{"gene":"ID1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1994,"finding":"Constitutive expression of Id1 in transgenic mice impairs B cell development at an early stage, reducing V(D)J recombination and expression of immunoglobulin, RAG-1, RAG-2, and lambda 5 genes, demonstrating that Id1 (as a dominant-negative inhibitor of bHLH transcription factors) blocks B lymphocyte differentiation.","method":"Transgenic mouse model with constitutive Id1 expression; B cell phenotyping by flow cytometry and PCR","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo transgenic loss-of-function with defined cellular and molecular phenotype, replicated across multiple readouts","pmids":["8001126"],"is_preprint":false},{"year":1995,"finding":"Id-1 suppresses mammary epithelial cell differentiation: stable Id-1 overexpression prevents beta-casein expression in response to differentiation signals and causes invasion of the basement membrane, while Id-1 antisense expression stabilizes differentiation, establishing Id-1 as an inhibitor of bHLH-driven mammary differentiation.","method":"Stable transfection of Id-1 expression and antisense vectors in SCp2 mammary epithelial cells; beta-casein expression, 3D culture morphology, and growth assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional (overexpression and antisense knockdown) in the same cellular system with multiple orthogonal phenotypic readouts","pmids":["7760836"],"is_preprint":false},{"year":1999,"finding":"Targeted disruption of Id1 and Id3 in mice causes premature neuroblast withdrawal from the cell cycle, expression of neural differentiation markers, vascular malformations in the forebrain, and failure of tumor xenograft angiogenesis, establishing Id1 as required for timing of neuronal differentiation and vascular invasiveness.","method":"Id1/Id3 double-knockout mice; tumor xenograft implantation; histological and immunological analysis of neurogenesis and angiogenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal phenotypic readouts replicated across several tumor types","pmids":["10537105"],"is_preprint":false},{"year":2002,"finding":"Id1 transcriptionally represses thrombospondin-1 (TSP-1): Id1-null mouse embryo fibroblasts secrete elevated TSP-1 that inhibits endothelial cell migration, and in vivo neovascularization defects in Id1-null mice are rescued by a TSP-1 neutralizing antibody, identifying TSP-1 as a major downstream effector through which Id1 promotes angiogenesis.","method":"PCR-select subtractive hybridization on wild-type vs. Id1 knockout MEFs; endothelial migration assay with TSP-1 depletion; in vivo Matrigel neovascularization assay with TSP-1 neutralizing antibody","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (subtractive hybridization, in vitro migration rescue, in vivo antibody rescue) in a single focused study","pmids":["12498716"],"is_preprint":false},{"year":2003,"finding":"Id-1 promotes cell survival in prostate cancer cells via activation of the NF-κB signaling pathway: ectopic Id-1 increases nuclear translocation of p65/p50, upregulates Bcl-xL and ICAM-1, inactivates Bax and caspase 3, conferring resistance to TNFα-induced apoptosis; antisense Id-1 reduces nuclear p65/p50 and sensitizes cells to apoptosis.","method":"Stable Id-1 transfection in LNCaP cells; NF-κB reporter assays; Western blot for p65/p50 nuclear translocation; apoptosis assays; antisense knockdown in DU145 cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (overexpression and antisense) with multiple orthogonal assays (reporter, fractionation, apoptosis) in a single lab","pmids":["12881706"],"is_preprint":false},{"year":2004,"finding":"BMP-2 increases Id1 expression, which in turn destabilizes Mash1 protein by shifting the E47/Id1 ratio: elevated Id1 promotes proteasomal degradation of Mash1, whereas E47 stabilizes Mash1; the E47/Id1 ratio also regulates CK2-mediated phosphorylation of Mash1 on Ser152, modulating Mash1-E47 heterodimer interaction.","method":"BMP-2 treatment of neuroendocrine lung carcinoma cells; Id1 overexpression and knockout; E47 overexpression; pulse-chase protein stability assays; phosphorylation analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (stability assays, genetic rescue with Id1-deficient cells, E47 overexpression, phosphorylation mapping) in a single rigorous study","pmids":["15318167"],"is_preprint":false},{"year":2004,"finding":"Id1 is a downstream effector of the p53-dependent DNA damage response: DNA damage represses ID1 expression in a p53-dependent manner via the p53 target DEC1, which inhibits ID1 promoter activity; overexpression of ID1 promotes cell proliferation through inhibition of p21 and substantially decreases DNA damage-induced premature senescence.","method":"DNA damage treatment of cells; siRNA knockdown of DEC1; ID1 promoter deletion/mutation assays; ID1 overexpression with proliferation and senescence assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — promoter mapping, siRNA epistasis, and functional phenotype assays with multiple orthogonal methods in one study","pmids":["18556654"],"is_preprint":false},{"year":2004,"finding":"E12 and E47 physically interact with Id1 to stabilize it: cotransfection of E12 or E47 with Id1 markedly reduces Id1 degradation rate (t1/2 from ~1 h to ~8 h) and alters its subcellular localization, demonstrating that E-protein heterodimerization regulates Id1 protein stability via the ubiquitin-proteasome system.","method":"Co-transfection of E12/E47 with Id1 in non-muscle cells; pulse-chase degradation assays; NLS-mutant subcellular localization analysis; proteasome inhibitor experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (degradation kinetics, localization, NLS mutants) addressing the same mechanism in one focused study","pmids":["16007194"],"is_preprint":false},{"year":2004,"finding":"Ubiquitin-dependent degradation of Id1 and Id3 is mediated by the COP9 signalosome (CSN): Id1/Id3 (but not Id2/Id4) bind CSN subunit CSN5 in mammalian two-hybrid assays; Id3 physically interacts with the CSN complex and CSN5/CSN7; curcumin and emodin (CSN-associated kinase inhibitors) stimulate Id1/Id3 ubiquitination and proteasomal degradation; overexpression of CSN2 stabilizes Id3 protein.","method":"Mammalian two-hybrid analysis; pull-down and far-Western experiments; transfection with His-ubiquitin and Id3; pharmacological treatment with curcumin/emodin; CSN2 overexpression","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding demonstrated by multiple methods (two-hybrid, pulldown, far-Western) plus functional ubiquitination assay and rescue by CSN2 overexpression","pmids":["15451666"],"is_preprint":false},{"year":2007,"finding":"Id1 protein undergoes PKA-regulated nucleocytoplasmic shuttling in endothelial cells: Id1 is nuclear in HUVECs on uncoated plates but translocates to the cytoplasm during capillary-like structure formation on Matrigel via CRM1/exportin-dependent nuclear export; PKA activation inhibits this export (Ser-5 phosphorylation implicated), suggesting nuclear Id1 function is controlled by localization during angiogenesis.","method":"Live imaging of GFP-Id1 in HUVECs; leptomycin B treatment (CRM1 inhibitor); PKA activators (dbcAMP, forskolin) and inhibitors (H-89); Ser-5 mutagenesis of Id1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by live imaging with pharmacological and mutagenesis validation in a single focused mechanistic study","pmids":["17412691"],"is_preprint":false},{"year":2007,"finding":"Id1 promotes the generation of endothelial progenitor cells (EPCs) in bone marrow by restraining expression of p21: Id1 knockout mice lack circulating EPCs and show increased p21 expression; genetic ablation of p21 in Id1-null mice rescues the EPC population, restores BM-derived angiogenesis, and normalizes tumor growth.","method":"Genetically modified mouse models (Id1-KO, p21-KO, Id1/p21 double-KO); flow cytometry for EPCs; tumor growth assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double-KO rescue) with multiple orthogonal in vivo functional readouts","pmids":["18092003"],"is_preprint":false},{"year":2007,"finding":"Id1, but not Id3, is expressed in long-term repopulating hematopoietic stem cells (LT-HSCs) and is required for their maintenance: Id1-GFP knock-in marks LT-HSCs; Id1-deficient (but not Id3-deficient) bone marrow shows impaired engraftment in secondary transplantation assays, demonstrating a unique role for Id1 in LT-HSC self-renewal.","method":"Id1-GFP knock-in mouse model; serial bone marrow transplantation; flow cytometry for HSC populations","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knock-in reporter plus functional transplantation assay with Id3-KO as internal negative control, single lab","pmids":["17622570"],"is_preprint":false},{"year":2007,"finding":"Id1 overexpression inhibits BMP signaling by inducing Twist-1 degradation: Twist-1 inhibits BMP signaling