View source for Sterol regulatory element-binding protein

{{infobox protein
| Name = Sterol regulatory element-binding transcription factor 1
| caption = [[X-ray crystallography#Biological macromolecular crystallography|X-ray crystallography]] of Sterol Regulatory Element Binding Protein 1A with polydeoxyribonucleotide.<ref name="Parraga_1998">{{PDB|1AM9}}; {{cite journal | vauthors = Párraga A, Bellsolell L, Ferré-D'Amaré AR, Burley SK | title = Co-crystal structure of sterol regulatory element binding protein 1a at 2.3 A resolution | journal = Structure | volume = 6 | issue = 5 | pages = 661–72 | year = 1998 | pmid = 9634703 | doi = 10.1016/S0969-2126(98)00067-7 }}</ref>
| image = Sterol Regulatory Element Binding Protein 1A.png
| width = 
| HGNCid = 11289
| Symbol = SREBF1
| AltSymbols = 
| EntrezGene = 6720
| OMIM = 184756
| RefSeq = NM_004176
| UniProt = P36956
| PDB = 1am9
| ECnumber = 
| Chromosome = 17
| Arm = p
| Band = 11.2
| LocusSupplementaryData = 
}}
{{infobox protein
| Name = sterol regulatory element-binding transcription factor 2
| caption = 
| image = 
| width = 
| HGNCid = 11290
| Symbol = SREBF2
| AltSymbols = 
| EntrezGene = 6721
| OMIM = 600481
| RefSeq = NM_004599
| UniProt = Q12772
| PDB = 
| ECnumber = 
| Chromosome = 22
| Arm = q
| Band = 13
| LocusSupplementaryData = 
}}

'''Sterol regulatory element-binding proteins''' ('''SREBPs''') are [[transcription factor]]s that bind to the [[sterol]] regulatory element [[DNA]] sequence TCACNCCAC.  Mammalian SREBPs are encoded by the genes ''[[SREBF1]]'' and ''[[SREBF2]]''. SREBPs belong to the [[basic-helix-loop-helix]] [[leucine zipper]] class of transcription factors.<ref name="pmid8402897">{{cite journal | vauthors = Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS | title = SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene | journal = Cell | volume = 75 | issue = 1 | pages = 187–97 | date = Oct 1993 | pmid = 8402897 | doi = 10.1016/S0092-8674(05)80095-9 | url = http://www.cell.com/content/article/abstract?uid=PII009286749390690R }}</ref> Unactivated SREBPs are attached to the [[nuclear envelope]] and [[endoplasmic reticulum]] membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis.<ref name="pmid8156598">{{cite journal | vauthors = Wang X, Sato R, Brown MS, Hua X, Goldstein JL | title = SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis | journal = Cell | volume = 77 | issue = 1 | pages = 53–62 | date = Apr 1994 | pmid = 8156598 | doi = 10.1016/0092-8674(94)90234-8 }}</ref><ref name="pmid8156593">{{cite journal | vauthors = Gasic GP | title = Basic-helix-loop-helix transcription factor and sterol sensor in a single membrane-bound molecule | journal = Cell | volume = 77 | issue = 1 | pages = 17–9 | date = Apr 1994 | pmid = 8156593 | doi = 10.1016/0092-8674(94)90230-5 }}</ref> Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

== Isoforms ==
Mammalian genomes have two separate SREBP genes ({{gene|SREBF1}} and {{gene|SREBF2}}):
* SREBP-1 expression produces two different isoforms, SREBP-1a and -1c. These isoforms differ in their first exons owing to the use of different transcriptional start sites for the SREBP-1 gene. SREBP-1c was also identified in rats as ADD-1. SREBP-1c is responsible for regulating the genes required for ''de novo'' lipogenesis.<ref name="pmid23859617">{{cite journal | vauthors=Guo D, Bell EH, Mischel P, Chakravarti A | title=Targeting SREBP-1-driven lipid metabolism to treat cancer | journal=[[Current Pharmaceutical Design]] | volume=20 | issue=15 | pages=2619–2626 | year=2014 | doi = 10.2174/13816128113199990486 | pmc=4148912 | pmid=23859617  }}</ref>
* SREBP-2 regulates the genes of cholesterol metabolism.<ref name="pmid23859617" />

