SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP-1), a basic helix-loop-helix leucine zipper (bHLH-ZIP) transcription factor made as an inactive ~125 kDa precursor anchored in the endoplasmic reticulum membrane by two transmembrane segments. Its C-terminal regulatory domain binds the sterol-sensing escort protein SCAP. When ER sterols are high, SCAP binds INSIG proteins and the SCAP-SREBP complex is held in the ER. When sterols fall, SCAP carries SREBP-1 in COPII vesicles to the Golgi, where site-1 protease (MBTPS1) cuts the luminal loop and site-2 protease (MBTPS2) cuts within the first transmembrane segment. This releases the N-terminal transactivation/bHLH-ZIP fragment (~68 kDa), which dimerizes, enters the nucleus via importin-beta, and binds sterol regulatory elements (direct-repeat SRE-1, ATCACCCCAC) and E-boxes in target promoters, often with NF-Y or SP1. The nuclear form is short-lived and is degraded by the ubiquitin-proteasome system. Alternative first exons give two main isoforms. SREBP-1a has a long acidic transactivation domain and strongly activates both cholesterogenic (HMGCR, HMGCS1, LDLR) and lipogenic genes. SREBP-1c, the predominant form in liver and adipose tissue, has a short activation domain and preferentially activates fatty acid and triglyceride synthesis genes (ACLY, ACACA, FASN, SCD, ELOVL6). SREBP-1c transcription is induced by insulin (via mTORC1) and LXR, and repressed by glucagon/cAMP and polyunsaturated fatty acids, making it the main transcriptional link between feeding/insulin and hepatic lipogenesis. Truncated isoforms lacking the membrane anchor (SREBP-1aDelta, -1cDelta) are constitutively nuclear. Heterozygous variants at the S1P cleavage site cause autosomal dominant IFAP syndrome 2, and SREBF1 variants also cause hereditary mucoepithelial dysplasia.
Curated functional classes representing distinct biological activities. These may be splice variants, cleavage products, or other forms with different functions.
SREBF1_1ASREBF1_1CSREBF1_DELTASREBF1_NUCLEARPRO_0000314029 (residues 1-490) | GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi membrane from UniProt subcellular location mapping. Reason: SREBP-1 is a cargo of SCAP; the SCAP-SREBP complex moves to the Golgi, where S1P and S2P cleave the precursor while it is embedded in the Golgi membrane. Golgi membrane is a genuine location of the precursor during activation. Supporting Evidence: PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis Reactome:R-HSA-1655842 S1P (MBTPS1, SKI-1), a membrane-bound protease in the Golgi, cleaves the intralumenal loop of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2, which remains bound to the membrane. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1655842 | ACCEPT | Summary: Reactome: S1P cleaves SREBP1A/1C/2 in the Golgi. Reason: SREBP-1 is a cargo of SCAP; the SCAP-SREBP complex moves to the Golgi, where S1P and S2P cleave the precursor while it is embedded in the Golgi membrane. Golgi membrane is a genuine location of the precursor during activation. Supporting Evidence: Reactome:R-HSA-1655842 S1P (MBTPS1, SKI-1), a membrane-bound protease in the Golgi, cleaves the intralumenal loop of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2, which remains bound to the membrane. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1655851 | ACCEPT | Summary: Reactome: S2P cleaves SREBP1A/1C/2 in the Golgi membrane. Reason: SREBP-1 is a cargo of SCAP; the SCAP-SREBP complex moves to the Golgi, where S1P and S2P cleave the precursor while it is embedded in the Golgi membrane. Golgi membrane is a genuine location of the precursor during activation. Supporting Evidence: Reactome:R-HSA-1655851 S2P(MBTPS2), a membrane-bound protease in the Golgi, cleaves within the transmembrane region of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2 into the cytosol. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | KEEP AS NON CORE | Summary: Chromatin location inferred from TFClass membership (bHLH-ZIP, class 1.2.6). Reason: The nuclear form binds promoter DNA of target genes and is found on chromatin by ChIP (e.g. Fasn and miR-148a promoters). Correct, but the core location is the nucleus. Supporting Evidence: PMID:26437365 SREBP1 was significantly enriched in the promoters of Srebp1, Fasn, and miR-148a upon refeeding PMID:23610160 chromatin immunoprecipitation assay demonstrated that Bt2cAMP signaling increased the recruitment of SF1 and SREBP1 to the DGKΞΈ promoter |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:23610160 cAMP-stimulated transcription of DGKΞΈ requires steroidogenic... | MODIFY | Summary: ChIP shows SREBP1 recruitment to the DGKtheta promoter in H295R adrenocortical cells. Reason: Correct but general. SREBP-1 binds cis-regulatory SRE and E-box elements in RNA polymerase II promoters, so the child term GO:0000978, already carried by this gene (IBA, IEA), is the appropriate term. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:23610160 chromatin immunoprecipitation assay demonstrated that Bt2cAMP signaling increased the recruitment of SF1 and SREBP1 to the DGKΞΈ promoter PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for RNA pol II cis-regulatory region sequence-specific DNA binding across the SREBP family. Reason: Sequence-specific binding to SRE and E-box elements in RNA polymerase II promoters is the defining activity of the SREBP family, and the human protein has its own experimental evidence for it. The PAINT node placement (PTN002488844, SREBP clade) is sound. Supporting Evidence: PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism PMID:7739539 we demonstrate that ADD1/SREBP1 has dual DNA sequence specificity, binding to both an E-box motif (ATCACGTGA) and a non-E-box sequence previously shown to be important in cholesterol metabolism, sterol regulatory element 1 (SRE-1; ATCACCCCAC) PMID:27614840 in vitro-translated nSREBP-1c and nSREBP-2 bind only the wild-type but not the mutated SRE at -38 of NIS |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for cis-regulatory region DNA binding from ortholog/combined pipeline. Reason: Consistent with experimental data on the human and rodent proteins (SRE-1 and E-box binding). Supporting Evidence: PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism PMID:7739539 we demonstrate that ADD1/SREBP1 has dual DNA sequence specificity, binding to both an E-box motif (ATCACGTGA) and a non-E-box sequence previously shown to be important in cholesterol metabolism, sterol regulatory element 1 (SRE-1; ATCACCCCAC) |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for DNA-binding TF activity, RNA pol II-specific (SREBP family). Reason: SREBP-1 is a DNA-binding transcription factor acting at RNA polymerase II promoters. This term is the standard TF MF used by PAINT and by the human GO-CAM (gocams/6205c24300000880, enabled_by SREBF1, part_of GO:0045542). The more specific activator term GO:0001228 is also accepted. Supporting Evidence: PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:12177166 Transcriptional activities of nuclear SREBP-1a, -1c, and -2 ... | ACCEPT | Summary: Reporter assays in HepG2 cells comparing nuclear SREBP-1a, -1c and -2 on SRE, SRE-like and E-box promoters. Reason: SREBP-1 is a DNA-binding transcription factor acting at RNA polymerase II promoters. This term is the standard TF MF used by PAINT and by the human GO-CAM (gocams/6205c24300000880, enabled_by SREBF1, part_of GO:0045542). The more specific activator term GO:0001228 is also accepted. Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c PMID:12177166 promoters of lipogenic enzymes containing variations of SRE (SRE-like sequences) are strongly activated by SREBP-1a, and only modestly and equally by both SREBP-1c and -2 |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from mouse Srebf1 via Ensembl Compara. Reason: SREBP-1 is a DNA-binding transcription factor acting at RNA polymerase II promoters. This term is the standard TF MF used by PAINT and by the human GO-CAM (gocams/6205c24300000880, enabled_by SREBF1, part_of GO:0045542). The more specific activator term GO:0001228 is also accepted. Supporting Evidence: PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:32497488 Mutations in SREBF1, Encoding Sterol Regulatory Element Bind... | ACCEPT | Summary: IFAP2 variants that block S1P cleavage reduce SREBP1 transcriptional activity in reporter assays. Reason: SREBP-1 is a DNA-binding transcription factor acting at RNA polymerase II promoters. This term is the standard TF MF used by PAINT and by the human GO-CAM (gocams/6205c24300000880, enabled_by SREBF1, part_of GO:0045542). The more specific activator term GO:0001228 is also accepted. Supporting Evidence: PMID:32497488 SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay PMID:32497488 This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE) |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based assignment of DNA-binding TF activity. Reason: SREBP-1 is a DNA-binding transcription factor acting at RNA polymerase II promoters. This term is the standard TF MF used by PAINT and by the human GO-CAM (gocams/6205c24300000880, enabled_by SREBF1, part_of GO:0045542). The more specific activator term GO:0001228 is also accepted. Supporting Evidence: PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism |
| GO:0001221 transcription coregulator binding | IPI PMID:14701856 Transcription factors and nuclear receptors interact with th... | KEEP AS NON CORE | Summary: Interaction with BAF60c (SMARCD3), a SWI/SNF subunit acting as coregulator. Reason: The abstract reports that BAF60c binds several transcription factors; the curator recorded SREBP-1 among them from the full text. Coregulator binding (BAF60c, and in the literature CBP and MED15) is how the acidic transactivation domain recruits the transcription machinery. It supports the activator function but is not itself the core activity. Supporting Evidence: PMID:14701856 Both BAF60c isoforms bind to several nuclear receptors and transcription factors of various families PMID:9062341 SREBP-1a and -1c are alternate transcripts from a single gene that differ in the first exon, which encodes part of an acidic activation domain |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:31501273 MicroRNA 7 Impairs Insulin Signaling and Regulates AΞ² Levels... | ACCEPT | Summary: Overexpressed nuclear SREBP1c increases HNRNPK/miR-7 host gene transcription in neuronal cells. Reason: SREBP-1 activates target genes by binding SRE or E-box elements in RNA polymerase II promoters (LDLR, HMGCS1, FASN, PCSK9, NIS, miR-148a host region). This is the core molecular function. Supporting Evidence: PMID:31501273 These results, together with the data showing an increase in miR-7 with the host gene upon overexpression of an active SREBP1c form in neuronal cells, suggest a possible SREBP1c-mediated transcriptional mechanism of HNRNPK/miR-7 through insulin/LXR pathways PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from rat Srebf1 via Ensembl Compara. Reason: SREBP-1 activates target genes by binding SRE or E-box elements in RNA polymerase II promoters (LDLR, HMGCS1, FASN, PCSK9, NIS, miR-148a host region). This is the core molecular function. Supporting Evidence: PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase PMID:16407292 Adenoviral mediated overexpression of a dominant or negative form of SREBP-1c confirmed the implication of this transcription factor in insulin-mediated stimulation of PCSK9 expression |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: Generic DNA binding from mouse Srebf1. Reason: Correct but general. SREBP-1 binds specific cis-regulatory elements (SRE-1, E-box) in RNA polymerase II promoters, so the descendant GO:0000978, already accepted for this gene, should be used. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism PMID:7739539 we demonstrate that ADD1/SREBP1 has dual DNA sequence specificity, binding to both an E-box motif (ATCACGTGA) and a non-E-box sequence previously shown to be important in cholesterol metabolism, sterol regulatory element 1 (SRE-1; ATCACCCCAC) |
| GO:0003677 DNA binding | ISS GO_REF:0000024 | MODIFY | Summary: Generic DNA binding by similarity to mouse Srebf1. Reason: Correct but general. SREBP-1 binds specific cis-regulatory elements (SRE-1, E-box) in RNA polymerase II promoters, so the descendant GO:0000978, already accepted for this gene, should be used. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism PMID:7739539 we demonstrate that ADD1/SREBP1 has dual DNA sequence specificity, binding to both an E-box motif (ATCACGTGA) and a non-E-box sequence previously shown to be important in cholesterol metabolism, sterol regulatory element 1 (SRE-1; ATCACCCCAC) |
| GO:0003682 chromatin binding | IEA GO_REF:0000120 | MODIFY | Summary: Chromatin binding from combined IEA pipeline. Reason: SREBP-1 is found on chromatin because it binds specific promoter DNA elements. Sequence-specific cis-regulatory DNA binding (GO:0000978) describes its activity better than generic chromatin binding. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:26437365 SREBP1 was significantly enriched in the promoters of Srebp1, Fasn, and miR-148a upon refeeding PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:16407292 Hepatic PCSK9 expression is regulated by nutritional status ... | MODIFY | Summary: SREBP-1c drives the PCSK9 promoter through an SRE in hepatocytes. Reason: Correct but general. The evidence (dominant-positive and dominant-negative SREBP-1c, PCSK9 promoter SRE) shows a DNA-binding transcription activator at an RNA polymerase II promoter, so GO:0001228 is the appropriate descendant. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: PMID:16407292 Adenoviral mediated overexpression of a dominant or negative form of SREBP-1c confirmed the implication of this transcription factor in insulin-mediated stimulation of PCSK9 expression |
| GO:0004879 nuclear receptor activity | IDA PMID:23610160 cAMP-stimulated transcription of DGKΞΈ requires steroidogenic... | REMOVE | Summary: Nuclear receptor activity assigned from the DGKtheta/SF1 paper. Reason: SREBP-1 is a bHLH-ZIP transcription factor, not a member of the nuclear hormone receptor superfamily, and is not activated by binding a ligand. In this paper the nuclear receptor is SF1 (NR5A1), which binds phosphatidic acid. SREBP1 co-occupies the DGKtheta promoter with SF1 and interacts with it. The term is wrong for this gene whatever the full-text details, because the activity is defined by membership of the nuclear receptor class. SREBP1's role here is captured by the accepted DNA-binding TF activity and positive regulation of transcription rows. Supporting Evidence: PMID:23610160 We have previously shown that PA is a ligand for the nuclear receptor steroidogenic factor 1 (SF1) PMID:23610160 Coimmunoprecipitation assay revealed that SF1 and SREBP1 interact, suggesting that the two transcription factors form a complex on the DGKΞΈ promoter PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism |
| GO:0005515 protein binding | IPI PMID:16713569 A protein-protein interaction network for human inherited at... | REMOVE | Summary: Yeast two-hybrid interaction with ATXN1 in an ataxia interactome screen. Reason: Bare protein binding is uninformative. The reported interaction is not disputed, but it does not specify a molecular function. Supporting Evidence: PMID:16713569 We identified 770 mostly novel protein-protein interactions using a stringent yeast two-hybrid screen |
| GO:0005515 protein binding | IPI PMID:23610160 cAMP-stimulated transcription of DGKΞΈ requires steroidogenic... | REMOVE | Summary: Co-IP with SF1 (NR5A1) in adrenocortical cells. Reason: Bare protein binding is uninformative. The reported interaction is not disputed, but it does not specify a molecular function. The SF1 interaction supports cooperative activation of the DGKtheta promoter, which is captured by the transcription rows. Supporting Evidence: PMID:23610160 Coimmunoprecipitation assay revealed that SF1 and SREBP1 interact, suggesting that the two transcription factors form a complex on the DGKΞΈ promoter |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Yeast two-hybrid interaction with HTT in a neurodegeneration interactome map. Reason: Bare protein binding is uninformative. The reported interaction is not disputed, but it does not specify a molecular function. Supporting Evidence: PMID:32814053 Interactome maps are valuable resources to elucidate protein function and disease mechanisms |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Yeast two-hybrid interaction with ATXN1 in a neurodegeneration interactome map. Reason: Bare protein binding is uninformative. The reported interaction is not disputed, but it does not specify a molecular function. Supporting Evidence: PMID:32814053 Interactome maps are valuable resources to elucidate protein function and disease mechanisms |
| GO:0005634 nucleus | EXP PMID:11477106 Direct demonstration of rapid degradation of nuclear sterol ... | ACCEPT | Summary: Nuclear SREBP-1a and its proteasomal turnover were followed in HeLa and CHO cells. Reason: After SCAP-dependent transport and S1P/S2P cleavage, the N-terminal bHLH-ZIP fragment enters the nucleus, where it activates target genes and is rapidly turned over. Nucleus is the core location of the active form. Supporting Evidence: PMID:11477106 The active SREBPs translocate to the nucleus, induce the expression of responsive genes, and are degraded very rapidly PMID:11477106 The nuclear SREBPs are found conjugated with a polyubiquitin chain |