by forming a complex with Smad4 and HDAC1; Id1 promotes Twist-1 degradation and thereby de-represses BMP target gene expression, establishing Id1 as a positive regulator of BMP signaling through a feedback loop.","method":"Co-immunoprecipitation in MC3T3-E1 cells; osteoblast differentiation assays; HDAC inhibitor (trichostatin) treatment; Id1 overexpression and Twist-1 stability assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP demonstrates complex; functional osteoblast readout; single lab, limited mutagenesis","pmids":["17374642"],"is_preprint":false},{"year":2008,"finding":"COX-2-derived PGE2 activates Id-1 transcription via the EP4 receptor → EGFR → ERK1/2 → Egr-1 pathway: PGE2 induces amphiregulin release to transactivate EGFR, leading to Egr-1 binding to the Id-1 promoter; this cascade increases Id-1 expression and mammary epithelial cell invasiveness.","method":"EP4 agonist treatment; EGFR/ERK inhibitor experiments; chromatin immunoprecipitation for Egr-1 at the Id-1 promoter; COX-2 siRNA silencing; cell migration/invasion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP identifies direct Egr-1 binding to Id-1 promoter; pathway established by pharmacological and siRNA dissection with multiple orthogonal methods","pmids":["18842581"],"is_preprint":false},{"year":2008,"finding":"Id-1 activates the Akt pathway by inhibiting PTEN transcription through downregulation of p53: Id-1 reduces p53 binding to the PTEN promoter (confirmed by ChIP and serial promoter deletion); this activates Akt→ canonical Wnt signaling, leading to GSK-3β phosphorylation, β-catenin nuclear localization, and p27(Kip1) cytoplasmic sequestration.","method":"Id-1 overexpression in MCF7 cells; promoter deletion assays and ChIP for p53 at PTEN promoter; Western blot for Akt/β-catenin/p27 phosphorylation; TCF/LEF reporter assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP plus promoter deletion identifies molecular mechanism; multiple downstream pathway readouts in one focused study","pmids":["19079342"],"is_preprint":false},{"year":2009,"finding":"ID1 is a transcriptional target of JAK2-STAT5 signaling in erythroid cells: STAT5 binds and transactivates a downstream enhancer of ID1 (confirmed by ChIP); ID1 promotes survival of primary erythroid cells; ID1 expression correlates with JAK2V617F mutation in erythroid cells and polycythemia vera patients.","method":"Comparative genomics and chromatin immunoprecipitation for STAT5 at ID1 enhancer; ID1 knockdown and overexpression in primary fetal liver erythroid differentiation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct ChIP evidence of STAT5 binding plus functional validation by loss-/gain-of-function in primary cells","pmids":["19571317"],"is_preprint":false},{"year":2009,"finding":"High expression of Id1 identifies a rare population of B1-type adult neural stem cells (GFAP+ astrocytes) in the subventricular zone; Id1-high cells self-renew asymmetrically generating progeny with progressively lower Id1; Id genes are necessary for self-renewal capacity, demonstrated by loss-of-function.","method":"Id1-GFP knock-in reporter mouse; FACS isolation of Id1-high cells; neurosphere and in vivo transplantation assays; Id gene knockout","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knock-in reporter for direct identification plus multiple functional stem cell assays and genetic knockout validation","pmids":["19896442"],"is_preprint":false},{"year":2009,"finding":"Id1 has a non-cell-autonomous role in maintaining the hematopoietic progenitor cell niche: transplantation experiments show that Id1(-/-) microenvironment impairs normal hematopoietic development; Id1(-/-) stromal cells display altered cytokine production, demonstrating that Id1 regulates the niche rather than HSC intrinsic function.","method":"Reciprocal bone marrow transplantation between WT and Id1-KO mice; in vitro cytokine production assays of Id1-KO stromal cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean reciprocal transplantation epistasis experiment with cytokine mechanistic follow-up, single lab","pmids":["19478045"],"is_preprint":false},{"year":2011,"finding":"Smurf2 is the E3 ubiquitin ligase that ubiquitinates Id1 and Id3: Smurf2-mediated ubiquitination and degradation of Id1 regulates p16 expression during cellular senescence, establishing a mechanistic link between Smurf2, Id1, and p16 in senescence.","method":"Co-immunoprecipitation; ubiquitination assays; Smurf2 overexpression and knockdown; senescence assays; p16 expression analysis","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination assay with E3 ligase identification plus functional senescence/p16 readout, single lab with multiple methods","pmids":["21933340"],"is_preprint":false},{"year":2013,"finding":"Id1 promotes breast cancer metastasis by interacting with TFAP2A to suppress S100A9 expression: ID1-TFAP2A interaction suppresses S100A9, which in turn permits elevated RhoC expression; reestablishment of S100A9 rescues the migratory/invasive and in vivo metastatic phenotypes induced by Id1.","method":"Co-immunoprecipitation of Id1 with TFAP2A; S100A9 knockdown/overexpression rescue; in vitro migration/invasion assays; in vivo metastasis assay","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP demonstrates Id1-TFAP2A interaction; epistasis rescue confirms S100A9 pathway; single lab","pmids":["24948111"],"is_preprint":false},{"year":2013,"finding":"E47 and Id1 physically interact in mesenchymal breast carcinoma and MDCK-E47 EMT cells; ChIP demonstrates that E47 binds the endogenous E-cadherin promoter in a complex devoid of Id1; both E47 and Id1 are required to maintain the mesenchymal phenotype, operating through mechanisms independent of Id1 dominant-negative action on E-cadherin transcription.","method":"Co-immunoprecipitation of E47 and Id1; chromatin immunoprecipitation at E-cadherin promoter; Id1 knockdown in EMT cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP in the same system; single lab","pmids":["23555842"],"is_preprint":false},{"year":2013,"finding":"p53 represses Id1 expression through BMP-Smad1-dependent and -independent mechanisms: p53 deficiency leads to elevated Smad1 and Id1 expression; Id1 upregulation contributes to both augmented NSC proliferation and accelerated neuronal differentiation in p53-null neural stem cells.","method":"p53-knockout neural stem cells; in vivo BrdU labeling; Smad1 siRNA; Id1 overexpression; differentiation assays","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic knockout with functional differentiation readouts and siRNA epistasis; single lab","pmids":["23199293"],"is_preprint":false},{"year":2013,"finding":"Serum induction of Id1 is mediated by a BMP-responsive element (BRE) in the Id1 promoter: BMP pathway inhibition (Smad4 siRNA, noggin, dorsomorphin) blocks serum induction of Id1; BMP2 alone is sufficient to induce Id1; the BRE is necessary and sufficient for serum responsiveness of Id1.","method":"Id1 promoter deletion/mapping in serum-stimulated fibroblasts; siRNA depletion of Smad4; BMP antagonist (noggin) and receptor inhibitor (dorsomorphin) treatment; BMP2 stimulation","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — promoter mapping identifies BRE as necessary and sufficient; multiple pathway inhibition approaches confirm mechanism; single lab","pmids":["23948603"],"is_preprint":false},{"year":2015,"finding":"Id1 upregulation in response to tumour-derived TGFβ drives a switch from dendritic cell differentiation to myeloid-derived suppressor cell expansion: genetic inactivation of Id1 corrects the myeloid imbalance, and Id1 overexpression in the absence of tumour-derived factors re-creates immunosuppression and suppresses CD8 T-cell proliferation, identifying Id1 as a key mediator of tumour-induced immunosuppression.","method":"Id1 genetic inactivation and overexpression in mouse models; TGFβ stimulation; DC differentiation assays; CD8 T-cell proliferation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation with functional immune cell differentiation readouts; single lab","pmids":["25924227"],"is_preprint":false},{"year":2016,"finding":"COX-2-derived PGE2 induces Id1 in GBM cells via the EP4 receptor → ERK1/2 MAPK → Egr1 transcription factor pathway; this induction of Id1 is required for optimal GBM cell self-renewal and radiation resistance, demonstrated by siRNA and pharmacological pathway inhibition combined with chromatin immunoprecipitation.","method":"dmPGE2 stimulation of mouse and human GBM cells; siRNA knockdown and small molecule inhibitors of EP4, ERK1/2, Egr1; ChIP for Egr1 at Id1 promoter; sphere formation and radiation resistance assays","journal":"Neuro-oncology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP confirms direct Egr1 binding; multiple orthogonal pathway inhibitors; functional phenotype readout; single lab","pmids":["27022132"],"is_preprint":false},{"year":2016,"finding":"ID1 