== Function ==
SREB proteins are indirectly required for [[cholesterol]] biosynthesis and for uptake and [[fatty acid]] biosynthesis. These proteins work with asymmetric sterol regulatory element (StRE). SREBPs have a structure similar to [[E-box]]-binding [[helix-loop-helix]] (HLH) proteins. However, in contrast to E-box-binding HLH proteins, an arginine residue is replaced with tyrosine making them capable of recognizing StREs and thereby regulating membrane biosynthesis.<ref name="pmid9634703">{{cite journal | vauthors = Párraga A, Bellsolell L, Ferré-D'Amaré AR, Burley SK | title = Co-crystal structure of sterol regulatory element binding protein 1a at 2.3 A resolution | journal = Structure | volume = 6 | issue = 5 | pages = 661–72 | date = May 1998 | pmid = 9634703 | doi = 10.1016/S0969-2126(98)00067-7 }}</ref>

== Mechanism of action ==
[[File:WikF1.png|thumb|right|upright=2.0|alt=caption|{{abbr|SREBP|sterol regulatory element-binding protein}} activation by proteolytic cleavage. SREBP precursors are retained in the {{abbrlink|ER|endoplasmic reticulum}} membranes through a tight association with {{abbrlink|SCAP|SREBP cleavage-activating protein}} and a protein of the {{abbrlink|INSIG|insulin-induced gene protein}} family. Under the appropriate conditions, SCAP dissociates from INSIG and escorts the SREBP precursors from the ER to the [[Golgi apparatus]]. Once there, two proteases, {{abbrlink|S1P|site-1 protease}} and {{abbrlink|S2P|site-2 protease}}, sequentially cleave the precursor protein, releasing the mature form of SREBPs into the cytoplasm. The mature form then migrates to the nucleus, where it activates the promoter of genes involved in [[LDL receptor|cholesterol uptake]] or in [[cholesterol synthesis]]. SREBP processing can be controlled by the cellular sterol content.]]

Animal cells maintain proper levels of intracellular [[lipid]]s (fats and oils) under widely varying circumstances (lipid [[homeostasis]]).<ref name="pmid9150132">{{cite journal | vauthors = Brown MS, Goldstein JL | title = The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor | journal = Cell | volume = 89 | issue = 3 | pages = 331–40 | date = May 1997 | pmid = 9150132 | doi = 10.1016/S0092-8674(00)80213-5 }}</ref><ref name="pmid10500120">{{cite journal | vauthors = Brown MS, Goldstein JL | title = A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 20 | pages = 11041–8 | date = Sep 1999 | pmid = 10500120 | pmc = 34238 | doi = 10.1073/pnas.96.20.11041 }}</ref><ref name="pmid10693756">{{cite journal | vauthors = Brown MS, Ye J, Rawson RB, Goldstein JL | title = Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans | journal = Cell | volume = 100 | issue = 4 | pages = 391–8 | date = Feb 2000 | pmid = 10693756 | doi = 10.1016/S0092-8674(00)80675-3 }}</ref> For example, when cellular [[cholesterol]] levels fall below the level needed, the cell makes more of the enzymes necessary to make cholesterol. A principle step in this response is to make more of the [[mRNA]] transcripts that direct the synthesis of these [[enzymes]]. Conversely, when there is enough cholesterol around, the cell stops making those mRNAs and the level of the enzymes falls. As a result, the cell quits making cholesterol once it has enough.
	
A notable feature of this regulatory feedback machinery was first observed for the SREBP pathway - [[regulated intramembrane proteolysis]] (RIP). Subsequently, RIP was found to be used in almost all organisms from bacteria to human beings and regulates a wide range of processes ranging from development to neurodegeneration.

A feature of the SREBP pathway is the proteolytic release of a membrane-bound transcription factor, SREBP. Proteolytic cleavage frees it to move through the cytoplasm to the nucleus. Once in the nucleus, SREBP can bind to specific DNA sequences (the sterol regulatory elements or SREs) that are found in the control regions of the genes that encode enzymes needed to make lipids. This binding to [[DNA]] leads to the increased transcription of the target [[genes]].

The ~120 kDa SREBP precursor protein is anchored in the membranes of the [[endoplasmic reticulum]] (ER) and nuclear envelope by virtue of two membrane-spanning helices in the middle of the [[protein]]. The precursor has a hairpin orientation in the membrane, so that both the amino-terminal [[transcription factor]] domain and the COOH-terminal regulatory domain face the [[cytoplasm]]. The two membrane-spanning helices are separated by a loop of about 30 [[amino acids]] that lies in the lumen of the ER. Two separate, site-specific proteolytic cleavages are necessary for release of the transcriptionally active amino-terminal domain. These cleavages are carried out by two distinct [[protease]]s, called site-1 protease ([[membrane-bound transcription factor peptidase, site 1|S1P]]) and site-2 protease ([[membrane-bound transcription factor peptidase, site 2|S2P]]).

