Oncofusion

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Geneweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q78-interactome-absent

SREBF1 / SREBP-1 - the weakest of the three MEN1 sterol partners, because it is simultaneously the pathway's readout

also called SREBP1 · SREBP-1 · SREBP-1c · BHLHD1 · Sterol regulatory element-binding protein 1 · SREBF1

SREBP-1 is the master switch for making fat. In the one paper that connects it to menin it is both a protein menin sticks to and the thing menin was measured to turn down - and those are two different claims that the experiment cannot separate.

The same thing, for a scientist

SREBF1 (P36956, 1,147 aa) encodes the sterol regulatory element-binding protein 1 precursor, a membrane-bound bHLH-zip transcription factor cleaved in the Golgi to release a nuclear form that drives fatty-acid synthesis. Its whole connection to this project is **one non-spoke MEN1 co-immunoprecipitation in supplementary figure 6 of Cheng et al. 2015** [E1]. The difficulty is structural, not evidential: in the same paper **SREBP-1c is the LXR target gene whose reduction is the readout of menin's repression of LXR-alpha** [E2]. So SREBF1 appears as a binding partner and as the downstream reporter of the pathway in the same figure set, and a single co-IP cannot tell a direct contact from co-recovery of an abundant, co-regulated factor. Compounding it, **SREBF1 is proteolytically processed** and neither the abstract nor the IntAct record says whether the precursor or the mature nuclear form was blotted - which is a question about which compartment menin is in. Graded **weak**, written because the granularity rule asks for one entry per interactor and because the ambiguity is the useful content.

Go deeper
Partner or readout - what would separate them

Three experiments, none of which has been done 12:

  1. Reciprocal co-IP. Pull SREBF1 and blot menin. The LXR-alpha arm of the same paper has both directions curated; SREBF1 has one.
  2. Menin binding with LXR-alpha removed. If the menin-SREBF1 co-recovery is LXR-alpha-dependent, it is a ternary complex and not a contact.
  3. Which form. Precursor (ER/Golgi membrane) or mature nuclear bHLH-zip. Menin is nuclear; a co-IP with the precursor would be hard to interpret and a co-IP with the nuclear form would be the interesting result.

Until one of these exists this node records a curated contact and an unresolved role, not a partner.

What SREBF1 is doing in this graph at all

Lipogenesis is not a random topic for a leukaemia graph. concept-metabolic-dependency-consequence-or-independent-kmt2a exists because this project has repeatedly had to ask whether a metabolic phenotype is driven by the fusion or is a property of the lineage. The menin-LXR-SREBP axis is a third possibility: a metabolic axis driven by the drug target rather than by the fusion, and therefore one that a menin inhibitor would perturb in every tissue regardless of what the fusion is doing. That is what this node is here to carry.