suppresses CULLIN3 ubiquitin ligase in glioblastoma stem cells (GSCs): ID1 promotes GSC proliferation, self-renewal, and tumorigenicity by suppressing CULLIN3, leading to accumulation of CYCLIN E and CULLIN3 substrates GLI2 and DVL2 (confirmed by proteomics showing CULLIN3-GLI2/DVL2 interaction and ubiquitination); combined pharmacological inhibition of GLI2 and β-CATENIN diminishes GSC properties.","method":"ID1 knockdown/overexpression in human GSCs; proteomics analysis of CULLIN3 interactome; ubiquitination assays for GLI2/DVL2; combinatorial pharmacological inhibition; in vivo tumorigenicity assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — proteomics interactome plus ubiquitination assay plus in vivo functional validation; single lab with multiple orthogonal methods","pmids":["27477274"],"is_preprint":false},{"year":2016,"finding":"ID1 promotes resistance to etoposide-induced apoptosis through a c-Jun/c-Fos (AP-1)-dependent mechanism: AP-1 binding sites in the ID1 promoter mediate ID1 upregulation upon etoposide treatment; ablation of c-Jun/c-Fos or ID1 enhances etoposide-mediated apoptosis via caspase 3 activation and PARP cleavage.","method":"AP-1 site mutagenesis in ID1 promoter; c-Jun/c-Fos and ID1 siRNA knockdown; caspase 3 activity and PARP cleavage assays in esophageal cancer cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis defines AP-1 sites; functional apoptosis rescue; single lab","pmids":["26858249"],"is_preprint":false},{"year":2017,"finding":"Id1 promotes obesity by suppressing brown adipose thermogenesis through two direct molecular interactions: (1) Id1 binds and suppresses PGC1α transcriptional activity to reduce UCP1 and thermogenic gene expression; (2) Id1 directly interacts with and suppresses Ebf2 transcriptional activity, reducing Prdm16 expression and brown/beige adipocyte fate determination.","method":"Adipose-specific Id1 transgenic mice; Id1-deficient mouse embryonic fibroblasts; co-immunoprecipitation of Id1 with PGC1α and Ebf2; chromatin/reporter assays; cold-exposure and HFD phenotype analysis","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct Co-IP demonstrates Id1-PGC1α and Id1-Ebf2 interactions; supported by in vivo transgenic and KO phenotypes; single lab with multiple methods","pmids":["28270523"],"is_preprint":false},{"year":2017,"finding":"ID1 inhibits BMPR2 expression in glioblastoma stem cells through MYC-driven upregulation of miR-17 and miR-20a, thereby abrogating BMP differentiation signaling and promoting self-renewal; ID1 simultaneously activates WNT and SHH signaling by increasing MYC expression.","method":"ID1 overexpression and knockdown in GSCs; miRNA expression analysis; Western blotting for BMPR2; WNT/SHH inhibitor treatment; in vivo tumor survival assay","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — defined miRNA mechanism for BMPR2 suppression with functional in vivo validation; single lab","pmids":["29208670"],"is_preprint":false},{"year":2017,"finding":"ID1 confers oxaliplatin resistance in hepatocellular carcinoma by activating the pentose phosphate pathway (PPP): ID1 induces G6PD promoter transcription and activates PPP through Wnt/β-catenin/c-MYC signaling, increasing NADPH and reducing ROS; ID1 knockdown decreases G6PD expression, blocks PPP, elevates ROS, and induces apoptosis.","method":"lentiviral shRNA knockdown of ID1 in oxaliplatin-resistant HCC cells; G6PD promoter luciferase assay; NADPH/ROS measurement; β-catenin/c-MYC inhibitor experiments; in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assay defines mechanistic target; metabolic readouts (NADPH, ROS) confirm pathway; single lab with multiple methods","pmids":["29169374"],"is_preprint":false},{"year":2018,"finding":"Hyaluronic acid–CD44 interactions promote BMP4/7-dependent Id1/3 expression: Co-IP demonstrates that CD44 physically associates with the BMP type II receptor ACVR2B; depletion of HA or CD44 reduces BMP4/7-driven Id1/3 expression; exogenous HA enhances it, linking pericellular matrix to Id1 regulation in melanoma.","method":"HA depletion by hyaluronidase and 4-MU; CD44 knockdown; exogenous HA treatment; Co-immunoprecipitation of CD44 with ACVR2B; Western blot for Id1/3","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifies CD44-ACVR2B interaction; functional Id1/3 regulation confirmed; single lab","pmids":["30297743"],"is_preprint":false},{"year":2018,"finding":"Id1 ablation protects hematopoietic stem cells from stress-induced exhaustion: cytokine induction of Id1 drives HSC proliferation, mitochondrial biogenesis, and ROS production; Id1-/- HSCs are quiescent, accumulate less DNA damage, and display a blunted proliferative response to γ-irradiation, genotoxic stress, and aging.","method":"Id1 genetic ablation; serial bone marrow transplantation; BrdU proliferation assay; ROS measurement; mitochondrial biogenesis assay; γ-irradiation model","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (proliferation, ROS, DNA damage, transplantation) in a defined genetic model; replicated across multiple stress conditions","pmids":["30082068"],"is_preprint":false},{"year":2019,"finding":"ID1 expression is selected for in pancreatic ductal adenocarcinoma to escape TGFβ-induced tumor suppression: ID1 uncouples TGFβ-induced EMT from apoptosis by preventing the imbalance of SOX4 and KLF5 that normally triggers cell death; AKT signaling converges on ID1 to preserve its expression, and TGFβ-mediated repression of ID1 is evaded during PDA progression.","method":"Genetic loss-of-function and gain-of-function of ID1 in pancreatic progenitor cells; TGFβ treatment; apoptosis and EMT assays; analysis of PDA patient samples for ID1 genetic/epigenetic alterations; AKT inhibitor experiments","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic manipulation in multiple systems with mechanistic pathway dissection; supported by clinical genomics; single lab","pmids":["31582374"],"is_preprint":false},{"year":2019,"finding":"CRISPR-mediated knockout of ID1 in glioblastoma, breast adenocarcinoma, and melanoma cells dramatically reduces tumor progression through transcriptional downregulation of EGF, resulting in decreased EGFR phosphorylation; ID1-positive cells are enriched by temozolomide chemotherapy and drive tumor recurrence.","method":"CRISPR-Cas9 knockout of ID1 in three cancer cell lines; EGF/EGFR expression and phosphorylation analysis; in vivo tumor growth assays; temozolomide treatment and recurrence tracking","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO replicated across three independent cancer systems with mechanistic EGF/EGFR downstream link","pmids":["31292163"],"is_preprint":false},{"year":2019,"finding":"Salt-inducible kinase 1 (SIK1) negatively regulates Id1 expression in osteoblasts by phosphorylating CRTC1, preventing CRTC1 from enhancing CREB transcriptional activity at osteogenic genes including Id1; BMP2 suppresses SIK1 via PKA to permit Id1 expression and osteogenesis.","method":"SIK1 gene knockdown in primary preosteoblasts; SIK1-KO mice; CRTC1 phosphorylation assays; osteoblast differentiation and bone mineralization assays; BMP2/PKA pathway inhibitor experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase assay and KO mice with functional osteogenesis readout; single lab with multiple methods","pmids":["31672960"],"is_preprint":false},{"year":2020,"finding":"ID1 confers cancer cell chemoresistance through a STAT3/ATF6-mediated induction of autophagy: ID1 activates NF-κB p65 nuclear translocation, which increases IL-6 secretion, activating STAT3 (Y705 phosphorylation), which transcriptionally upregulates ATF6 to induce ER stress-dependent autophagy and resistance to cisplatin/paclitaxel.","method":"ID1 overexpression/siRNA in ovarian cancer cells; luciferase assays for NF-κB and STAT3/ATF6 promoters; IL-6 ELISA; phosphorylation Western blot; autophagy assays; clinical correlation in 1104 HGSOC samples","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — sequential pathway dissection with multiple reporter assays, phosphorylation analysis, and functional autophagy/chemoresistance readouts; single lab","pmids":["32080166"],"is_preprint":false},{"year":2020,"finding":"Id1-/-Id3-/- sinusoidal endothelial cells (SECs) undergo increased apoptosis due to reduced Bcl2-family gene expression, and show increased p21/p27 expression and impaired proliferation; reduced E2-2 expression rescues proliferation, demonstrating that Id1/Id3 maintain BM SEC survival and regeneration by suppressing E-protein activity.","method":"Conditional Id1/Id3 deletion in adult ECs; SEC apoptosis assays; Bcl2 family gene expression; p21/p27 analysis; E2-2 knockdown rescue; irradiation survival model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional genetic model with mechanistic E2-2 rescue and multiple cellular readouts; single lab","pmids":["32348770"],"is_preprint":false},{"year":2020,"finding":"BMP