In addition to S1P and S2P, the regulated release of transcriptionally active SREBP requires the cholesterol-sensing protein SREBP cleavage-activating protein ([[SREBP cleavage-activating protein|SCAP]]), which forms a complex with SREBP owing to interaction between their respective carboxy-terminal domains. SCAP, in turn, can bind reversibly with another ER-resident membrane protein, INSIG. In the presence of sterols, which bind to INSIG and SCAP, INSIG and SCAP also bind one another. INSIG always stays in the ER membrane and thus the SREBP-SCAP complex remains in the ER when SCAP is bound to INSIG. When sterol levels are low, INSIG and SCAP no longer bind. Then, SCAP undergoes a conformational change that exposes a portion of the protein ('MELADL') that signals it to be included as cargo in the COPII vesicles that move from the ER to the Golgi apparatus. In these vesicles, SCAP, dragging SREBP along with it, is transported to the Golgi. The regulation of SREBP cleavage employs a notable feature of [[eukaryotic cells]], subcellular compartmentalization defined by intracellular membranes, to ensure that cleavage occurs only when needed.

Once in the Golgi apparatus, the SREBP-SCAP complex encounters active S1P. S1P cleaves SREBP at site-1, cutting it into two halves. Because each half still has a membrane-spanning helix, each remains bound in the membrane. The newly generated amino-terminal half of SREBP (which is the ‘business end' of the molecule) then goes on to be cleaved at site-2 that lies within its membrane-spanning helix. This is the work of S2P, an unusual metalloprotease. This releases the cytoplasmic portion of SREBP, which then travels to the nucleus where it activates transcription of target genes (e.g. [[LDL receptor]] gene)

== Regulation ==
Absence of sterols activates SREBP, thereby increasing cholesterol synthesis.<ref name="pmid18279733 ">{{cite journal | vauthors=Espenshade PJ, Hughes AL | title=Regulation of sterol synthesis in eukaryotes | journal= [[Annual Review of Genetics]] | volume=41 | pages=401-427 | year=2007 | doi= 10.1146/annurev.genet.41.110306.130315 | url = https://pdfs.semanticscholar.org/6745/d483deae6673cfb0f58869d353c324ea04c9.pdf| PMID = 18279733 }}</ref>

Insulin, cholesterol derivatives, T3 and other endogenous molecules have been demonstrated to regulate the SREBP1c expression, particularly in rodents. Serial deletion and mutation assays reveal that both SREBP (SRE) and [[liver X receptor|LXR]] (LXRE) response elements are involved in SREBP-1c transcription regulation mediated by insulin and cholesterol derivatives. Peroxisome proliferation-activated receptor alpha ([[peroxisome proliferator-activated receptor alpha|PPARα]]) agonists enhance the activity of the SREBP-1c promoter via a DR1 element at -453 in the human promoter. PPARα agonists act in cooperation with LXR or insulin to induce lipogenesis.<ref name="pmid21540177">{{cite journal | vauthors = Fernández-Alvarez A, Alvarez MS, Gonzalez R, Cucarella C, Muntané J, Casado M | title = Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) | journal = The Journal of Biological Chemistry | volume = 286 | issue = 24 | pages = 21466–77 | date = Jun 2011 | pmid = 21540177 | pmc = 3122206 | doi = 10.1074/jbc.M110.209973 }}</ref>

A medium rich in branched-chain amino acids stimulates expression of the SREBP-1c gene via the [[Mammalian target of rapamycin#mTORC1|mTORC1]]/[[P70-S6 Kinase 1|S6K1]] pathway. The [[phosphorylation]] of S6K1 was increased in the liver of obese db/db mice. Furthermore, depletion of hepatic S6K1 in db/db mice with the use of an adenovirus vector encoding S6K1 shRNA resulted in down-regulation of SREBP-1c gene expression in the liver as well as a reduced hepatic triglyceride content and serum triglyceride concentration.<ref name="pmid21806970">{{cite journal | vauthors = Li S, Ogawa W, Emi A, Hayashi K, Senga Y, Nomura K, Hara K, Yu D, Kasuga M | title = Role of S6K1 in regulation of SREBP1c expression in the liver | journal = Biochemical and Biophysical Research Communications | volume = 412 | issue = 2 | pages = 197–202 | date = Aug 2011 | pmid = 21806970 | doi = 10.1016/j.bbrc.2011.07.038 }}</ref>

