681-11686, 2005.
2. DeBose-Boyd, R. A.; Brown, M. S.; Li, W.-P.; Nohturfft, A.; Goldstein,
J. L.; Espenshade, P. J.: Transport-dependent proteolysis of SREBP:
relocation of Site-1 protease from Golgi to ER obviates the need for
SREBP transport to Golgi. Cell 99: 703-712, 1999.
3. Hua, X.; Wu, J.; Goldstein, J. L.; Brown, M. S.; Hobbs, H. H.:
Structure of the human gene encoding sterol regulatory element binding
protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes
17p11.2 and 22q13. Genomics 25: 667-673, 1995.
4. Lin, J.; Yang, R.; Tarr, P. T.; Wu, P.-H.; Handschin, C.; Li, S.;
Yang, W.; Pei, L.; Uldry, M.; Tontonoz, P.; Newgard, C. B.; Spiegelman,
B. M.: Hyperlipidemic effects of dietary saturated fats mediated
through PGC-1-beta coactivation of SREBP. Cell 120: 261-273, 2005.
5. Lloyd, D. J.; Trembath, R. C.; Shackleton, S.: A novel interaction
between lamin A and SREBP1: implications for partial lipodystrophy
and other laminopathies. Hum. Molec. Genet. 11: 769-777, 2002.
6. Nagata, R.; Nishio, Y.; Sekine, O.; Nagai, Y.; Maeno, Y.; Ugi,
S.; Maegawa, H.; Kashiwagi, A.: Single nucleotide polymorphism (-468
G to A) at the promoter region of SREBP-1c associates with genetic
defect of fructose-induced hepatic lipogenesis. J. Biol. Chem. 279:
29031-29042, 2004. Note: Erratum: J. Biol. Chem. 279: 37210 only,
2004.
7. Najafi-Shoushtari, S. H.; Kristo, F.; Li, Y.; Shioda, T.; Cohen,
D. E.; Gerszten, R. E.; Naar, A. M.: MicroRNA-33 and the SREBP host
genes cooperate to control cholesterol homeostasis. Science 328:
1566-1569, 2010.
8. Osborne, T. F.: CREating a SCAP-less liver keeps SREBPs pinned
in the ER membrane and prevents increased lipid synthesis in response
to low cholesterol and high insulin. Genes Dev. 15: 1873-1878, 2001.
9. Shimano, H.; Shimomura, I.; Hammer, R. E.; Herz, J.; Goldstein,
J. L.; Brown, M. S.; Horton, J. D.: Elevated levels of SREBP-2 and
cholesterol synthesis in livers of mice homozygous for a targeted
disruption of the SREBP-1 gene. J. Clin. Invest. 100: 2115-2124,
1997.
10. Shimomura, I.; Hammer, R. E.; Richardson, J. A.; Ikemoto, S.;
Bashmakov, Y.; Goldstein, J. L.; Brown, M. S.: Insulin resistance
and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c
in adipose tissue: model for congenital generalized lipodystrophy. Genes
Dev. 12: 3182-3194, 1998.
11. Shimomura, I.; Matsuda, M.; Hammer, R. E.; Bashmakov, Y.; Brown,
M. S.; Goldstein, J. L.: Decreased IRS-2 and increased SREBP-1c lead
to mixed insulin resistance and sensitivity in livers of lipodystrophic
and ob/ob mice. Molec. Cell 6: 77-86, 2000.
12. Shimomura, I.; Shimano, H.; Horton, J. D.; Goldstein, J. L.; Brown,
M. S.: Differential expression of exons 1a and 1c in mRNAs for sterol
regulatory element binding protein-1 in human and mouse organs and
cultured cells. J. Clin. Invest. 99: 838-845, 1997.
13. Taghibiglou, C.; Martin, H. G. S.; Lai, T. W.; Cho, T.; Prasad,
S.; Kojic, L.; Lu, J.; Liu, Y.; Lo, E.; Zhang, S.; Wu, J. Z. Z.; Li,
Y. P.; Wen, Y. H.; Imm, J.-H.; Cynader, M. S.; Wang, Y. T.: Role
of NMDA receptor-dependent activation of SREBP1 in excitotoxic and
ischemic neuronal injuries. Nature Med. 15: 1399-1406, 2009.
14. Tobe, K.; Suzuki, R.; Aoyama, M.; Yamauchi, T.; Kamon, J.; Kubota,
N.; Terauchi, Y.; Matsui, J.; Akanuma, Y.; Kimura, S.; Tanaka, J.;
Abe, M.; Ohsumi, J.; Nagai, R.; Kadowaki, T.: Increased expression
of the sterol regulatory element-binding protein-1 gene in insulin
receptor substrate-2 -/- mouse liver. J. Biol. Chem. 276: 38337-38340,
2001.
15. Wang, X.; Sato, R.; Brown, M. S.; Hua, X.; Goldstein, J. L.:
SREBP-1, a membrane-bound transcription factor released by sterol-regulated
proteolysis. Cell 77: 53-62, 1994.
16. Yang, F.; Vought, B. W.; Satterlee, J. S.; Walker, A. K.; Sun,
Z.-Y. J.; Watts, J. L.; DeBeaumont, R.; Saito, R. M.; Hyberts, S.
G.; Yang, S.; Macol, C.; Iyer, L.; Tjian, R.; van den Heuvel, S.;
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17. Yokoyama, C.; Wang, X.; Briggs, M. R.; Admon, A.; Wu, J.; Hua,
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*FIELD* CN
Ada Hamosh - updated: 7/12/2010
Cassandra L. Kniffin - updated: 12/17/2009
Patricia A. Hartz - updated: 11/1/2006
Ada Hamosh - updated: 9/8/2006
Stylianos E. Antonarakis - updated: 2/16/2005
Cassandra L. Kniffin - updated: 7/16/2004
George E. Tiller - updated: 10/28/2002
Dawn Watkins-Chow - updated: 6/13/2002
Patricia A. Hartz - updated: 4/18/2002
Stylianos E. Antonarakis - updated: 9/11/2000
Stylianos E. Antonarakis - updated: 1/19/2000
Ada Hamosh - updated: 9/3/1999
Victor A. McKusick - updated: 11/7/1997
*FIELD* CD
Victor A. McKusick: 2/4/1994
*FIELD* ED
terry: 06/07/2012
alopez: 3/7/2012
alopez: 7/16/2010
alopez: 7/14/2010
terry: 7/12/2010
wwang: 1/6/2010
ckniffin: 12/17/2009
mgross: 11/3/2006
terry: 11/1/2006
alopez: 9/19/2006
terry: 9/8/2006
mgross: 2/16/2005
terry: 8/17/2004
tkritzer: 7/26/2004
ckniffin: 7/16/2004
tkritzer: 2/28/2003
cwells: 10/28/2002
cwells: 6/13/2002
ckniffin: 6/5/2002
carol: 4/18/2002
mgross: 9/11/2000
mgross: 1/19/2000
alopez: 9/3/1999
terry: 9/3/1999
dkim: 12/10/1998
jenny: 11/12/1997
terry: 11/7/1997
mark: 4/7/1995
jason: 7/13/1994
carol: 2/4/1994