signaling controls id1 expression in neural stem cells through conserved Smad1/5 and Smad4 binding motifs in a cis-regulatory module (CRM): deletion mapping and mutation of these binding sites in stable transgenic zebrafish reveal that BMP-Smad signaling is required for id1 expression in radial glial NSCs under both homeostatic and regenerative neurogenesis.","method":"Systematic CRM deletion mapping in stable transgenic zebrafish; Smad binding site mutation; pharmacological BMP pathway inhibition; transcriptome analysis of injured/uninjured telencephala","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct cis-regulatory mapping with binding site mutagenesis in stable transgenics plus pharmacological and transcriptomic validation","pmids":["32246536"],"is_preprint":false},{"year":2021,"finding":"rHDL-apoE3 promotes endothelial cell migration through ID1-mediated activation of ERK1/2 and AKT: siRNA silencing of ID1 markedly reduces rHDL-apoE3-triggered EC migration and inhibits phosphorylation of ERK1/2 and AKT, placing ID1 upstream of MEK1/2 and PI3K pathways in EC migration.","method":"siRNA-mediated ID1 knockdown in HCAEC and EA.hy926 cells; wound healing and transwell migration assays; Western blot for phospho-ERK1/2, AKT, eNOS, p38 MAPK; pathway inhibitors PD98059 and LY294002","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA epistasis with phosphorylation readouts and functional migration assay; single lab","pmids":["34875308"],"is_preprint":false},{"year":2023,"finding":"ID1 in tumor-associated macrophages (TAMs) interacts with STAT1 to promote its cytoplasmic distribution, inhibiting STAT1-mediated transcription of SerpinB2 and CCL4, two secretory factors that suppress cancer stemness and recruit CD8+ T cells; reducing ID1 in TAMs ameliorates CRC progression and improves immunotherapy sensitivity.","method":"Co-immunoprecipitation of ID1 with STAT1; STAT1 subcellular localization assays; SerpinB2/CCL4 promoter analysis; ID1 knockdown in TAMs; CD8+ T cell infiltration measurement; in vivo CRC tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrates ID1-STAT1 interaction; localization assay links to function; mechanistic transcriptional target identification; in vivo validation; single lab with multiple methods","pmids":["37996458"],"is_preprint":false},{"year":2023,"finding":"ID1 in bone marrow mesenchymal stem cells promotes AML progression through a non-cell-autonomous mechanism: ID1 interacts with RNF4 (E3 ubiquitin ligase), reducing SP1 ubiquitination; preserved SP1 drives Angptl7 expression in the microenvironment, which supports AML cell proliferation.","method":"ID1-interactome analysis by proteomics; Co-IP of ID1 with RNF4; SP1 ubiquitination assays; ID1 truncation to disrupt ID1-RNF4 interaction; AML co-culture and mouse model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — proteomics interactome, direct Co-IP, ubiquitination assay, and truncation mutant; in vivo validation; single lab","pmids":["37319434"],"is_preprint":false},{"year":2005,"finding":"CASK physically interacts with Id1: yeast two-hybrid screening identified Id1 as a novel CASK-interacting protein, confirmed by endogenous co-immunoprecipitation from ECV304 cells; mammalian two-hybrid assays show differential CASK binding to Id1 and its alternative splicing variant.","method":"Yeast two-hybrid screening; co-immunoprecipitation of endogenous CASK and Id1; mammalian two-hybrid interaction assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP confirmation; no functional mechanism established beyond growth correlation","pmids":["15694377"],"is_preprint":false}],"current_model":"ID1 is a dominant-negative HLH protein that lacks a DNA-binding domain and acts primarily by heterodimerizing with bHLH transcription factors (E-proteins, tissue-specific bHLH factors) to inhibit their DNA binding and transcriptional activity, thereby suppressing differentiation across multiple lineages (B cells, neural, mammary, muscle, adipose); its transcription is directly induced by BMP-Smad1/4/5 signaling through a conserved BRE in its promoter, as well as by PGE2-EP4-ERK1/2-Egr1 and JAK2V617F-STAT5 pathways; ID1 protein stability and localization are regulated by ubiquitin-proteasome degradation (via Smurf2 E3 ligase and the COP9 signalosome), by heterodimerization with E-proteins that stabilize it, and by PKA-regulated CRM1-dependent nuclear export during angiogenesis; downstream, ID1 promotes cell survival and proliferation by activating NF-κB, suppressing PTEN transcription to activate Akt/Wnt signaling, restraining p21 expression, transcriptionally repressing TSP-1 (promoting angiogenesis) and STAT1-mediated target genes (promoting immunosuppression), suppressing CULLIN3 to stabilize oncogenic substrates, and activating the pentose phosphate pathway; in stem cells, ID1 maintains quiescence and self-renewal in LT-HSCs and adult neural stem cells, and its loss or gain dictates cell fate in hematopoietic, neural, and adipose progenitor compartments."},"narrative":{"mechanistic_narrative":"ID1 is a dominant-negative helix-loop-helix protein that controls the balance between differentiation, proliferation, and survival across hematopoietic, neural, mammary, endothelial, and adipose lineages, acting as a downstream node of BMP and other growth-factor signals [PMID:8001126, PMID:10537105, PMID:19896442]. By heterodimerizing with bHLH E-proteins (E12/E47), ID1 sequesters them from DNA and blocks lineage differentiation programs—impairing V(D)J recombination and B cell development, preventing beta-casein induction in mammary epithelium, and destabilizing the proneural factor Mash1 by shifting the E47/Id1 ratio [PMID:8001126, PMID:7760836, PMID:15318167]; reciprocally, E-protein binding stabilizes ID1 protein and alters its localization [PMID:16007194]. Beyond E-protein antagonism, ID1 engages additional transcriptional partners directly—binding TFAP2A to suppress S100A9, PGC1α and Ebf2 to suppress brown-adipose thermogenic programs, and STAT1 in tumor-associated macrophages to drive its cytoplasmic retention and silence SerpinB2/CCL4 [PMID:24948111, PMID:28270523, PMID:37996458]. ID1 transcription is induced through a BMP-responsive element bound by Smad1/5 and Smad4, and through parallel PGE2-EP4-ERK1/2-Egr1 and JAK2-STAT5 cascades, while it is repressed by p53 acting via DEC1 and BMP-Smad1 [PMID:23948603, PMID:32246536, PMID:18842581, PMID:27022132, PMID:19571317, PMID:18556654, PMID:23199293]. ID1 abundance is set by ubiquitin-proteasome degradation through the COP9 signalosome and the Smurf2 E3 ligase, and its nuclear export is controlled by PKA-regulated CRM1-dependent shuttling during angiogenesis [PMID:15451666, PMID:21933340, PMID:17412691]. Functionally, ID1 promotes survival and proliferation by activating NF-κB, suppressing PTEN to engage Akt/Wnt signaling, restraining p21/p27, repressing thrombospondin-1 to enable angiogenesis, suppressing CULLIN3 to stabilize GLI2/DVL2, and activating the pentose phosphate pathway to lower ROS [PMID:12881706, PMID:19079342, PMID:18092003, PMID:12498716, PMID:27477274, PMID:29169374]. In stem-cell compartments ID1 maintains long-term HSC and adult neural stem cell self-renewal and dictates their proliferative versus quiescent state, with its loss protecting HSCs from stress-induced exhaustion [PMID:17622570, PMID:19896442, PMID:30082068]. These activities make ID1 a recurrent driver of tumor progression, chemoresistance, metastasis, and immunosuppression across multiple cancers [PMID:25924227, PMID:31292163, PMID:32080166, PMID:31582374].","teleology":[{"year":1994,"claim":"Established that ID1 functions in vivo as a dominant-negative inhibitor of bHLH factors that blocks lineage differentiation, using B lymphopoiesis as the first defined system.","evidence":"Constitutive Id1 expression in transgenic mice with B cell phenotyping","pmids":["8001126"],"confidence":"High","gaps":["Did not identify the specific bHLH partners sequestered in B cells","Did not address whether the same mechanism operates in other lineages"]},{"year":1995,"claim":"Showed ID1 inhibits differentiation bidirectionally in epithelial cells and promotes invasive behavior, generalizing its anti-differentiation role beyond hematopoiesis.","evidence":"Overexpression and antisense knockdown in SCp2 mammary epithelial cells with beta-casein and 3D morphology readouts","pmids":["7760836"],"confidence":"High","gaps":["Molecular partners mediating beta-casein suppression not defined","Mechanism of basement-membrane invasion not resolved"]},{"year":1999,"claim":"Genetic loss-of-function established ID1 (with ID3) as required for proper timing of neuronal differentiation and for tumor angiogenesis/vascular invasion in vivo.","evidence":"Id1/Id3 double-knockout mice with neurogenesis and xenograft angiogenesis analysis","pmids":["10537105"],"confidence":"High","gaps":["Redundancy