mTORC1 activation is not sufficient to stimulate hepatic SREBP-1c in the absence of [[Akt/PKB signaling pathway|Akt signaling]], revealing the existence of an additional downstream pathway also required for this induction which is proposed to involve mTORC1-independent Akt-mediated suppression of [[INSIG2|INSIG-2a]], a liver-specific transcript encoding the SREBP-1c inhibitor INSIG2.<ref name="pmid21723501">{{cite journal | vauthors = Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI, Gorgun C, Kwiatkowski DJ, Hotamisligil GS, Lee CH, Manning BD | title = Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways | journal = Cell Metabolism | volume = 14 | issue = 1 | pages = 21–32 | date = Jul 2011 | pmid = 21723501 | doi = 10.1016/j.cmet.2011.06.002 }}</ref>

[[FGF21]] has been shown to repress the transcription of sterol regulatory element binding protein 1c (SREBP-1c). Overexpression of FGF21 ameliorated the up-regulation of SREBP-1c and fatty acid synthase (FAS) in HepG2 cells elicited by FFAs treatment. Moreover, FGF21 could inhibit the transcriptional levels of the key genes involved in processing and nuclear translocation of SREBP-1c, and decrease the protein amount of mature SREBP-1c. Unexpectedly, overexpression of SREBP-1c in HepG2 cells could also inhibit the endogenous FGF21 transcription by reducing FGF21 promoter activity.<ref name="pmid21664250">{{cite journal | vauthors = Zhang Y, Lei T, Huang JF, Wang SB, Zhou LL, Yang ZQ, Chen XD | title = The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes | journal = Molecular and Cellular Endocrinology | volume = 342 | issue = 1-2 | pages = 41–7 | date = Aug 2011 | pmid = 21664250 | doi = 10.1016/j.mce.2011.05.003 }}</ref>

SREBP-1c has also been shown to upregulate in a tissue specific manner the expression of [[PPARGC1A|PGC1alpha]] expression in brown adipose tissue.<ref name="pmid19962449">{{cite journal | vauthors = Hao Q, Hansen JB, Petersen RK, Hallenborg P, Jørgensen C, Cinti S, Larsen PJ, Steffensen KR, Wang H, Collins S, Wang J, Gustafsson JA, Madsen L, Kristiansen K | title = ADD1/SREBP1c activates the PGC1-alpha promoter in brown adipocytes | journal = Biochimica et Biophysica Acta | volume = 1801 | issue = 4 | pages = 421–9 | date = Apr 2010 | pmid = 19962449 | doi = 10.1016/j.bbalip.2009.11.008 }}</ref>

[[Nerve Growth factor IB|Nur77]] is suggested to inhibit LXR and downstream SREBP-1c expression modulating hepatic lipid metabolism.<ref name="pmid18086558">{{cite journal | vauthors = Pols TW, Ottenhoff R, Vos M, Levels JH, Quax PH, Meijers JC, Pannekoek H, Groen AK, de Vries CJ | title = Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity | journal = Biochemical and Biophysical Research Communications | volume = 366 | issue = 4 | pages = 910–6 | date = Feb 2008 | pmid = 18086558 | doi = 10.1016/j.bbrc.2007.12.039 }}</ref>

==History==

The SREBPs were elucidated in the laboratory of Nobel laureates [[Michael Stuart Brown|Michael Brown]] and [[Joseph L. Goldstein|Joseph Goldstein]] at the University of Texas Southwestern Medical Center in Dallas. Their first publication on this subject appeared in October 1993.<ref name="pmid8402897"/><ref name="pmid14507481">{{cite journal | vauthors = Anderson RG | title = Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology | journal = Trends in Cell Biology | volume = 13 | issue = 10 | pages = 534–9 | date = Oct 2003 | pmid = 14507481 | doi = 10.1016/j.tcb.2003.08.007
 }}</ref>

== References ==
{{Reflist|2}}

== External links ==
*{{MeshName|Sterol+Regulatory+Element+Binding+Proteins}}
*[http://www4.utsouthwestern.edu/moleculargenetics/pages/brown/lab.html The Brown and Goldstein Lab].
*[http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm Cholesterol Synthesis] - has some good regulatory details
*[http://www.pdb.org/pdb/explore/explore.do?structureId=1AM9 Protein Data Base (PDB)], Sterol Regulatory Element Binding 1A structure.

{{Transcription factors|g1}}

[[Category:Transcription factors]]