Facts and figures
uniprotP36956
length AA1147
gene symbolSREBF1
protein nameSterol regulatory element-binding protein 1 (SREBP-1), class D basic helix-loop-helix protein 1
uniprot resolutionaccession:P36956, reviewed human, one record; primary gene name read back as SREBF1 (entry SRBP1_HUMAN), synonyms BHLHD1, SREBP1; length 1,147 aa checked against UniProt 2026-09-21.
symbol collision checkdata/symbol-collisions.json greped 2026-09-21 for SREBF1 and SREBP: no row existed and none is proposed; the SREBF1/SREBF2 pair is distinguishable by length (1,147 vs 1,141) only barely, which is noted here but not proposed as a registry row because the symbols themselves do not alias.
baitMEN1 (O00255)
processingmembrane-bound precursor (1,147 aa) cleaved to a mature nuclear bHLH-zip transcription factor
shown for fusionNO - nobody has looked in any KMT2A fusion, in any lineage.
fetched2026-09-21
subnuclear localizationNUCLEAR PERIPHERY for the PROTEIN, by sequestration: A-type lamin tail regions bind an SREBP1 polypeptide in vitro and in HeLa cells, and lamin overexpression - wild-type and the R482W lipodystrophy and delta607-656 progeria variants - favours SREBP1 localisation at the INTRANUCLEAR PERIPHERY (PMID 21993218) [E_q95_srebf1_loc2]. TWO THINGS THIS IS NOT. It is not a nucleolar assignment: the paper's nucleolar observation concerns an SREBP1 polypeptide fused to an ARTIFICIAL nucleolar localisation signal. And it is not the same as the other nuclear address in this literature, which is for the GENE: DNA immuno-FISH places the SREBF1 LOCUS non-randomly relative to SC-35 speckle domains, association tracking upregulation, with PPARG, SREBF1 and FABP4 clustering around shared speckles in differentiated adipocytes (PMID 21127962) [E_q95_srebf1_loc2]. Protein address and locus address are different facts and neither supports the other.
localization shown for fusionNO - nobody has looked in any KMT2A fusion, in any lineage: 0 records for the gene clause against a localisation clause AND the fusion clause and 0 against a subnuclear clause AND the fusion clause, from an operand control of 4,584 [E_q95_srebf1_loc4]. This entry already carries shown_for_fusion as a string in the interactome sense and it is left untouched (brief rule 86). The gap is a FRACTIONATION gap rather than an imaging one: for a protein whose two forms are two compartments, the informative experiment is a nuclear-versus-membrane western blot on a KMT2A-rearranged line, which needs no microscopy and could ride along with this project's existing banked-sample LXR target-panel proposal.
interaction with men1
{
  "source_pmid": "25962847",
  "source_class": "focused mechanistic study; this pair is a supplementary panel",
  "n_intact_records": 1,
  "n_spoke_expanded": 0,
  "n_source_publications": 1,
  "intact_acs": [
    "EBI-11364879"
  ],
  "figure": "supplementary figure 6",
  "system": "Homo sapiens HepG2 hepatocellular carcinoma cell",
  "reciprocal_tested": false,
  "form_detected": "unknown - precursor or mature nuclear form not stated in the record",
  "role_ambiguity": "SREBP-1c is also the LXR target gene whose reduction is the paper's readout of menin repression",
  "shared_pdb_entries": []
}
localization
{
  "TWO_STATE_BY_DESIGN": "PRECURSOR: endoplasmic reticulum membrane (ECO:0000269), Golgi apparatus membrane (ECO:0000305 curator inference), COPII-coated vesicle membrane (ECO:0000250 from a rodent accession), multi-pass with cytoplasmic 1-487, TM 488-508, lumenal 509-547, TM 548-568, cytoplasmic 569-1147. PROCESSED FORM and the constitutively active SREBP-1aDelta and SREBP-1cDelta isoforms: NUCLEUS [E_q95_srebf1_loc1].",