between Id1 and Id3 not separated","Downstream angiogenic effectors not yet identified"]},{"year":2002,"claim":"Identified thrombospondin-1 as a major downstream effector through which ID1 promotes angiogenesis, providing the first molecular target explaining the vascular phenotype.","evidence":"Subtractive hybridization on Id1-null MEFs plus in vitro and in vivo TSP-1 neutralization rescue","pmids":["12498716"],"confidence":"High","gaps":["How ID1 represses TSP-1 transcriptionally not defined","Cell type in which repression is most relevant not pinned down"]},{"year":2003,"claim":"Defined a survival mechanism in which ID1 activates NF-κB to confer apoptosis resistance, linking ID1 to anti-apoptotic signaling in cancer.","evidence":"Bidirectional Id1 manipulation in prostate cancer cells with NF-κB reporter, fractionation, and apoptosis assays","pmids":["12881706"],"confidence":"High","gaps":["Direct molecular link between ID1 and NF-κB activation not established","Whether effect is transcription-factor sequestration or another route unknown"]},{"year":2004,"claim":"Connected ID1 to proliferation/senescence control by showing DNA damage represses ID1 via p53/DEC1 and that ID1 overexpression restrains p21 and blunts senescence.","evidence":"DNA damage, DEC1 siRNA, ID1 promoter mapping, and proliferation/senescence assays","pmids":["18556654"],"confidence":"High","gaps":["How ID1 represses p21 mechanistically not resolved","Direct p53/DEC1 binding kinetics on ID1 promoter not detailed"]},{"year":2004,"claim":"Demonstrated that ID1 controls proneural factor stability by shifting the E47/Id1 ratio to degrade Mash1, mechanistically tying ID1 dosage to neural differentiation output.","evidence":"BMP-2 treatment, Id1 gain/loss, E47 overexpression, and pulse-chase stability assays in neuroendocrine cells","pmids":["15318167"],"confidence":"High","gaps":["E3 ligase degrading Mash1 not identified","Relevance to normal neurogenesis vs. carcinoma not separated"]},{"year":2004,"claim":"Established that E-protein heterodimerization is itself a stability switch for ID1, showing partner binding controls ID1 half-life and localization.","evidence":"Co-transfection of E12/E47 with Id1, pulse-chase degradation kinetics, NLS-mutant localization, and proteasome inhibition","pmids":["16007194"],"confidence":"High","gaps":["The E3 ligase governing free vs. bound ID1 not identified here","How localization change maps to function not resolved"]},{"year":2004,"claim":"Identified the COP9 signalosome as a regulator of ID1/ID3 ubiquitin-dependent degradation, distinguishing ID1/ID3 from ID2/ID4 at the level of turnover.","evidence":"Two-hybrid, pulldown and far-Western with CSN5, His-ubiquitin assays, and CSN-kinase inhibitor treatment","pmids":["15451666"],"confidence":"High","gaps":["The cognate E3 ligase acting with CSN not defined here","Physiological contexts where CSN sets ID1 levels not established"]},{"year":2007,"claim":"Showed ID1 localization is dynamically regulated by PKA-controlled CRM1-dependent nuclear export during capillary morphogenesis, adding spatial control to ID1 function.","evidence":"Live GFP-Id1 imaging in HUVECs, leptomycin B, PKA modulators, and Ser-5 mutagenesis","pmids":["17412691"],"confidence":"High","gaps":["Functional consequence of cytoplasmic ID1 not directly demonstrated","Export receptor binding site not mapped"]},{"year":2007,"claim":"Placed ID1 upstream of p21 in endothelial progenitor cell generation, with genetic p21 ablation rescuing the Id1-null EPC and angiogenesis defects.","evidence":"Id1-KO, p21-KO, and double-KO mice with EPC flow cytometry and tumor growth assays","pmids":["18092003"],"confidence":"High","gaps":["How ID1 restrains p21 in EPCs mechanistically not defined","Cell-autonomy of the EPC defect not fully separated"]},{"year":2007,"claim":"Defined a non-redundant, Id3-independent requirement for ID1 in long-term HSC self-renewal, distinguishing ID family members functionally in hematopoiesis.","evidence":"Id1-GFP knock-in and serial bone marrow transplantation with Id3-KO control","pmids":["17622570"],"confidence":"High","gaps":["bHLH partners ID1 sequesters in LT-HSCs not identified","Whether the role is intrinsic vs. niche not resolved here"]},{"year":2007,"claim":"Revealed a non-cell-autonomous niche role for ID1 in hematopoiesis through altered stromal cytokine production, complicating the intrinsic-stem-cell view.","evidence":"Reciprocal WT/Id1-KO bone marrow transplantation and stromal cytokine assays","pmids":["19478045"],"confidence":"High","gaps":["Specific cytokines and their bHLH-dependent regulation not defined","Reconciliation with intrinsic LT-HSC role not provided"]},{"year":2007,"claim":"Showed ID1 acts as a positive feedback amplifier of BMP signaling by promoting Twist-1 degradation to de-repress BMP targets.","evidence":"Co-IP in MC3T3-E1 cells, Twist-1 stability assays, and osteoblast differentiation readouts","pmids":["17374642"],"confidence":"Medium","gaps":["Direct vs. indirect promotion of Twist-1 degradation not distinguished","E3 ligase involved not identified","Single lab, limited mutagenesis"]},{"year":2008,"claim":"Mapped a PGE2-EP4-EGFR-ERK1/2-Egr1 cascade that transcriptionally induces ID1, linking inflammatory eicosanoid signaling to ID1 in epithelial invasion.","evidence":"EP4 agonist, EGFR/ERK inhibitors, COX-2 siRNA, and ChIP for Egr-1 at the Id-1 promoter","pmids":["18842581"],"confidence":"High","gaps":["Generality of the cascade beyond mammary cells not tested here","Other Egr-1 cofactors at the promoter not defined"]},{"year":2008,"claim":"Defined an ID1→p53→PTEN→Akt/Wnt axis, showing ID1 activates proliferative signaling by transcriptionally suppressing PTEN.","evidence":"Id1 overexpression in MCF7, ChIP and promoter deletion for p53 at the PTEN promoter, and pathway/reporter readouts","pmids":["19079342"],"confidence":"High","gaps":["How ID1 downregulates p53 not mechanistically resolved","In vivo relevance not addressed in this study"]},{"year":2009,"claim":"Identified ID1 as a JAK2-STAT5 transcriptional target supporting erythroid survival, linking ID1 to myeloproliferative disease driven by JAK2V617F.","evidence":"ChIP for STAT5 at an ID1 enhancer plus ID1 gain/loss in primary erythroid differentiation","pmids":["19571317"],"confidence":"High","gaps":["bHLH targets of ID1 in erythroid survival not defined","Causal role in PV pathogenesis not directly tested"]},{"year":2009,"claim":"Showed Id1-high marks self-renewing adult neural stem cells and that Id genes are required for asymmetric self-renewal capacity.","evidence":"Id1-GFP knock-in reporter, FACS, neurosphere/transplantation assays, and Id knockout","pmids":["19896442"],"confidence":"High","gaps":["Mechanism linking Id1 dosage to asymmetric division not defined","Partner factors in NSCs not identified"]},{"year":2013,"claim":"Identified a partner-mediated metastasis pathway: ID1 binds TFAP2A to suppress S100A9 and elevate RhoC, providing a transcriptional route to invasion.","evidence":"Co-IP of Id1-TFAP2A and S100A9 rescue in migration/invasion and in vivo metastasis assays","pmids":["24948111"],"confidence":"Medium","gaps":["Direct ID1-TFAP2A interaction interface not mapped","Single lab; reciprocal validation limited"]},{"year":2013,"claim":"Demonstrated ID1 and E47 cooperate to maintain a mesenchymal EMT phenotype through mechanisms beyond classic dominant-negative repression of E-cadherin.","evidence":"Reciprocal Co-IP of E47 and Id1, ChIP at E-cadherin promoter, and Id1 knockdown in EMT cells","pmids":["23555842"],"confidence":"Medium","gaps":["The non-dominant-negative mechanism not defined","Single lab"]},{"year":2013,"claim":"Showed p53 represses ID1 via BMP-Smad1-dependent and -independent routes, with ID1 controlling both proliferation and differentiation in neural stem cells.","evidence":"p53-KO NSCs, Smad1 siRNA, BrdU labeling, and differentiation assays","pmids":["23199293"],"confidence":"Medium","gaps":["The Smad1-independent repression mechanism not identified","Single lab"]},{"year":2013,"claim":"Established the BMP-responsive element as necessary and sufficient for ID1 induction by serum, anchoring BMP-Smad as the principal upstream activator.","evidence":"ID1 promoter mapping, Smad4 siRNA, noggin/dorsomorphin, and BMP2 stimulation in fibroblasts","pmids":["23948603"],"confidence":"High","gaps":["Smad cofactors at the BRE not enumerated","Cell-type specificity of BRE usage not addressed"]},{"year":2015,"claim":"Identified ID1 as a key mediator of tumor-induced immunosuppression by switching dendritic cell differentiation toward myeloid-derived suppressor cell expansion downstream of TGFβ.","evidence":"Bidirectional Id1 genetic manipulation in mice with DC differentiation and CD8 T-cell proliferation assays","pmids":["25924227"],"confidence":"High","gaps":["Transcriptional targets in myeloid cells not defined here","Link to later STAT1 