| GO:0005634 nucleus | EXP PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li... | ACCEPT | Summary: Nuclear accumulation of SREBP1 after PCK1-INSIG phosphorylation in HCC cells. Reason: After SCAP-dependent transport and S1P/S2P cleavage, the N-terminal bHLH-ZIP fragment enters the nucleus, where it activates target genes and is rapidly turned over. Nucleus is the core location of the active form. Supporting Evidence: PMID:32322062 is not only positively correlated with the nuclear accumulation of SREBP1 in samples from patients with HCC PMID:32322062 leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for nucleus (SREBP family). Reason: After SCAP-dependent transport and S1P/S2P cleavage, the N-terminal bHLH-ZIP fragment enters the nucleus, where it activates target genes and is rapidly turned over. Nucleus is the core location of the active form. Supporting Evidence: PMID:8156598 In sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that translocates to the nucleus |
| GO:0005634 nucleus | IDA PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | ACCEPT | Summary: Nuclear localization; paper mainly on SREBP2 regulation of ABCA1 in endothelial cells. Reason: After SCAP-dependent transport and S1P/S2P cleavage, the N-terminal bHLH-ZIP fragment enters the nucleus, where it activates target genes and is rapidly turned over. Nucleus is the core location of the active form. The cached abstract describes SREBP2; the curator presumably saw SREBP1 data in the full text, and the localization is well established for SREBP-1, so the row is accepted on the gene-level evidence. Supporting Evidence: PMID:15358760 Furthermore sterol depletion and SREBP2(N) overexpression induced the binding of SREBP2(N) to both consensus and ABCA1-specific E-box PMID:8156598 In sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that translocates to the nucleus |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nucleus from combined IEA (ortholog and SubCell). Reason: After SCAP-dependent transport and S1P/S2P cleavage, the N-terminal bHLH-ZIP fragment enters the nucleus, where it activates target genes and is rapidly turned over. Nucleus is the core location of the active form. Supporting Evidence: PMID:8156598 In sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that translocates to the nucleus |
| GO:0005634 nucleus | IMP PMID:32497488 Mutations in SREBF1, Encoding Sterol Regulatory Element Bind... | ACCEPT | Summary: IFAP2 cleavage-site mutants fail to reach the nucleus. Reason: After SCAP-dependent transport and S1P/S2P cleavage, the N-terminal bHLH-ZIP fragment enters the nucleus, where it activates target genes and is rapidly turned over. Nucleus is the core location of the active form. Supporting Evidence: PMID:32497488 In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1 |
| GO:0005634 nucleus | TAS PMID:8156598 SREBP-1, a membrane-bound transcription factor released by s... | ACCEPT | Summary: Nuclear translocation of the 68 kDa fragment. Reason: After SCAP-dependent transport and S1P/S2P cleavage, the N-terminal bHLH-ZIP fragment enters the nucleus, where it activates target genes and is rapidly turned over. Nucleus is the core location of the active form. Supporting Evidence: PMID:8156598 In sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that translocates to the nucleus |
| GO:0005635 nuclear envelope | TAS PMID:8156598 SREBP-1, a membrane-bound transcription factor released by s... | KEEP AS NON CORE | Summary: The precursor is attached to the nuclear envelope and ER. Reason: The 125 kDa precursor is an integral membrane protein of the ER, which is continuous with the outer nuclear membrane; its nuclear-envelope location follows from that. The main precursor location is the ER membrane. Supporting Evidence: PMID:8156598 is synthesized as a 125 kd precursor that is attached to the nuclear envelope and endoplasmic reticulum |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence: nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: PMID:11477106 The active SREBPs translocate to the nucleus, induce the expression of responsive genes, and are degraded very rapidly PMID:8156598 In sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that translocates to the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-1655831 | ACCEPT | Summary: Reactome event "SREBP1A,1C,2 translocates to the nucleus" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-1655831 The N-terminal domain of SREBP1A,1C,2 (SREBF1A,1C,2) dimerizes and is imported from the cytosol into the nucleus by importin-beta (Nagoshi et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2065539 | ACCEPT | Summary: Reactome event "SREBP1A,1C,2:Importin beta-1 dissociates" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2065539 SREBP1A/1C/2 (SREBF1A/1C/2) dimer dissociates from Importin beta-1 in response to Ran-GTP in the nucleoplasm (Nagoshi et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2065966 | ACCEPT | Summary: Reactome event "SREBP1A,1C,2 binds the TM7SF2 promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2065966 SREBP2 (SREBF2) binds and transactivates an unusual sterol regulatory element in the promoter of the TM7SF2 gene (Schiavoni et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426144 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the MVD promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426144 SREBP1A (SREBF1A) or SREBP2 binds and transactivates the promoter of the MVD gene (Rome et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426146 | ACCEPT | Summary: Reactome event "SREBP1A,1C,2 binds the FDFT1 promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426146 SREBP1A/1C/2 (SREBF1A/1C/2), together with NF-Y and SP1, bind and transactivate the promoter of the FDFT1 gene (Inoue et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426147 | ACCEPT | Summary: Reactome event "SREBP1A,1C,2 binds the FDPS promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426147 SREBP1A/1C/2 (SREBF1A/1C/2), together with NF-Y, bind and transactivate the promoter of the FDPS gene (Ericsson et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426148 | ACCEPT | Summary: Reactome event "SREBP1A,1C binds the FASN promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426148 SREBP1A (SREBF1A) or SREBP1C, together with NF-Y and SP1, bind and transactivate the promoter of the FASN gene (Bennett et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426150 | ACCEPT | Summary: Reactome event "SREBP1A,1C,2 binds the HMGCS1 promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426150 SREBP1A/1C/2 (SREBF1A/1C/2), together with NF-Y, bind and transactivate the promoter of the HMGCS1 gene (Maeda et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426151 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the SQLE promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426151 SREBP1A (SREBF1A) or SREBP2 binds and transactivates the promoter of the SQLE gene (Reed et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426152 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the IDI1 promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426152 SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the IDI1 gene (Reed et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426153 | ACCEPT | Summary: Reactome event "SREBP1A,1C binds the ACACB promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426153 SREBP1A (SREBF1A) or SREBP1C, together with SP1, bind and transactivate promoter II of the ACACB gene in human HepG2 cells (Oh et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426154 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the LSS promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426154 SREBP1A (SREBF1A) or SREBP2 binds and transactivates the promoter of the LSS gene (Pai et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426155 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the DHCR7 promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426155 SREBP1A (SREBF1A) and SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the DHCR7 gene (Reed et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426156 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the PMVK promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426156 SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the PMVK gene (Reed et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426157 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the MVK promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426157 SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the MVK gene (Reed et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426160 | ACCEPT | Summary: Reactome event "SREBP1A,1C binds the ACACA promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426160 SREBP1A (SREBF1A) or SREBP1C bind two sites in the promoter of the ACACA gene (Magana et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426161 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the GGPS1 promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426161 SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the GGPS1 gene (Reed et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426162 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the HMGCR promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426162 SREBP1A (SREBF1A) or SREBP2, together with NF-Y, bind and transactivate the promoter of the HMGCR gene (Vallett et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426163 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the CYP51A1 promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426163 SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the CYP51A1 gene (Pai et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426164 | ACCEPT | Summary: Reactome event "SREBP1A,2 binds the SC5DL promoter" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-2426164 SREBP1A (SREBF1A) or SREBP2, together with NF-Y, bind and transactivate the promoter of the SC5DL gene (Reed et al |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6800052 | ACCEPT | Summary: Reactome event "SREBP1A,1C binds the SCD gene" places the nuclear SREBP-1 fragment in the nucleoplasm. Reason: The processed N-terminal fragment acts in the nucleoplasm, binding promoter elements of its target genes. Nucleoplasm is accurate for the active form. Supporting Evidence: Reactome:R-HSA-6800052 SREBF1A (SREBP1A) and SREBF1C (SREBP1C) bind the promoter of the Stearoyl CoA Desaturase 1 (SCD1) gene and enhance transcription (Pai et al |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MODIFY | Summary: Cytoplasm from mouse Srebf1. Reason: Correct but general. Before cleavage SREBP-1 is an integral membrane protein of the ER (and later the Golgi), so the specific location within the cytoplasm is ER membrane (GO:0005789), already accepted for this gene. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:8156598 is synthesized as a 125 kd precursor that is attached to the nuclear envelope and endoplasmic reticulum |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | MODIFY | Summary: Cytoplasm by similarity to mouse Srebf1. Reason: Correct but general. Before cleavage SREBP-1 is an integral membrane protein of the ER (and later the Golgi), so the specific location within the cytoplasm is ER membrane (GO:0005789), already accepted for this gene. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:8156598 is synthesized as a 125 kd precursor that is attached to the nuclear envelope and endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ER membrane from UniProt subcellular location. Reason: The precursor is a hairpin membrane protein of the ER, held there in complex with SCAP and INSIG when sterols are abundant. ER membrane is the core location of the inactive precursor. Supporting Evidence: PMID:8156598 is synthesized as a 125 kd precursor that is attached to the nuclear envelope and endoplasmic reticulum PMID:12202038 facilitates retention of the SCAP/SREBP complex in the ER |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin... | ACCEPT | Summary: SCAP/SREBP retention in ER by INSIG-1. Reason: The precursor is a hairpin membrane protein of the ER, held there in complex with SCAP and INSIG when sterols are abundant. ER membrane is the core location of the inactive precursor. Supporting Evidence: PMID:12202038 facilitates retention of the SCAP/SREBP complex in the ER PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis |
| GO:0005789 endoplasmic reticulum membrane | TAS PMID:8156598 SREBP-1, a membrane-bound transcription factor released by s... | ACCEPT | Summary: Precursor attached to ER and nuclear envelope. Reason: The precursor is a hairpin membrane protein of the ER, held there in complex with SCAP and INSIG when sterols are abundant. ER membrane is the core location of the inactive precursor. Supporting Evidence: PMID:8156598 is synthesized as a 125 kd precursor that is attached to the nuclear envelope and endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9605056 | ACCEPT | Summary: Reactome: SREBF1 expression event places the precursor in the ER membrane. Reason: The precursor is a hairpin membrane protein of the ER, held there in complex with SCAP and INSIG when sterols are abundant. ER membrane is the core location of the inactive precursor. Supporting Evidence: Reactome:R-HSA-9605056 The SREBF1 gene can produce two proteins, SREBP1a and SREBP1c, by use of different promoters PMID:8156598 is synthesized as a 125 kd precursor that is attached to the nuclear envelope and endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-NUL-2317526 | ACCEPT | Summary: Reactome: SREBP retained in the ER by SCAP:cholesterol:INSIG. Reason: The precursor is a hairpin membrane protein of the ER, held there in complex with SCAP and INSIG when sterols are abundant. ER membrane is the core location of the inactive precursor. Supporting Evidence: Reactome:R-NUL-2317526 SREBPs (SREBP1A/1C/2, SREBFs) bind SCAP in the endoplasmic reticulum membrane. |
| GO:0005794 Golgi apparatus | NAS PMID:23564452 Point mutation in luminal loop 7 of Scap protein blocks inte... | MODIFY | Summary: Golgi apparatus, from a paper on SCAP transport of SREBPs to Golgi. Reason: Correct but general. In the Golgi SREBP-1 is an integral membrane protein, cleaved within its luminal loop and first TM segment, so the specific location is Golgi membrane (GO:0000139), already accepted for this gene. Proposed replacements: Golgi membrane Supporting Evidence: PMID:23564452 Scap is a polytopic protein of the endoplasmic reticulum (ER) that controls cholesterol homeostasis by transporting sterol regulatory element-binding proteins (SREBPs) from the ER to the Golgi complex Reactome:R-HSA-1655842 S1P (MBTPS1, SKI-1), a membrane-bound protease in the Golgi, cleaves the intralumenal loop of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2, which remains bound to the membrane. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1655831 | KEEP AS NON CORE | Summary: Reactome: nuclear import of SREBP dimers from the cytosol. Reason: In Reactome the N-terminal fragment released by S2P passes through the cytosol, dimerizes and binds importin-beta for nuclear import. This is a real but transient location of the processed form. It is not where the protein acts. Supporting Evidence: Reactome:R-HSA-1655831 The N-terminal domain of SREBP1A,1C,2 (SREBF1A,1C,2) dimerizes and is imported from the cytosol into the nucleus by importin-beta |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1655851 | KEEP AS NON CORE | Summary: Reactome: S2P releases the N-terminal domain into the cytosol. Reason: In Reactome the N-terminal fragment released by S2P passes through the cytosol, dimerizes and binds importin-beta for nuclear import. This is a real but transient location of the processed form. It is not where the protein acts. Supporting Evidence: Reactome:R-HSA-1655851 S2P(MBTPS2), a membrane-bound protease in the Golgi, cleaves within the transmembrane region of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2 into the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2065549 | KEEP AS NON CORE | Summary: Reactome: SREBP N-terminal domains dimerize. Reason: In Reactome the N-terminal fragment released by S2P passes through the cytosol, dimerizes and binds importin-beta for nuclear import. This is a real but transient location of the processed form. It is not where the protein acts. Supporting Evidence: Reactome:R-HSA-2065549 The N-terminal domains of SREBPs (SREBP1A/1C/2, SREBFs) dimerize via interaction of their helix-loop-helix leucine zipper domains |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2065550 | KEEP AS NON CORE | Summary: Reactome: SREBP dimers bind importin beta-1. Reason: In Reactome the N-terminal fragment released by S2P passes through the cytosol, dimerizes and binds importin-beta for nuclear import. This is a real but transient location of the processed form. It is not where the protein acts. Supporting Evidence: Reactome:R-HSA-2065550 SREBP2 dimer (also called SREBF2 dimer) and, by inference SREBP1A,1C dimer, binds Importin beta-1 via the helix-loop-helix leucine zipper domain of SREBP1A,1C,2 |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA for regulation of transcription by RNA polymerase II. Reason: Correct but general. SREBP-1 regulates RNA polymerase II transcription mainly as an activator of SRE- and E-box-containing genes, and the review accepts the more specific GO:0045944 positive regulation of transcription by RNA polymerase II. Same verdict as the SREBF2 review for this term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002488844 Β· PTN002488844 SUPPORTS TRANSFER The node correctly places Pol II transcription regulation on SREBPs; the review refines it to the positive-regulation child GO:0045944. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:32432943 Discovery of a potent SCAP degrader that ameliorates HFD-ind... | MODIFY | Summary: Lycorine-induced SCAP degradation lowers SREBF1 maturation and target gene expression. Reason: Correct but general. SREBP-1 regulates RNA polymerase II transcription mainly as an activator of SRE- and E-box-containing genes, and the review accepts the more specific GO:0045944 positive regulation of transcription by RNA polymerase II. Same verdict as the SREBF2 review for this term. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:32432943 The hepatic SREBF1 and SREBF2 target genes were obviously downregulated in lycorine-treated HFD-induced obese mice |