  "SWITCH": "sterol concentration. High sterol retains SCAP-SREBP in the ER; low sterol promotes COPII recruitment and Golgi transport where the protein is cleaved and the N-terminal bHLH-zip fragment enters the nucleus [E_q95_srebf1_loc1]. A second, kinase-driven control on the precursor pool operates in leukaemia: quizartinib degrades the precursor via FLT3/AKT/GSK3 [E_q95_srebf1_loc3].",
  "WHY_THE_FORM_MATTERS_HERE": "this graph's only menin-SREBP1 interaction record explicitly does not state which form was detected (data.interaction_with_men1.form_detected = 'unknown'). Because the two forms occupy different compartments and are annotated as different molecules, an interaction assigned to the wrong form is a different claim about biology [E_q95_srebf1_loc3].",
  "systems": "HeLa for the lamin work, HepG2 for the menin interaction, porcine mesenchymal stem cells and adipocytes for the locus study, FLT3/ITD AML patients and mice for the degradation work."
}
cell type
{
  "measured_in": "HeLa for the protein's subnuclear position; porcine mesenchymal stem cells and adipocytes for the locus position; HepG2 for the menin interaction. NOTHING HAEMATOPOIETIC has been imaged or fractionated for SREBP-1 form in this literature.",
  "expression": "UniProt: expressed in a wide variety of tissues, most abundant in LIVER and adrenal gland; fetal lung and liver highest; predominates in hepatoma cell lines; also kidney, brain, white fat and muscle. Blood is not named.",
  "in_leukaemia": "functionally yes, positionally no. FLT3/ITD AML patients show upregulated SREBP target genes [E_q95_srebf1_loc3], and the 21-record leukaemia literature spans AML, CLL and T-ALL lipid metabolism without a single compartment measurement [E_q95_srebf1_loc4]."
}
cell state
{
  "STEROL_STATUS": "the defining state variable, and it sets the compartment directly [E_q95_srebf1_loc1].",
  "FLT3_SIGNALLING": "FLT3/ITD raises SREBP target genes and FLT3 inhibition degrades the precursor through AKT/GSK3, with cardiolipin loss and mitochondrial depolarisation downstream [E_q95_srebf1_loc3]. KMT2A-rearranged disease is characterised by high FLT3 EXPRESSION rather than ITD, so this is adjacent rather than identical.",
  "DIFFERENTIATION_MOVES_THE_LOCUS": "during adipogenesis the SREBF1 gene becomes more internally located and speckle-associated as it is upregulated [E_q95_srebf1_loc2] - a cell-state-dependent nuclear repositioning of the gene, in pig.",
  "not_recorded": "nothing under menin inhibition, and no form-resolved measurement in any haematopoietic cell."
}
localization bounded absence
{
  "date": "2026-09-22",
  "tool": "NCBI E-utilities esearch, db=pubmed",
  "run_by": "Q95",
  "shape": "one [tiab] tag per term (rule 94); cytogenetic terms quoted (rule 95); querytranslation read back and stored (rule 90)",
  "absence_class": "measured-not-reported",
  "absence_class_reasoning": "unlike the never-measured cases in this tranche, any western blot of SREBP-1 in a leukaemia line generates the form-resolved information this question needs, because the precursor and the mature form run at different molecular weights; the 21-record leukaemia literature includes several SREBP1 blots whose form assignment was simply not the point of the paper.",
  "queries": {
    "gene_clause_alone": {
      "query": "SREBF1[tiab] OR \"SREBP-1\"[tiab] OR SREBP1[tiab]",
      "count": 4584,
      "querytranslation": "\"SREBF1\"[Title/Abstract] OR \"SREBP-1\"[Title/Abstract] OR \"SREBP1\"[Title/Abstract]"
    },
    "gene_AND_loc": {