mechanism not made"]},{"year":2016,"claim":"Showed PGE2-EP4-ERK1/2-Egr1 induction of ID1 is required for glioblastoma stem-cell self-renewal and radiation resistance, extending the eicosanoid-ID1 axis to brain cancer.","evidence":"dmPGE2 with EP4/ERK/Egr1 inhibitors and siRNA, ChIP for Egr1, and sphere/radiation assays","pmids":["27022132"],"confidence":"High","gaps":["bHLH effectors of self-renewal downstream of ID1 not identified","Mechanism of radiation resistance not detailed"]},{"year":2016,"claim":"Defined an ID1→CULLIN3 suppression mechanism stabilizing GLI2/DVL2 and CYCLIN E to drive glioblastoma stem-cell tumorigenicity.","evidence":"ID1 gain/loss in GSCs, CULLIN3 interactome proteomics, ubiquitination assays, and in vivo tumorigenicity","pmids":["27477274"],"confidence":"High","gaps":["How ID1 suppresses CULLIN3 transcriptionally/post-transcriptionally not resolved","Direct vs. indirect link unproven"]},{"year":2016,"claim":"Showed AP-1 (c-Jun/c-Fos) drives ID1 induction upon genotoxic stress to confer apoptosis resistance, adding a stress-responsive transcriptional input to ID1.","evidence":"AP-1 site mutagenesis in the ID1 promoter, c-Jun/c-Fos/ID1 knockdown, and caspase 3/PARP assays","pmids":["26858249"],"confidence":"Medium","gaps":["Direct AP-1 binding by ChIP not shown here","Single lab"]},{"year":2017,"claim":"Identified direct ID1 binding to PGC1α and Ebf2 to suppress brown/beige adipose thermogenesis, expanding ID1's partner repertoire to metabolic transcription factors.","evidence":"Adipose-specific Id1 transgenic and Id1-deficient models with Co-IP and thermogenic phenotype analysis","pmids":["28270523"],"confidence":"High","gaps":["Interaction interfaces and stoichiometry not mapped","Whether suppression is HLH-dependent not resolved"]},{"year":2017,"claim":"Defined an ID1→MYC→miR-17/20a axis suppressing BMPR2 to block BMP differentiation signaling while activating WNT/SHH in glioblastoma stem cells.","evidence":"ID1 gain/loss in GSCs, miRNA/BMPR2 analysis, WNT/SHH inhibitors, and in vivo survival","pmids":["29208670"],"confidence":"Medium","gaps":["How ID1 increases MYC not defined","Single lab"]},{"year":2017,"claim":"Linked ID1 to metabolic chemoresistance by showing it activates the pentose phosphate pathway via G6PD/Wnt/c-MYC to lower ROS.","evidence":"ID1 shRNA in oxaliplatin-resistant HCC, G6PD promoter luciferase, NADPH/ROS measurement, and xenografts","pmids":["29169374"],"confidence":"Medium","gaps":["Direct vs. indirect G6PD promoter regulation not resolved","Single lab"]},{"year":2018,"claim":"Connected pericellular matrix to ID1 regulation, showing hyaluronic acid-CD44 association with the BMP receptor ACVR2B enhances BMP4/7-driven Id1/3 expression.","evidence":"HA/CD44 depletion, exogenous HA, and Co-IP of CD44 with ACVR2B in melanoma cells","pmids":["30297743"],"confidence":"Medium","gaps":["Whether CD44-ACVR2B interaction is direct not resolved","Single lab"]},{"year":2018,"claim":"Showed ID1 drives stress-induced HSC exhaustion: cytokine-induced ID1 promotes proliferation, mitochondrial biogenesis and ROS, while Id1 loss enforces protective quiescence.","evidence":"Id1 genetic ablation with serial transplantation, BrdU, ROS, mitochondrial assays, and irradiation/aging stress","pmids":["30082068"],"confidence":"High","gaps":["bHLH targets enforcing quiescence not identified","How ID1 induces mitochondrial biogenesis not defined"]},{"year":2019,"claim":"Defined ID1 as the factor selected during pancreatic cancer to uncouple TGFβ-driven EMT from apoptosis by preventing SOX4/KLF5 imbalance, with AKT preserving ID1 expression.","evidence":"ID1 gain/loss in pancreatic progenitors with TGFβ treatment, apoptosis/EMT assays, AKT inhibition, and patient genomics","pmids":["31582374"],"confidence":"High","gaps":["How ID1 maintains SOX4/KLF5 balance mechanistically not detailed","Direct ID1 partners in this context not identified"]},{"year":2019,"claim":"CRISPR knockout across three cancer types showed ID1 sustains tumor progression through transcriptional EGF upregulation and EGFR phosphorylation, and that ID1+ cells drive chemotherapy recurrence.","evidence":"CRISPR-Cas9 ID1 KO in glioblastoma, breast, and melanoma cells with EGF/EGFR analysis and in vivo growth/temozolomide tracking","pmids":["31292163"],"confidence":"High","gaps":["How ID1 upregulates EGF transcriptionally not defined","Direct promoter mechanism not shown"]},{"year":2020,"claim":"Mapped an ID1→NF-κB→IL-6→STAT3→ATF6 cascade inducing autophagy to confer platinum/taxane chemoresistance in ovarian cancer.","evidence":"ID1 gain/loss with NF-κB/STAT3/ATF6 reporters, IL-6 ELISA, autophagy assays, and clinical HGSOC correlation","pmids":["32080166"],"confidence":"High","gaps":["Direct molecular link from ID1 to NF-κB activation not resolved","Single lab"]},{"year":2020,"claim":"Showed Id1/Id3 maintain bone marrow sinusoidal endothelial cell survival and regeneration by suppressing E-protein E2-2 activity, with E2-2 knockdown rescuing proliferation.","evidence":"Conditional Id1/Id3 deletion in adult ECs with apoptosis, Bcl2-family, p21/p27 analysis, and E2-2 rescue","pmids":["32348770"],"confidence":"High","gaps":["Direct E2-2 targets driving Bcl2/p21/p27 not enumerated","Relative contribution of Id1 vs Id3 not separated"]},{"year":2020,"claim":"Confirmed BMP-Smad1/5/Smad4 binding motifs in a conserved cis-regulatory module drive id1 expression in radial glial neural stem cells in vivo across homeostatic and regenerative neurogenesis.","evidence":"CRM deletion/mutation in stable transgenic zebrafish with BMP inhibition and transcriptomics","pmids":["32246536"],"confidence":"High","gaps":["Smad-associated cofactors at the CRM not defined","Conservation of this CRM in mammals not tested here"]},{"year":2021,"claim":"Placed ID1 upstream of ERK1/2 and AKT in endothelial migration triggered by rHDL-apoE3, extending ID1's role to lipoprotein-stimulated angiogenic signaling.","evidence":"ID1 siRNA in HCAEC/EA.hy926 with migration assays and phospho-ERK/AKT readouts plus pathway inhibitors","pmids":["34875308"],"confidence":"Medium","gaps":["How ID1 activates ERK/AKT mechanistically not defined","Single lab"]},{"year":2023,"claim":"Identified ID1-STAT1 interaction in tumor-associated macrophages as a driver of immunosuppression by promoting STAT1 cytoplasmic retention to silence SerpinB2 and CCL4.","evidence":"Co-IP of ID1 with STAT1, STAT1 localization assays, target promoter analysis, and in vivo CRC immunotherapy model","pmids":["37996458"],"confidence":"High","gaps":["Direct ID1-STAT1 interaction interface not mapped","Single lab"]},{"year":2023,"claim":"Defined a niche mechanism whereby ID1 in mesenchymal stem cells interacts with the E3 ligase RNF4 to stabilize SP1 and drive Angptl7, promoting AML in a non-cell-autonomous manner.","evidence":"ID1 interactome proteomics, Co-IP with RNF4, SP1 ubiquitination assays, truncation mutants, and AML mouse model","pmids":["37319434"],"confidence":"High","gaps":["How ID1 inhibits RNF4 catalytically not resolved","Single lab"]},{"year":null,"claim":"Despite extensive partner and pathway mapping, the structural basis and partner-selection rules governing which bHLH and non-bHLH factors ID1 sequesters in a given lineage, and how its many context-specific transcriptional outputs are coordinated, remain unresolved.","evidence":"No timeline discovery provides a structural model or systematic partner-affinity hierarchy","pmids":[],"confidence":"Low","gaps":["No structural model of ID1-partner complexes in the corpus","Rules dictating lineage-specific partner choice undefined","Integration of competing transcriptional outputs not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,5,19,27,39]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,12,19,27,39,40]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7,36]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,7,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,39]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[22,14,13,24,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,5,19,27,39]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,16,11,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,23,39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[25,32,33,35]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,8,18,25,40]}],"complexes":[],"partners":["E47","E12","TFAP2A","PGC1A","EBF2","STAT1","RNF4","CUL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P41134","full_name":"DNA-binding protein inhibitor ID-1","aliases":["Class B basic helix-loop-helix protein 24","bHLHb24","Inhibitor of DNA binding 1","Inhibitor of differentiation 1"],"length_aa":155,"mass_kda":16.1,"function":"Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity. Implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. Inhibits skeletal muscle and cardiac myocyte differentiation. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P41134/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ID1","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ID1","total_profiled":1310},"omim":[{"mim_id":"621327","title":"FAMILY WITH SEQUENCE SIMILARITY 110, MEMBER D; FAM110D","url":"https://www.omim.org/entry/621327"},{"mim_id":"620305","title":"NEUROOCULORENAL SYNDROME; NORS","url":"https://www.omim.org/entry/620305"},{"mim_id":"616941","title":"AGAMMAGLOBULINEMIA 8A, AUTOSOMAL DOMINANT; AGM8A","url":"https://www.omim.org/entry/616941"},{"mim_id":"610376","title":"ATYPICAL CHEMOKINE RECEPTOR 3; ACKR3","url":"https://www.omim.org/entry/610376"},{"mim_id":"606908","title":"ADP-RIBOSYLATION FACTOR GTPase-ACTIVATING PROTEIN 2; ARFGAP2","url":"https://www.omim.org/entry/606908"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ID1"},"hgnc":{"alias_symbol":["dJ857M17.1.2","bHLHb24"],"prev_symbol":[]},"alphafold":{"accession":"P41134","domains":[{"cath_id":"4.10.280.10","chopping":"55-112","consensus_level":"medium","plddt":86.3181,"start":55,"end":112}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41134","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41134-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41134-F1-predicted_aligned_error_v6.png","plddt_mean":65.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ID1","jax_strain_url":"https://www.jax.org/strain/search?query=ID1"},"sequence":{"accession":"P41134","fasta_url":"https://rest.uniprot.org/uniprotkb/P41134.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41134/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41134"}},"corpus_meta":[{"pmid":"10537105","id":"PMC_10537105","title":"Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10537105","citation_count":757,"is_preprint":false},{"pmid":"21156287","id":"PMC_21156287","title":"TGF-β Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma.","date":"2010","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/21156287","citation_count":484,"is_preprint":false},{"pmid":"8001126","id":"PMC_8001126","title":"Constitutive expression of the Id1 gene impairs mouse B cell development.","date":"1994","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8001126","citation_count":248,"is_preprint":false},{"pmid":"19896442","id":"PMC_19896442","title":"High levels of Id1 expression define B1 type adult neural stem cells.","date":"2009","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/19896442","citation_count":218,"is_preprint":false},{"pmid":"7760836","id":"PMC_7760836","title":"Suppression of mammary epithelial cell differentiation by the helix-loop-helix protein Id-1.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7760836","citation_count":170,"is_preprint":false},{"pmid":"12498716","id":"PMC_12498716","title":"Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1.","date":"2002","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/12498716","citation_count":164,"is_preprint":false},{"pmid":"8922523","id":"PMC_8922523","title":"Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis.","date":"1996","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/8922523","citation_count":164,"is_preprint":false},{"pmid":"12881706","id":"PMC_12881706","title":"Id-1 expression promotes cell survival through activation of NF-kappaB signalling pathway in prostate cancer cells.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12881706","citation_count":139,"is_preprint":false},{"pmid":"10487839","id":"PMC_10487839","title":"Id-1 and Id-2 are overexpressed in pancreatic cancer and in dysplastic lesions in chronic pancreatitis.","date":"1999","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10487839","citation_count":131,"is_preprint":false},{"pmid":"15041724","id":"PMC_15041724","title":"Id-1 and Id-2 proteins as molecular markers for human prostate cancer progression.","date":"2004","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/15041724","citation_count":99,"is_preprint":false},{"pmid":"25924227","id":"PMC_25924227","title":"Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25924227","citation_count":98,"is_preprint":false},{"pmid":"15258459","id":"PMC_15258459","title":"Id-1 expression and cell survival.","date":"2004","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/15258459","citation_count":96,"is_preprint":false},{"pmid":"15318167","id":"PMC_15318167","title":"BMP-2 decreases Mash1 stability by increasing Id1 expression.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15318167","citation_count":92,"is_preprint":false},{"pmid":"17177845","id":"PMC_17177845","title":"The multiple roles of Id-1 in cancer progression.","date":"2006","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/17177845","citation_count":90,"is_preprint":false},{"pmid":"29169374","id":"PMC_29169374","title":"ID1 promotes hepatocellular carcinoma proliferation and confers chemoresistance to oxaliplatin by activating pentose phosphate pathway.","date":"2017","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/29169374","citation_count":88,"is_preprint":false},{"pmid":"17374642","id":"PMC_17374642","title":"Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17374642","citation_count":85,"is_preprint":false},{"pmid":"17622570","id":"PMC_17622570","title":"Id1, but not Id3, directs long-term repopulating hematopoietic stem-cell maintenance.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17622570","citation_count":85,"is_preprint":false},{"pmid":"32410828","id":"PMC_32410828","title":"Inhibitor of Differentiation 1 (Id1) in Cancer and Cancer Therapy.","date":"2020","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32410828","citation_count":81,"is_preprint":false},{"pmid":"32080166","id":"PMC_32080166","title":"ID1 confers cancer cell chemoresistance through STAT3/ATF6-mediated induction of autophagy.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32080166","citation_count":78,"is_preprint":false},{"pmid":"25496992","id":"PMC_25496992","title":"Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25496992","citation_count":77,"is_preprint":false},{"pmid":"11275368","id":"PMC_11275368","title":"Id1 expression is associated with histological grade and invasive behavior in endometrial carcinoma.","date":"2001","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/11275368","citation_count":68,"is_preprint":false},{"pmid":"27022132","id":"PMC_27022132","title":"Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma.","date":"2016","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27022132","citation_count":66,"is_preprint":false},{"pmid":"18092003","id":"PMC_18092003","title":"Id1 restrains p21 expression to control endothelial progenitor cell formation.","date":"2007","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18092003","citation_count":65,"is_preprint":false},{"pmid":"23199293","id":"PMC_23199293","title":"p53 regulates neural stem cell proliferation and differentiation via BMP-Smad1 signaling and Id1.","date":"2013","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/23199293","citation_count":63,"is_preprint":false},{"pmid":"31582374","id":"PMC_31582374","title":"ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer.","date":"2019","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/31582374","citation_count":62,"is_preprint":false},{"pmid":"25376791","id":"PMC_25376791","title":"The helix-loop-helix protein id1 controls stem cell proliferation during regenerative neurogenesis in the adult zebrafish telencephalon.","date":"2015","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/25376791","citation_count":60,"is_preprint":false},{"pmid":"18158619","id":"PMC_18158619","title":"Id-1 regulates Bcl-2 and Bax expression through p53 and NF-kappaB in MCF-7 breast cancer cells.","date":"2007","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/18158619","citation_count":59,"is_preprint":false},{"pmid":"30082068","id":"PMC_30082068","title":"Id1 Ablation Protects Hematopoietic Stem Cells from Stress-Induced Exhaustion and Aging.","date":"2018","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/30082068","citation_count":58,"is_preprint":false},{"pmid":"22592211","id":"PMC_22592211","title":"MicroRNA-381 represses ID1 and is deregulated in lung adenocarcinoma.","date":"2012","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22592211","citation_count":58,"is_preprint":false},{"pmid":"19079342","id":"PMC_19079342","title":"Id-1 activates Akt-mediated Wnt signaling and p27(Kip1) phosphorylation through PTEN inhibition.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19079342","citation_count":58,"is_preprint":false},{"pmid":"23877317","id":"PMC_23877317","title":"TGM2 inhibition attenuates ID1 expression in CD44-high glioma-initiating cells.","date":"2013","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23877317","citation_count":56,"is_preprint":false},{"pmid":"21933340","id":"PMC_21933340","title":"Smurf2-mediated ubiquitination and degradation of Id1 regulates p16 expression during senescence.","date":"2011","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/21933340","citation_count":54,"is_preprint":false},{"pmid":"26577912","id":"PMC_26577912","title":"Peritoneal VEGF-A expression is regulated by TGF-β1 through an ID1 pathway in women with endometriosis.