| GO:0006357 regulation of transcription by RNA polymerase II | NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | MODIFY | Summary: Nuclear SREBP-1a induces insig-1 transcription. Reason: Correct but general. SREBP-1 regulates RNA polymerase II transcription mainly as an activator of SRE- and E-box-containing genes, and the review accepts the more specific GO:0045944 positive regulation of transcription by RNA polymerase II. Same verdict as the SREBF2 review for this term. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:12242332 Ponasterone A-mediated induction of nuclear SREBP-1a or SREBP-2 in these cells led to a marked increase in insig-1 mRNA |
| GO:0006357 regulation of transcription by RNA polymerase II | TAS PMID:8156598 SREBP-1, a membrane-bound transcription factor released by s... | MODIFY | Summary: Nuclear fragment activates LDLR and HMG CoA synthase transcription. Reason: Correct but general. SREBP-1 regulates RNA polymerase II transcription mainly as an activator of SRE- and E-box-containing genes, and the review accepts the more specific GO:0045944 positive regulation of transcription by RNA polymerase II. Same verdict as the SREBF2 review for this term. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase |
| GO:0006629 lipid metabolic process | TAS PMID:8156598 SREBP-1, a membrane-bound transcription factor released by s... | MODIFY | Summary: Lipid metabolic process (TAS) from the SREBP-1 proteolysis paper. Reason: SREBP-1 does not catalyse any step of lipid metabolism; it activates transcription of the enzymes and the LDL receptor. The accurate process terms are positive regulation of cholesterol biosynthesis (GO:0045542) and of fatty acid biosynthesis (GO:0045723). Proposed replacements: positive regulation of cholesterol biosynthetic process positive regulation of fatty acid biosynthetic process Supporting Evidence: PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase PMID:11994399 SREBP-1a is a potent activator of all SREBP-responsive genes, including those that mediate the synthesis of cholesterol, fatty acids, and triglycerides. |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to nutrient transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0007623 circadian rhythm | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Circadian rhythm from mouse Srebf1. Reason: Srebf1 expression and processing oscillate with feeding/fasting cycles in liver. That does not make SREBP-1 a component of the circadian clock, and no human evidence supports this term. Over-annotation. Supporting Evidence: PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0008203 cholesterol metabolic process | IDA PMID:32432943 Discovery of a potent SCAP degrader that ameliorates HFD-ind... | MODIFY | Summary: SCAP degrader reduces SREBF1/2 activity and hepatic cholesterol. Reason: SREBP-1 (mainly SREBP-1a) controls cholesterol metabolism as a transcriptional activator of cholesterogenic genes and LDLR. It is not an enzyme of the pathway. The accurate term is positive regulation of cholesterol biosynthetic process (GO:0045542), which is accepted here and used in the human GO-CAM. Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:32432943 The hepatic SREBF1 and SREBF2 target genes were obviously downregulated in lycorine-treated HFD-induced obese mice PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c |
| GO:0008203 cholesterol metabolic process | IEA GO_REF:0000107 | MODIFY | Summary: Cholesterol metabolic process from rat Srebf1. Reason: SREBP-1 (mainly SREBP-1a) controls cholesterol metabolism as a transcriptional activator of cholesterogenic genes and LDLR. It is not an enzyme of the pathway. The accurate term is positive regulation of cholesterol biosynthetic process (GO:0045542), which is accepted here and used in the human GO-CAM. Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c |
| GO:0008203 cholesterol metabolic process | NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | MODIFY | Summary: Cholesterol metabolic process from the Insig-2 paper. Reason: SREBP-1 (mainly SREBP-1a) controls cholesterol metabolism as a transcriptional activator of cholesterogenic genes and LDLR. It is not an enzyme of the pathway. The accurate term is positive regulation of cholesterol biosynthetic process (GO:0045542), which is accepted here and used in the human GO-CAM. Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:12242332 Insig-1 and -2 had the same effect on the processing of SREBP-1a that they had on SREBP-2 PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis |
| GO:0008610 lipid biosynthetic process | IEA GO_REF:0000107 | MODIFY | Summary: Lipid biosynthetic process from mouse Srebf1. Reason: SREBP-1 activates transcription of fatty acid, triglyceride and cholesterol biosynthetic genes but does not carry out any step of lipid synthesis. The accurate terms are positive regulation of lipid biosynthetic process (GO:0046889) and, more specifically, of fatty acid (GO:0045723) and cholesterol (GO:0045542) biosynthesis. Proposed replacements: positive regulation of fatty acid biosynthetic process positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:11994399 SREBP-1a is a potent activator of all SREBP-responsive genes, including those that mediate the synthesis of cholesterol, fatty acids, and triglycerides. |
| GO:0008610 lipid biosynthetic process | IMP PMID:32497488 Mutations in SREBF1, Encoding Sterol Regulatory Element Bind... | MODIFY | Summary: IFAP2 variants reduce SREBP1 activity on lipogenic targets. Reason: SREBP-1 activates transcription of fatty acid, triglyceride and cholesterol biosynthetic genes but does not carry out any step of lipid synthesis. The accurate terms are positive regulation of lipid biosynthetic process (GO:0046889) and, more specifically, of fatty acid (GO:0045723) and cholesterol (GO:0045542) biosynthesis. Proposed replacements: positive regulation of fatty acid biosynthetic process positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:32497488 SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols PMID:32497488 SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay |
| GO:0008610 lipid biosynthetic process | ISS GO_REF:0000024 | MODIFY | Summary: Lipid biosynthetic process by similarity to mouse Srebf1. Reason: SREBP-1 activates transcription of fatty acid, triglyceride and cholesterol biosynthetic genes but does not carry out any step of lipid synthesis. The accurate terms are positive regulation of lipid biosynthetic process (GO:0046889) and, more specifically, of fatty acid (GO:0045723) and cholesterol (GO:0045542) biosynthesis. Proposed replacements: positive regulation of fatty acid biosynthetic process positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:11994399 SREBP-1a is a potent activator of all SREBP-responsive genes, including those that mediate the synthesis of cholesterol, fatty acids, and triglycerides. |
| GO:0009267 cellular response to starvation | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Cellular response to starvation from rat Srebf1. Reason: Fasting lowers, and refeeding restores, SREBP-1c expression and processing. This change in SREBF1 expression is what was observed, not participation of SREBP-1 in a starvation response. Over-annotation. Supporting Evidence: PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0009267 cellular response to starvation | ISS PMID:16407292 Hepatic PCSK9 expression is regulated by nutritional status ... | MARK AS OVER ANNOTATED | Summary: Cellular response to starvation by similarity to rat Srebf1, from the PCSK9 nutritional regulation paper. Reason: Fasting lowers, and refeeding restores, SREBP-1c expression and processing. This change in SREBF1 expression is what was observed, not participation of SREBP-1 in a starvation response. Over-annotation. Supporting Evidence: PMID:16407292 We showed that PCSK9 mRNA quantity is decreased by 73% in mice after 24 h of fasting PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to xenobiotic stimulus transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0009750 response to fructose | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to fructose transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0010867 positive regulation of triglyceride biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of triglyceride biosynthesis from mouse Srebf1. Reason: Nuclear SREBP-1c (and SREBP-1a) drive triglyceride accumulation in liver by inducing the fatty acid and glycerolipid synthesis programme. This is a valid downstream regulatory outcome; it is non-core next to the fatty acid and cholesterol biosynthesis regulation. Supporting Evidence: PMID:11994399 Overexpression of nSREBP-1c in the liver of transgenic mice produces a triglyceride-enriched fatty liver with no increase in cholesterol PMID:11994399 SREBP-1a is a potent activator of all SREBP-responsive genes, including those that mediate the synthesis of cholesterol, fatty acids, and triglycerides. |