      "query": "(SREBF1[tiab] OR \"SREBP-1\"[tiab] OR SREBP1[tiab]) AND (localization[tiab] OR localisation[tiab] OR subcellular[tiab] OR immunofluorescence[tiab] OR nuclear[tiab] OR cytoplasmic[tiab] OR compartment[tiab])",
      "count": 825,
      "querytranslation": "(\"SREBF1\"[Title/Abstract] OR \"SREBP-1\"[Title/Abstract] OR \"SREBP1\"[Title/Abstract]) AND (\"localization\"[Title/Abstract] OR \"localisation\"[Title/Abstract] OR \"subcellular\"[Title/Abstract] OR \"immunofluorescence\"[Title/Abstract] OR \"nuclear\"[Title/Abstract] OR \"cytoplasmic\"[Title/Abstract] OR \"compartment\"[Title/Abstract])"
    },
    "gene_AND_subnuclear": {
      "query": "(SREBF1[tiab] OR \"SREBP-1\"[tiab] OR SREBP1[tiab]) AND (\"nuclear speckle\"[tiab] OR \"nuclear speckles\"[tiab] OR nucleolus[tiab] OR nucleolar[tiab] OR \"PML body\"[tiab] OR \"PML bodies\"[tiab] OR \"nuclear matrix\"[tiab] OR \"Polycomb bodies\"[tiab] OR \"Polycomb body\"[tiab] OR subnuclear[tiab] OR \"nuclear bodies\"[tiab] OR \"nuclear body\"[tiab] OR chromocent*[tiab] OR heterochromat*[tiab])",
      "count": 6,
      "querytranslation": "(\"SREBF1\"[Title/Abstract] OR \"SREBP-1\"[Title/Abstract] OR \"SREBP1\"[Title/Abstract]) AND (\"nuclear speckle\"[Title/Abstract] OR \"nuclear speckles\"[Title/Abstract] OR \"nucleolus\"[Title/Abstract] OR \"nucleolar\"[Title/Abstract] OR \"PML body\"[Title/Abstract] OR \"PML bodies\"[Title/Abstract] OR \"nuclear matrix\"[Title/Abstract] OR \"Polycomb bodies\"[Title/Abstract] OR \"Polycomb body\"[Title/Abstract] OR \"subnuclear\"[Title/Abstract] OR \"nuclear bodies\"[Title/Abstract] OR \"nuclear body\"[Title/Abstract] OR \"chromocent*\"[Title/Abstract] OR \"heterochromat*\"[Title/Abstract])"
    },
    "gene_AND_fusion": {
      "query": "(SREBF1[tiab] OR \"SREBP-1\"[tiab] OR SREBP1[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL1\"[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab] OR \"MLL-ENL\"[tiab] OR \"MLL-AF10\"[tiab] OR \"t(4;11)\"[tiab] OR \"t(11;19)\"[tiab])",
      "count": 3,
      "querytranslation": "(\"SREBF1\"[Title/Abstract] OR \"SREBP-1\"[Title/Abstract] OR \"SREBP1\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"MLL-AF10\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 11 19\"[Title/Abstract])"
    },
    "gene_AND_loc_AND_fusion": {
      "query": "(SREBF1[tiab] OR \"SREBP-1\"[tiab] OR SREBP1[tiab]) AND (localization[tiab] OR localisation[tiab] OR subcellular[tiab] OR immunofluorescence[tiab] OR nuclear[tiab] OR cytoplasmic[tiab] OR compartment[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL1\"[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab] OR \"MLL-ENL\"[tiab] OR \"MLL-AF10\"[tiab] OR \"t(4;11)\"[tiab] OR \"t(11;19)\"[tiab])",
      "count": 0,
      "querytranslation": "(\"SREBF1\"[Title/Abstract] OR \"SREBP-1\"[Title/Abstract] OR \"SREBP1\"[Title/Abstract]) AND (\"localization\"[Title/Abstract] OR \"localisation\"[Title/Abstract] OR \"subcellular\"[Title/Abstract] OR \"immunofluorescence\"[Title/Abstract] OR \"nuclear\"[Title/Abstract] OR \"cytoplasmic\"[Title/Abstract] OR \"compartment\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"MLL-AF10\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 11 19\"[Title/Abstract])"
    },
    "gene_AND_subnuclear_AND_fusion": {
      "query": "(SREBF1[tiab] OR \"SREBP-1\"[tiab] OR SREBP1[tiab]) AND (\"nuclear speckle\"[tiab] OR \"nuclear speckles\"[tiab] OR nucleolus[tiab] OR nucleolar[tiab] OR \"PML body\"[tiab] OR \"PML bodies\"[tiab] OR \"nuclear matrix\"[tiab] OR \"Polycomb bodies\"[tiab] OR \"Polycomb body\"[tiab] OR subnuclear[tiab] OR \"nuclear bodies\"[tiab] OR \"nuclear body\"[tiab] OR chromocent*[tiab] OR heterochromat*[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL1\"[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab] OR \"MLL-ENL\"[tiab] OR \"MLL-AF10\"[tiab] OR \"t(4;11)\"[tiab] OR \"t(11;19)\"[tiab])",
      "count": 0,
      "querytranslation": "(\"SREBF1\"[Title/Abstract] OR \"SREBP-1\"[Title/Abstract] OR \"SREBP1\"[Title/Abstract]) AND (\"nuclear speckle\"[Title/Abstract] OR \"nuclear speckles\"[Title/Abstract] OR \"nucleolus\"[Title/Abstract] OR \"nucleolar\"[Title/Abstract] OR \"PML body\"[Title/Abstract] OR \"PML bodies\"[Title/Abstract] OR \"nuclear matrix\"[Title/Abstract] OR \"Polycomb bodies\"[Title/Abstract] OR \"Polycomb body\"[Title/Abstract] OR \"subnuclear\"[Title/Abstract] OR \"nuclear bodies\"[Title/Abstract] OR \"nuclear body\"[Title/Abstract] OR \"chromocent*\"[Title/Abstract] OR \"heterochromat*\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"MLL-AF10\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 11 19\"[Title/Abstract])"
    },
    "srebf1_nuclear": {
      "query": "(SREBF1[tiab] OR \"SREBP-1\"[tiab]) AND (\"nuclear translocation\"[tiab] OR \"nuclear form\"[tiab] OR proteolytic*[tiab])",
      "count": 117,
      "querytranslation": "(\"SREBF1\"[Title/Abstract] OR \"SREBP-1\"[Title/Abstract]) AND (\"nuclear translocation\"[Title/Abstract] OR \"nuclear form\"[Title/Abstract] OR \"proteolytic*\"[Title/Abstract])"
    },
    "srebf1_leuk": {
      "query": "(SREBF1[tiab] OR \"SREBP-1\"[tiab] OR SREBP1[tiab]) AND (leukemia[tiab] OR leukaemia[tiab])",
      "count": 21,
      "querytranslation": "(\"SREBF1\"[Title/Abstract] OR \"SREBP-1\"[Title/Abstract] OR \"SREBP1\"[Title/Abstract]) AND (\"leukemia\"[Title/Abstract] OR \"leukaemia\"[Title/Abstract])"
    }
  },
  "title_check": "gene_AND_subnuclear, 6 records: 21993218 and 14755333 (A-type lamins, on topic), 21127962 (SC-35 locus study, on topic), and 42453921, 35998542, 30638930 off topic - two of those three matching through SNHG 'small nucleolar RNA host gene' nomenclature, the registry-documented contamination firing again."
}
How this could bite us back
  • Writing SREBF1 as a menin partner on this record would put a master lipogenic regulator into the KMT2A interactome on one supplementary panel that cannot distinguish a contact from a readout. The entry is deliberately graded weak and says so in its title.
  • The temptation is to inherit the grade of the LXR-alpha arm because the partners share a paper. Sharing a paper is not evidence; it is the reason the three partners looked like three findings in the first place.
  • If a menin inhibitor does raise SREBP-1c, the population receiving it also receives asparaginase and corticosteroids, both of which drive hypertriglyceridaemia. That is an interaction nobody has looked for.
Still open
  1. Is menin-SREBF1 a direct contact or co-recovery through LXR-alpha? A menin co-IP in LXR-alpha-depleted cells answers it in one experiment.
  2. Which SREBF1 form binds menin - the membrane precursor or the mature nuclear factor? The answer decides whether this is a nuclear transcription-factor contact or something in the secretory pathway.
  3. Does menin inhibition raise SREBP-1c in any human tissue? That is the measurable clinical consequence of the whole LXR arm, and it has never been reported in a menin-inhibitor trial.
Every source behind this entry (7)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    IntAct's REST record holds exactly one MEN1-SREBF1 row, EBI-11364879, typed MI:0915 physical association, anti-bait co-immunoprecipitation in human HepG2 cells, not spoke-expanded, annotated by the curator to supplementary figure 6 of PMID 25962847.