| GO:0010867 positive regulation of triglyceride biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of triglyceride biosynthesis by similarity to mouse Srebf1. Reason: Nuclear SREBP-1c (and SREBP-1a) drive triglyceride accumulation in liver by inducing the fatty acid and glycerolipid synthesis programme. This is a valid downstream regulatory outcome; it is non-core next to the fatty acid and cholesterol biosynthesis regulation. Supporting Evidence: PMID:11994399 Overexpression of nSREBP-1c in the liver of transgenic mice produces a triglyceride-enriched fatty liver with no increase in cholesterol |
| GO:0012507 ER to Golgi transport vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ER to Golgi transport vesicle membrane from UniProt SubCell (COPII vesicle). Reason: The SCAP-SREBP complex is packaged into COPII vesicles for ER-to-Golgi transport in sterol-depleted cells, so the SREBP-1 precursor is a COPII vesicle membrane cargo. That transport is the regulated step of the SREBP pathway, so the location is accepted, as in the SREBF2 and SCAP reviews. Supporting Evidence: PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis PMID:23564452 Scap is a polytopic protein of the endoplasmic reticulum (ER) that controls cholesterol homeostasis by transporting sterol regulatory element-binding proteins (SREBPs) from the ER to the Golgi complex |
| GO:0016020 membrane | IEA GO_REF:0000107 | MODIFY | Summary: Membrane from mouse Srebf1. Reason: Correct but general. The precursor is an integral ER membrane protein (later Golgi), so ER membrane (GO:0005789) is the specific supported location. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:8156598 is synthesized as a 125 kd precursor that is attached to the nuclear envelope and endoplasmic reticulum |
| GO:0019901 protein kinase binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Protein kinase binding from mouse Srebf1. Reason: SREBP-1 is a substrate of several kinases (AMPK, SIK1, GSK3 and others in UniProt PTM notes) that regulate its processing or activity. Being phosphorylated does not make kinase binding a function of SREBP-1. Over-annotation. Supporting Evidence: PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase |
| GO:0030324 lung development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Lung development from rat Srebf1. Reason: SREBF1 is expressed in fetal lung and SREBP activity supports surfactant lipid synthesis, but that is lipogenic gene regulation, not a developmental process role. No human evidence; over-annotation. Supporting Evidence: PMID:11994399 SREBP-1a is a potent activator of all SREBP-responsive genes, including those that mediate the synthesis of cholesterol, fatty acids, and triglycerides. |
| GO:0030522 intracellular receptor signaling pathway | IEA GO_REF:0000108 | REMOVE | Summary: Intracellular receptor signaling pathway inferred from GO:0004879 nuclear receptor activity. Reason: This row is derived automatically from the nuclear receptor activity annotation, which is wrong for this bHLH-ZIP protein (see that row). SREBP-1 activation is better described by the SREBP signaling pathway (GO:0032933), which is accepted. Supporting Evidence: PMID:23610160 We have previously shown that PA is a ligand for the nuclear receptor steroidogenic factor 1 (SF1) PMID:8156598 In sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that translocates to the nucleus |
| GO:0031647 regulation of protein stability | IMP PMID:24912190 Genome-wide RNAi screen identifies the Parkinson disease GWA... | MARK AS OVER ANNOTATED | Summary: RNAi of SREBF1 attenuates PINK1 stabilization on depolarized mitochondria. Reason: From a genome-wide RNAi screen for Parkin translocation. SREBF1 loss also reduced PINK1 stabilization, but the paper attributes the SREBP pathway effects to lipid supply (exogenous lipids bypass the block). The effect on PINK1 stability is indirect and not a function of SREBP-1. Supporting Evidence: PMID:24912190 Interestingly, loss of SREBF1 but not FBXW7 also attenuates the stabilization of PINK1 on the OMM upon ablation of ΞΞ¨m, suggesting a complex regulation of this process by the SREBP pathway PMID:24912190 We have shown that loss of SREBF1 , FBXW7 , and GSK3A inhibits Parkin translocation and mitophagy following mitochondrial depolarization, and that provision of exogenous lipids circumvents this block |
| GO:0032094 response to food | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to food transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0032526 response to retinoic acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to retinoic acid transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0032570 response to progesterone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to progesterone transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0032810 sterol response element binding | IDA PMID:16407292 Hepatic PCSK9 expression is regulated by nutritional status ... | ACCEPT | Summary: SREBP-1c acts through an SRE in the PCSK9 proximal promoter. Reason: Binding to the sterol regulatory element is the activity the protein was cloned for and named after, so it is core. Supporting Evidence: PMID:16407292 Adenoviral mediated overexpression of a dominant or negative form of SREBP-1c confirmed the implication of this transcription factor in insulin-mediated stimulation of PCSK9 expression PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism |
| GO:0032810 sterol response element binding | IDA PMID:31501273 MicroRNA 7 Impairs Insulin Signaling and Regulates AΞ² Levels... | ACCEPT | Summary: SRE binding recorded from the miR-7/HNRNPK study. Reason: SRE binding is a well-established core activity of SREBP-1. The cached text does not show the assay the curator used, but the annotation agrees with the gene-level evidence. Supporting Evidence: PMID:8402897 We report the cDNA cloning of human SREBP-1, a protein that binds SRE-1, activates transcription, and thereby mediates the final regulatory step in LDL metabolism PMID:27614840 in vitro-translated nSREBP-1c and nSREBP-2 bind only the wild-type but not the mutated SRE at -38 of NIS |
| GO:0032869 cellular response to insulin stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cellular response to insulin stimulus from rat Srebf1. Reason: Insulin induces SREBP-1c, and SREBP-1c mediates insulin's stimulation of lipogenic gene transcription (dominant-negative SREBP-1c blocks it). SREBP-1c therefore does take part in the transcriptional arm of the insulin response, unlike the other response-to-X rows. It is kept as non-core because the core function is the transcription factor activity itself. Supporting Evidence: PMID:11994399 Multiple lines of evidence suggest that insulinβs stimulatory effect on fatty acid synthesis is mediated by an increase in SREBP-1c. PMID:9421459 These results indicate that ADD1/SREBP1 is a key transcription factor linking changes in nutritional status and insulin levels to the expression of certain genes that regulate systemic energy metabolism PMID:16407292 Adenoviral mediated overexpression of a dominant or negative form of SREBP-1c confirmed the implication of this transcription factor in insulin-mediated stimulation of PCSK9 expression |
| GO:0032933 SREBP signaling pathway | IDA PMID:27614840 Sterol regulatory element-binding proteins are regulators of... | ACCEPT | Summary: nSREBP-1c binds the NIS promoter SRE and activates NIS expression in MCF-7 cells. Reason: SREBP-1 is the transcription factor of the SREBP signaling pathway: an ER-bound precursor that SCAP escorts to the Golgi, where it is cleaved by S1P and S2P to release the nuclear activator. Core process. Supporting Evidence: PMID:27614840 in vitro-translated nSREBP-1c and nSREBP-2 bind only the wild-type but not the mutated SRE at -38 of NIS PMID:8156598 In sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that translocates to the nucleus |
| GO:0032933 SREBP signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: SREBP signaling pathway from ARBA. Reason: SREBP-1 is the transcription factor of the SREBP signaling pathway: an ER-bound precursor that SCAP escorts to the Golgi, where it is cleaved by S1P and S2P to release the nuclear activator. Core process. Supporting Evidence: PMID:8156598 In sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that translocates to the nucleus PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis |
| GO:0032933 SREBP signaling pathway | IMP PMID:27614840 Sterol regulatory element-binding proteins are regulators of... | ACCEPT | Summary: Knockdown of SREBP-1c reduces NIS expression. Reason: SREBP-1 is the transcription factor of the SREBP signaling pathway: an ER-bound precursor that SCAP escorts to the Golgi, where it is cleaved by S1P and S2P to release the nuclear activator. Core process. Supporting Evidence: PMID:27614840 Knockdown of SREBP-1c and SREBP-2 by RNA interference decreased the mRNA and protein concentration of NIS by 30 to 50% 48h after initiating knockdown |
| GO:0032936 SREBP-SCAP complex | IEA GO_REF:0000117 | ACCEPT | Summary: SREBP-SCAP complex from ARBA. Reason: SREBP-1 forms a tight complex with SCAP through its C-terminal regulatory domain; this complex is the unit that is retained in the ER or transported to the Golgi. Core location of the precursor. Supporting Evidence: PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis PMID:32432943 Consistently, lycorine increased endogenous SCAP-SQSTM1 interaction, reduced SCAP-INSIG1, and SCAP-SREBF1 interaction in hepatocytes |
| GO:0032936 SREBP-SCAP complex | IPI PMID:32432943 Discovery of a potent SCAP degrader that ameliorates HFD-ind... | ACCEPT | Summary: Co-IP of SCAP with SREBF1 in hepatocytes. Reason: SREBP-1 forms a tight complex with SCAP through its C-terminal regulatory domain; this complex is the unit that is retained in the ER or transported to the Golgi. Core location of the precursor. Supporting Evidence: PMID:32432943 Consistently, lycorine increased endogenous SCAP-SQSTM1 interaction, reduced SCAP-INSIG1, and SCAP-SREBF1 interaction in hepatocytes |
| GO:0032937 SREBP-SCAP-Insig complex | NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin... | ACCEPT | Summary: SREBP-SCAP-Insig complex formed when sterols are high. Reason: Sterols promote SCAP binding to INSIG and retention of the SCAP/SREBP complex in the ER, and INSIGs act the same way on SREBP-1a. The ternary complex is the sterol-replete form of the precursor. Supporting Evidence: PMID:12202038 facilitates retention of the SCAP/SREBP complex in the ER PMID:12242332 Insig-1 and -2 had the same effect on the processing of SREBP-1a that they had on SREBP-2 |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MODIFY | Summary: Protein-containing complex from rat Srebf1. Reason: Correct but general. The specific complex containing SREBP-1 is the SREBP-SCAP complex (GO:0032936), already accepted. Proposed replacements: SREBP-SCAP complex Supporting Evidence: PMID:32432943 Consistently, lycorine increased endogenous SCAP-SQSTM1 interaction, reduced SCAP-INSIG1, and SCAP-SREBF1 interaction in hepatocytes PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis |
| GO:0033762 response to glucagon | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to glucagon transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0033993 response to lipid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to lipid transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Rodents fed diets enriched in polyunsaturated fatty acids manifest reduced SREBP-1c mRNA expression and low rates of lipogenesis in liver PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. |
| GO:0043434 response to peptide hormone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to peptide hormone transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000120 | MODIFY | Summary: Sequence-specific DNA binding from combined IEA. Reason: Correct but general. SREBP-1 binds specific cis-regulatory elements (SRE-1, E-box) in RNA polymerase II promoters, so the descendant GO:0000978, already accepted for this gene, should be used. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:8402897 Instead of an inverted repeat (CANNTG), the target for all known bHLH-ZIP proteins, SRE-1 contains a direct repeat of CAC PMID:7739539 we demonstrate that ADD1/SREBP1 has dual DNA sequence specificity, binding to both an E-box motif (ATCACGTGA) and a non-E-box sequence previously shown to be important in cholesterol metabolism, sterol regulatory element 1 (SRE-1; ATCACCCCAC) |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Protein-containing complex binding from rat Srebf1. Reason: Over-annotation. SREBP-1 is itself a subunit of the SREBP-SCAP complex and recruits coactivator complexes, but "protein-containing complex binding" recasts that membership as an activity of SREBP-1. The real relationships are captured by the accepted SREBP-SCAP complex location and the coactivator binding rows. Supporting Evidence: PMID:32432943 Consistently, lycorine increased endogenous SCAP-SQSTM1 interaction, reduced SCAP-INSIG1, and SCAP-SREBF1 interaction in hepatocytes |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to ethanol transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IDA PMID:12177166 Transcriptional activities of nuclear SREBP-1a, -1c, and -2 ... | ACCEPT | Summary: Nuclear SREBP-1a strongly activates cholesterogenic SRE promoters in HepG2 cells. Reason: SREBP-1 (mainly the 1a isoform) activates cholesterogenic genes and LDLR. This is the process used in the human GO-CAM for SREBF1. SREBP-1c is weak on these promoters, so this is more an SREBP-1a property, but it holds at the gene level. Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c PMID:9062341 The mRNAs for the LDL receptor and several cholesterol biosynthetic enzymes were elevated in SREBP-la transgenic mice, but not in 1c transgenic mice |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA: positive regulation of cholesterol biosynthetic process. Reason: Consistent with experimental evidence for SREBP-1a activation of cholesterogenic genes. Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IMP PMID:12177166 Transcriptional activities of nuclear SREBP-1a, -1c, and -2 ... | ACCEPT | Summary: Tyr-to-Arg basic region mutant abolishes SRE transactivation. Reason: Mutational evidence from the same study supports SRE-dependent activation of cholesterogenic promoters. Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000120 | MODIFY | Summary: Positive regulation of DNA-templated transcription from combined IEA. Reason: Correct but general. SREBP-1 activates RNA polymerase II-transcribed genes, so GO:0045944 (already accepted) is the specific term. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:26437365 MicroRNA-148a regulates LDL receptor and ABCA1 expression to... | ACCEPT | Summary: nSREBP1c activates the miR-148a promoter via E-boxes and occupies it in vivo. Reason: SREBP-1 is a transcriptional activator of RNA polymerase II target genes. Core process. Supporting Evidence: PMID:26437365 overexpression of nSREBP1c significantly increased the expression of miR-148a (mature and precursor forms), as well as the SREBP1c target gene, FASN PMID:26437365 SREBP1 was significantly enriched in the promoters of Srebp1, Fasn, and miR-148a upon refeeding |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:31501273 MicroRNA 7 Impairs Insulin Signaling and Regulates AΞ² Levels... | ACCEPT | Summary: SREBP1c increases HNRNPK/miR-7 host gene expression. Reason: SREBP-1 is a transcriptional activator of RNA polymerase II target genes. Core process. Supporting Evidence: PMID:31501273 These results, together with the data showing an increase in miR-7 with the host gene upon overexpression of an active SREBP1c form in neuronal cells, suggest a possible SREBP1c-mediated transcriptional mechanism of HNRNPK/miR-7 through insulin/LXR pathways |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Positive regulation of Pol II transcription from rat Srebf1. Reason: SREBP-1 is a transcriptional activator of RNA polymerase II target genes. Core process. Supporting Evidence: PMID:8156598 This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:23610160 cAMP-stimulated transcription of DGKΞΈ requires steroidogenic... | ACCEPT | Summary: SF1 and SREBP1 cooperatively activate DGKtheta transcription. Reason: SREBP-1 is a transcriptional activator of RNA polymerase II target genes. Core process. Supporting Evidence: PMID:23610160 we demonstrate that SF1 and SREBP1 activate DGKΞΈ transcription in a cAMP-dependent manner in human adrenocortical cells |
| GO:0045944 positive regulation of transcription by RNA polymerase II | TAS PMID:23610160 cAMP-stimulated transcription of DGKΞΈ requires steroidogenic... | ACCEPT | Summary: SF1 and SREBP1 activate DGKtheta transcription. Reason: SREBP-1 is a transcriptional activator of RNA polymerase II target genes. Core process. Supporting Evidence: PMID:23610160 we demonstrate that SF1 and SREBP1 activate DGKΞΈ transcription in a cAMP-dependent manner in human adrenocortical cells |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Protein dimerization activity from InterPro bHLH domain. Reason: The bHLH-ZIP domain dimerizes, and dimerization is needed for efficient DNA binding. This is a true structural property of the DNA-binding domain and is kept as non-core. Supporting Evidence: Reactome:R-HSA-2065549 The N-terminal domains of SREBPs (SREBP1A/1C/2, SREBFs) dimerize via interaction of their helix-loop-helix leucine zipper domains |