    What this evidence cannot show

    One database on one day, REST endpoint (brief rule 93). A single row from a supplementary figure of a paper about a different protein. IntAct records no isoform or processed-chain identifier for the SREBF1 side, so the record does not say whether the precursor or the mature nuclear form was detected.

    Evidence that argues against this (2)
    • 'Exactly one' is exactly one AT THIS ENDPOINT, and the endpoint penalty for this accession is severe. Measured the same day, IntAct REST returns 93 records for P36956 where PSICQUIC id:P36956 returns 31 (33%) - so two thirds of SREBF1's curated record is invisible to the query form this project's earlier interactome analyses used, and a beat reading SREBF1 through PSICQUIC would have concluded something different. The uniformity assumption is also wrong: on the same day the same comparison for Q13309/SKP2 is 365 against 300. EMBL-EBI IntAct and PSICQUIC 2026
    • IntAct grades this row itself, and grades it low. Re-read at the endpoint on 2026-09-21, EBI-11364879 carries intactMiscore 0.4 and the single free-text annotation 'figure legend (sf6)'. The 'supplementary figure 6' in this claim is that curator string and not the paper's own statement, and with the full text unreachable behind Elsevier nothing in this entry can check it. A non-spoke row is a better row than a spoke row; it is not a well-scored one. EMBL-EBI IntAct 2026
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    In the same publication, SREBP-1c is one of the LXR-alpha target genes whose expression menin overexpression reduces - alongside FASN and SCD-1 - which makes SREBF1 both a candidate menin-binding partner and the downstream readout of the mechanism in one experiment set.

    PMID 25962847DOI
    What this evidence cannot show

    Abstract read this session; full text is Elsevier and route 5 returns HTTP 403, so the supplementary figure was not seen. HepG2 hepatoma and mouse liver; no haematopoietic system, no KMT2A fusion (brief rule 73). The dual role of SREBF1 in this paper is an inference from the abstract plus IntAct's figure annotation, not a statement the authors make.

    Evidence that argues against this (1)
    • An independent group reports the menin-represses-LXR direction in colorectal tissue via ABCG1 and ABCA1 rather than SREBF1, so the LXR arm of the mechanism replicates without SREBF1 being involved at all - which is consistent with SREBF1 being a readout rather than a partner. Nyul TE et al. 2023
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    SREBF1's product is a 1,147-residue membrane-bound precursor that is proteolytically processed to release a nuclear bHLH-zip transcription factor, so a co-immunoprecipitation that does not say which form was detected does not say which compartment the contact occurred in.

    What this evidence cannot show

    A statement about the protein's biology and about what the interaction record omits, not about the experiment. It is possible the source figure labels the form; the figure could not be retrieved.

    Evidence that argues against this (1)
    • 1,147 aa is one isoform's length, and it is not the isoform the same paper measures. Fetched from UniProt on 2026-09-21, P36956 declares six isoforms; the DISPLAYED canonical is SREBP-1A (P36956-1, 1,147 aa) and SREBP-1C is a separate described isoform, P36956-3. The LXR target gene whose reduction is Cheng et al.'s readout is SREBP-1c, so 'SREBF1's product is a 1,147-residue precursor' names the wrong species for the pathway this entry is about. UniProt also annotates the processed nuclear form as a distinct chain, residues 1-490, with the two transmembrane helices at 488-508 and 548-568 lying outside it - and a processed chain is a different identifier from its parent accession (brief rule 93), so a findInteractions query on P36956 is not the query that would find a record filed against the nuclear form. UniProtKB 2026
  4. E_q95_srebf1_loc1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    SREBF1's compartment is TWO-STATE BY DESIGN and UniProt models it molecule by molecule: the precursor 'Sterol regulatory element-binding protein 1' is annotated to the ENDOPLASMIC RETICULUM MEMBRANE, Golgi apparatus membrane and COPII-coated vesicle membrane as a multi-pass membrane protein, with a feature table giving cytoplasmic 1-487, transmembrane 488-508, lumenal 509-547, transmembrane 548-568 and cytoplasmic 569-1147; the separate molecule 'Processed sterol regulatory element-binding protein 1' is annotated to the NUCLEUS, as are the constitutively active splice isoforms SREBP-1aDelta and SREBP-1cDelta. At high sterol concentrations the SCAP-SREBP complex is retained in the ER; low sterol promotes COPII recruitment and transport to the Golgi, where it is processed.

    What this evidence cannot show

    The two-state topology is not in dispute, but the evidence classes differ sharply between the states and the entry should not imply otherwise: the ER retention call is ECO:0000269, the Golgi call is ECO:0000305 curator inference, the COPII call is ECO:0000250 by similarity from a rodent accession, and the multi-pass topology is ECO:0000255 sequence analysis. Only the ER and nuclear states rest on experimental codes.

    Evidence that argues against this (1)
    • AND ONE OF THE NUCLEAR CITATIONS IS A RULE-91 CASE THAT MATTERS BECAUSE IT CONCERNS WHICH SPECIES WAS MEASURED. The processed nuclear form carries two ECO:0000269s: PubMed 11477106, which is squarely on point - a direct demonstration of rapid degradation of NUCLEAR SREBPs by the ubiquitin-proteasome pathway, so it necessarily identifies a nuclear species - and PubMed 32322062, a paper about the gluconeogenic enzyme PCK1 phosphorylating INSIG1/2 for lipogenesis, whose subject is the ER retention machinery rather than the nuclear form. A curator reading the second paper for a NUCLEUS annotation is reading an ER-pathway paper. The practical hazard here is specific: because the two states are different molecules with different addresses, a citation attached to the wrong molecule silently converts a statement about a membrane precursor into a statement about a transcription factor, and this graph's only menin-SREBP1 record explicitly does not state which form was detected. Hirano Y et al. 2001
  5. E_q95_srebf1_loc2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    The nuclear form of SREBP-1 has a measured SUBNUCLEAR address and it is the NUCLEAR PERIPHERY: the tail regions of prelamin A, lamin A and lamin C bind an SREBP1 polypeptide in vitro and in HeLa cells, the tail regions of the A-type lamin variants found in Dunnigan-type familial partial lipodystrophy (R482W) and Hutchinson-Gilford progeria (delta607-656) also bind it, and overexpression of wild-type A-type lamins and variants favours SREBP1 polypeptide localisation AT THE INTRANUCLEAR PERIPHERY, which the authors read as sequestration at the nuclear envelope.

    Subcellular localization of SREBP1 depends on its interaction with the C-terminal region of wild-type and disease related A-type lamins. · Duband-Goulet I, Woerner S, Gasparini S, Attanda W, Kondé E, Tellier-Lebègue C, Craescu CT, Gombault A, Roussel P, Vadrot N, Vicart P, Ostlund C, Worman HJ, Zinn-Justin S, Buendia B · Exp Cell Res 2011
    PMID 21993218DOI
    What this evidence cannot show

    Overexpression of lamin constructs plus an SREBP1 POLYPEPTIDE rather than the full endogenous nuclear form, in HeLa cells - so this maps an interaction-driven sequestration, not the resting distribution of endogenous nuclear SREBP-1. One detail must not be misread: the paper's nucleolar observation is that lamin tails impede nucleolar accumulation of an SREBP1 polypeptide FUSED TO AN ARTIFICIAL NUCLEOLAR LOCALISATION SIGNAL - that is an engineered reporter and is NOT evidence that SREBP-1 is nucleolar.

    Evidence that argues against this (1)
    • A SECOND SUBNUCLEAR RESULT EXISTS AND IT IS ABOUT THE GENE, NOT THE PROTEIN - AND CONFLATING THE TWO WOULD BE A CATEGORY ERROR THIS GRAPH SHOULD NAME. DNA immuno-FISH during porcine adipogenesis places the SREBF1 LOCUS non-randomly relative to SC-35 domains - nuclear speckles enriched in splicing and RNA-metabolic factors - with association correlating with upregulation of expression, and more frequent clustering of PPARG, SREBF1 and FABP4 from different chromosomes around the same speckle in differentiated adipocytes than in mesenchymal stem cells. So for this gene there are two different nuclear addresses in the literature: where the PROTEIN goes (nuclear periphery, lamin-sequestered) and where the GENE sits (speckle-associated when active). They are not alternatives and neither is evidence for the other, and the speckle result is a cell-state-dependent locus repositioning rather than a compartment for a transcription factor. Szczerbal I et al. 2010
  6. E_q95_srebf1_loc3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    SREBF1's cell-state evidence in leukaemia is real, is myeloid, and runs through a kinase this graph already treats as a KMT2A-r co-lesion: FLT3/ITD oncogenic activation upregulates SREBP target genes in vivo and in AML patients, quizartinib facilitates degradation of the PRECURSOR form of SREBP1 via the FLT3/AKT/GSK3 axis and lowers its target FASN, inhibition of FLT3 reduces cardiolipin and other phospholipids with loss of mitochondrial membrane potential, and pharmacological inhibition of SREBP1 or FASN sensitises FLT3/ITD leukaemia cells to quizartinib with combination benefit in a murine FLT3/ITD model.