| GO:0051591 response to cAMP | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to cAMP transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. PMID:11994399 In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding |
| GO:0070542 response to fatty acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA response to fatty acid transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Rodents fed diets enriched in polyunsaturated fatty acids manifest reduced SREBP-1c mRNA expression and low rates of lipogenesis in liver PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. |
| GO:0071398 cellular response to fatty acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA cellular response to fatty acid transferred from rat Srebf1 via Ensembl Compara. Reason: This electronic transfer from rat Srebf1 reflects studies in which Srebf1 expression or processing changed after the stimulus. A change in the gene's own expression does not show that the SREBP-1 protein carries out the response. SREBF1 acts downstream as a transcriptional activator of lipogenic and cholesterogenic genes. Over-annotation. Supporting Evidence: PMID:11994399 Rodents fed diets enriched in polyunsaturated fatty acids manifest reduced SREBP-1c mRNA expression and low rates of lipogenesis in liver PMID:11994399 Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. |
| GO:0090209 negative regulation of triglyceride metabolic process | IDA PMID:28483554 Downregulation of miR-192 causes hepatic steatosis and lipid... | MODIFY | Summary: miR-192 suppression of SREBF1 reduces BPA-induced hepatic lipid accumulation. Reason: Sign correction. The abstract shows that SREBF1 upregulation drives de novo lipogenesis and steatosis, and that miR-192 improves steatosis by suppressing SREBF1. SREBF1 therefore promotes triglyceride accumulation. The negative regulation fits miR-192, not SREBF1. The supported term for SREBF1 is positive regulation of triglyceride biosynthetic process (GO:0010867), which the gene already carries from orthologs. Proposed replacements: positive regulation of triglyceride biosynthetic process Supporting Evidence: PMID:28483554 MiR-192 mimic and lentivirus-mediated overexpression of miR-192 improved BPA-induced hepatic steatosis by suppressing SREBF1 PMID:11994399 Overexpression of nSREBP-1c in the liver of transgenic mice produces a triglyceride-enriched fatty liver with no increase in cholesterol |
| GO:1901524 regulation of mitophagy | IMP PMID:24912190 Genome-wide RNAi screen identifies the Parkinson disease GWA... | MARK AS OVER ANNOTATED | Summary: SREBF1 RNAi reduces Parkin-mediated mitophagy. Reason: From a genome-wide RNAi screen. SREBF1 knockdown impaired Parkin translocation and mitophagy, but exogenous lipids bypassed the block, so the effect works through SREBP-driven lipid supply rather than a direct role of SREBP-1 in mitophagy. Supporting Evidence: PMID:24912190 We have shown that loss of SREBF1 , FBXW7 , and GSK3A inhibits Parkin translocation and mitophagy following mitochondrial depolarization, and that provision of exogenous lipids circumvents this block |
| GO:1902895 positive regulation of miRNA transcription | IDA PMID:31501273 MicroRNA 7 Impairs Insulin Signaling and Regulates AΞ² Levels... | KEEP AS NON CORE | Summary: SREBP1c increases transcription of the miR-7 host gene HNRNPK. Reason: SREBP-1c also activates miRNA host genes (miR-7 via HNRNPK; miR-148a; intronic miR-33b). These are true target-specific outcomes of its activator function, but peripheral to the core lipogenic programme. Supporting Evidence: PMID:31501273 These results, together with the data showing an increase in miR-7 with the host gene upon overexpression of an active SREBP1c form in neuronal cells, suggest a possible SREBP1c-mediated transcriptional mechanism of HNRNPK/miR-7 through insulin/LXR pathways PMID:26437365 overexpression of nSREBP1c significantly increased the expression of miR-148a (mature and precursor forms), as well as the SREBP1c target gene, FASN |
| GO:1903747 obsolete regulation of protein localization to mitochondrion | IMP PMID:24912190 Genome-wide RNAi screen identifies the Parkinson disease GWA... | MARK AS OVER ANNOTATED | Summary: SREBF1 RNAi reduces Parkin translocation to depolarized mitochondria (GOA label marks the term obsolete). Reason: From a genome-wide RNAi screen. SREBF1 knockdown impaired Parkin translocation and mitophagy, but exogenous lipids bypassed the block, so the effect works through SREBP-driven lipid supply rather than a direct role of SREBP-1 in mitophagy. The GOA label also marks this term as obsolete. Supporting Evidence: PMID:24912190 We have shown that loss of SREBF1 , FBXW7 , and GSK3A inhibits Parkin translocation and mitophagy following mitochondrial depolarization, and that provision of exogenous lipids circumvents this block |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | MODIFY | Summary: HT-SELEX of human TF DNA-binding domains recovered a binding motif for SREBF1. Reason: Correct but general. SREBP-1 binds cis-regulatory SRE and E-box motifs in RNA polymerase II promoters, so the descendant GO:0000978, already accepted, is the appropriate term. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:28473536 analysis of ~1000 human TF extended DNA binding domains (eDBDs; details are given in table S1 and the methods) and ~550 full-length TFs PMID:7739539 we demonstrate that ADD1/SREBP1 has dual DNA sequence specificity, binding to both an E-box motif (ATCACGTGA) and a non-E-box sequence previously shown to be important in cholesterol metabolism, sterol regulatory element 1 (SRE-1; ATCACCCCAC) |
| GO:0070888 E-box binding | ISS PMID:7739539 Dual DNA binding specificity of ADD1/SREBP1 controlled by a ... | NEW | Summary: Proposed: E-box binding, the second of the dual DNA specificities of SREBP-1. Reason: Besides SRE-1, SREBP-1 binds E-box motifs (ATCACGTGA), which mediate activation of lipogenic genes such as FASN. The atypical tyrosine in the basic region controls the dual specificity; replacing it with Arg restricts binding to E-boxes. In human cells, Tyr-to-Arg SREBP-1 shows increased E-box activity. GOA records SRE binding but not E-box binding for the human protein. Supporting Evidence: PMID:7739539 we demonstrate that ADD1/SREBP1 has dual DNA sequence specificity, binding to both an E-box motif (ATCACGTGA) and a non-E-box sequence previously shown to be important in cholesterol metabolism, sterol regulatory element 1 (SRE-1; ATCACCCCAC) PMID:9421459 A mutation in the basic domain of ADD1/SREBP1 that allows E-box binding but destroys sterol regulatory element-1 binding prevents leptin gene transactivation but has no effect on the increase in FAS promoter function PMID:12177166 conversely results in markedly increased activity of SREBP-1 but not activity of SREBP-2 for E-boxes |
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Download this section (compressed HTML)Q: The human GO-CAM 6205c24300000880 (and 66a3e0bb00000156) models SREBF1 with GO:0000981 part_of GO:0045542 positive regulation of cholesterol biosynthetic process. In liver and most tissues SREBP-1c is the dominant isoform and is weak on cholesterogenic SREs. Should the model record SREBP-1a (P36956-1) specifically for cholesterol biosynthesis, and add an SREBP-1c activity part_of GO:0045723 positive regulation of fatty acid biosynthetic process?
Q: GO:0004879 nuclear receptor activity (IDA, PMID:23610160) and its inferred GO:0030522 appear to have been assigned to SREBF1 instead of NR5A1/SF1. Can the source curator confirm and retract them?
Q: GO:0090209 negative regulation of triglyceride metabolic process (PMID:28483554) has the opposite sign to the paper's conclusion for SREBF1. Was it intended for MIR192, or for a different relation?
Q: To what extent do SREBP-1 repressive effects (for example on IRS2 or gluconeogenic genes) involve direct DNA-binding repression rather than coactivator competition? Would a DNA-binding transcription repressor activity annotation ever be warranted?
Experiment: Isoform-specific CUT&RUN or ChIP-seq with tagged endogenous SREBP-1a and SREBP-1c in human hepatocytes (primary or iPSC-derived) under sterol depletion and insulin stimulation, combined with isoform-specific CRISPR exon-1 deletion and RNA-seq.
Hypothesis: SREBP-1a and SREBP-1c occupy overlapping SRE/E-box sites, but differences in activation domain strength, not DNA site selection, explain the 1c bias toward lipogenic genes in human liver.
Type: genome-wide binding and transcriptomics
Experiment: Measure SRE-1 versus E-box binding affinities of purified human SREBP-1 bHLH-ZIP (wild type and Y335R) by quantitative EMSA or SPR, and test the IFAP2 variants (residues 527-530) for SCAP binding and S1P cleavage in reconstituted Golgi membranes.
Hypothesis: Human SREBP-1 dual DNA specificity depends on Tyr335, and IFAP2 variants act as cleavage-resistant precursors without altering SCAP binding.
Type: in vitro biochemistry
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