    PMID 40263296DOI
    What this evidence cannot show

    FLT3/ITD AML, human patient data plus a murine model - myeloid, not infant B-lineage KMT2A::AFF1, and FLT3/ITD rather than the high FLT3 EXPRESSION that characterises KMT2A-rearranged disease, which is a different lesion. The state variable measured is the amount of PRECURSOR, so this is a control point on the membrane-bound pool and says nothing about where either form sits.

    Evidence that argues against this (1)
    • THIS SHARPENS AN OBJECTION THIS ENTRY ALREADY CARRIES AND MAKES IT WORSE FOR THE MENIN STORY. The entry's existing position is that SREBF1 is the weakest of the three MEN1 sterol partners because it is simultaneously the pathway's readout - menin binds LXR-alpha and LXR-beta and lowers the LXR target gene SREBP-1c, so SREBP-1 is both a claimed interactor and the thing being measured. The FLT3 result adds a second, independent route to the same readout: a kinase pathway that degrades the SREBP1 precursor. So in a KMT2A-rearranged blast, which characteristically has high FLT3 signalling, SREBP-1 protein level is under at least two controls that have nothing to do with menin binding - and the one menin-SREBP1 IntAct record does not even state whether the precursor or the mature nuclear form was detected. Any menin-SREBF1 interaction claim in this graph therefore needs a form-resolved western blot before it can mean anything. Cheng P et al. 2015
  7. E_q95_srebf1_loc4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    Bounded 2026-09-22: no SREBP-1 compartment has been measured in any KMT2A-fusion context. The gene clause over SREBF1, 'SREBP-1' and SREBP1 returns 4,584 records and intersects the nine-term KMT2A/MLL fusion clause at 3; with a localisation clause the gene clause returns 825 and with the fusion clause added 0; with a subnuclear clause it returns 6 and with the fusion clause added 0. The leukaemia sub-query returns 21 records, of which the on-topic ones are all lipid-metabolism and drug-resistance studies in AML, CLL and T-ALL and none measures a compartment.

    What this evidence cannot show

    Titles and abstracts only; supporting figures not searched (rule 80), which is a real limitation for this protein because the form-resolved western blot that distinguishes precursor from nuclear form is exactly the kind of panel that lives in a supplementary figure. The subnuclear count of 6 was title-checked: 2 are the lamin papers, 1 is the SC-35 locus study, and 3 are SNHG/lipid-metabolism papers matching through 'small nucleolar RNA host gene'.

    Evidence that argues against this (1)
    • THE ABSENCE HERE IS UNUSUALLY CHEAP TO CLOSE AND THE ENTRY SHOULD SAY WHICH EXPERIMENT DOES IT, BECAUSE A TWO-STATE PROTEIN NEEDS NO MICROSCOPY. The question is not where SREBP-1 is but WHICH FORM is present, and that is a western blot on nuclear and membrane fractions from a KMT2A-rearranged line - a single gel, no imaging, no new reagent. This project already holds banked menin-inhibitor samples and an LXR target-panel experiment proposal (exp-lxr-target-panel-in-banked-menin-inhibitor-samples), so the fractionation could ride along with it. Recording this as 'nobody has imaged SREBP-1 in a leukaemia cell' would misdescribe the gap as an imaging gap when it is a fractionation gap. Yang T et al. 2002
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