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26577912","citation_count":53,"is_preprint":false},{"pmid":"37996458","id":"PMC_37996458","title":"ID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37996458","citation_count":52,"is_preprint":false},{"pmid":"31292163","id":"PMC_31292163","title":"ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma.","date":"2019","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31292163","citation_count":51,"is_preprint":false},{"pmid":"16271072","id":"PMC_16271072","title":"Targeting Id1 and Id3 inhibits peritoneal metastasis of gastric cancer.","date":"2005","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/16271072","citation_count":51,"is_preprint":false},{"pmid":"23555842","id":"PMC_23555842","title":"E47 and Id1 interplay in epithelial-mesenchymal transition.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23555842","citation_count":50,"is_preprint":false},{"pmid":"27477274","id":"PMC_27477274","title":"The ID1-CULLIN3 Axis Regulates Intracellular SHH and WNT Signaling in Glioblastoma Stem Cells.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27477274","citation_count":49,"is_preprint":false},{"pmid":"15451666","id":"PMC_15451666","title":"Ubiquitin-dependent degradation of Id1 and Id3 is mediated by the COP9 signalosome.","date":"2004","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15451666","citation_count":48,"is_preprint":false},{"pmid":"16007194","id":"PMC_16007194","title":"E12 and E47 modulate cellular localization and proteasome-mediated degradation of MyoD and Id1.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16007194","citation_count":46,"is_preprint":false},{"pmid":"23342268","id":"PMC_23342268","title":"Id1 and Id3 expression is associated with increasing grade of prostate cancer: Id3 preferentially regulates CDKN1B.","date":"2012","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23342268","citation_count":45,"is_preprint":false},{"pmid":"18556654","id":"PMC_18556654","title":"ID1, inhibitor of differentiation/DNA binding, is an effector of the p53-dependent DNA damage response pathway.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18556654","citation_count":44,"is_preprint":false},{"pmid":"19571317","id":"PMC_19571317","title":"ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signaling.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19571317","citation_count":41,"is_preprint":false},{"pmid":"23714001","id":"PMC_23714001","title":"Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-κB/MMP-2 signaling pathways.","date":"2013","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23714001","citation_count":41,"is_preprint":false},{"pmid":"26858249","id":"PMC_26858249","title":"Inhibitor of Differentiation/DNA Binding 1 (ID1) Inhibits Etoposide-induced Apoptosis in a c-Jun/c-Fos-dependent Manner.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26858249","citation_count":38,"is_preprint":false},{"pmid":"35163396","id":"PMC_35163396","title":"BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35163396","citation_count":35,"is_preprint":false},{"pmid":"19415678","id":"PMC_19415678","title":"Caspases and p53 modulate FOXO3A/Id1 signaling during mouse neural stem cell differentiation.","date":"2009","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19415678","citation_count":35,"is_preprint":false},{"pmid":"24948111","id":"PMC_24948111","title":"ID1 promotes breast cancer metastasis by S100A9 regulation.","date":"2014","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/24948111","citation_count":35,"is_preprint":false},{"pmid":"31646712","id":"PMC_31646712","title":"MicroRNA-338-5p reverses chemoresistance and inhibits invasion of esophageal squamous cell carcinoma cells by targeting Id-1.","date":"2019","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/31646712","citation_count":35,"is_preprint":false},{"pmid":"15575081","id":"PMC_15575081","title":"Expression and significances of Id1 helix-loop-helix protein overexpression in gastric cancer.","date":"2004","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/15575081","citation_count":33,"is_preprint":false},{"pmid":"21536374","id":"PMC_21536374","title":"Id1 promotes lung cancer cell proliferation and tumor growth through Akt-related pathway.","date":"2011","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/21536374","citation_count":33,"is_preprint":false},{"pmid":"34547407","id":"PMC_34547407","title":"Heme Oxygenase-1 (HMOX-1) and inhibitor of differentiation proteins (ID1, ID3) are key response mechanisms against iron-overload in pancreatic β-cells.","date":"2021","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34547407","citation_count":32,"is_preprint":false},{"pmid":"25204555","id":"PMC_25204555","title":"PTK7 regulates Id1 expression in CD44-high glioma cells.","date":"2014","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25204555","citation_count":31,"is_preprint":false},{"pmid":"29208670","id":"PMC_29208670","title":"Inhibition of ID1-BMPR2 Intrinsic Signaling Sensitizes Glioma Stem Cells to Differentiation Therapy.","date":"2017","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/29208670","citation_count":31,"is_preprint":false},{"pmid":"15986223","id":"PMC_15986223","title":"Cyclosporin A treatment upregulates Id1 and Smad3 expression and delays skeletal muscle regeneration.","date":"2005","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/15986223","citation_count":30,"is_preprint":false},{"pmid":"16686600","id":"PMC_16686600","title":"Id-1 modulates senescence and TGF-beta1 sensitivity in prostate epithelial cells.","date":"2006","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16686600","citation_count":30,"is_preprint":false},{"pmid":"34875308","id":"PMC_34875308","title":"Reconstituted HDL-apoE3 promotes endothelial cell migration through ID1 and its downstream kinases ERK1/2, AKT and p38 MAPK.","date":"2021","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/34875308","citation_count":28,"is_preprint":false},{"pmid":"30297743","id":"PMC_30297743","title":"Hyaluronic acid-CD44 interactions promote BMP4/7-dependent Id1/3 expression in melanoma cells.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30297743","citation_count":28,"is_preprint":false},{"pmid":"31672960","id":"PMC_31672960","title":"Salt-inducible kinase 1 regulates bone anabolism via the CRTC1-CREB-Id1 axis.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31672960","citation_count":27,"is_preprint":false},{"pmid":"19956687","id":"PMC_19956687","title":"Id1 represses osteoclast-dependent transcription and affects bone formation and hematopoiesis.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19956687","citation_count":27,"is_preprint":false},{"pmid":"32004572","id":"PMC_32004572","title":"ID1 overexpression increases gefitinib sensitivity in non-small cell lung cancer by activating RIP3/MLKL-dependent necroptosis.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/32004572","citation_count":26,"is_preprint":false},{"pmid":"28270523","id":"PMC_28270523","title":"Id1 Promotes Obesity by Suppressing Brown Adipose Thermogenesis and White Adipose Browning.","date":"2017","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/28270523","citation_count":26,"is_preprint":false},{"pmid":"33834612","id":"PMC_33834612","title":"BMP9-ID1 signaling promotes EpCAM-positive cancer stem cell properties in hepatocellular carcinoma.","date":"2021","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33834612","citation_count":25,"is_preprint":false},{"pmid":"17012234","id":"PMC_17012234","title":"Id1 potentiates NF-kappaB activation upon T cell receptor signaling.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17012234","citation_count":25,"is_preprint":false},{"pmid":"32547321","id":"PMC_32547321","title":"IL-1β Promotes Stemness of Tumor Cells by Activating Smad/ID1 Signaling Pathway.","date":"2020","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32547321","citation_count":25,"is_preprint":false},{"pmid":"30453304","id":"PMC_30453304","title":"SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30453304","citation_count":24,"is_preprint":false},{"pmid":"32246536","id":"PMC_32246536","title":"Bone morphogenetic protein signaling regulates Id1-mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module.","date":"2020","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/32246536","citation_count":24,"is_preprint":false},{"pmid":"32348770","id":"PMC_32348770","title":"Id1 and Id3 Maintain Steady-State Hematopoiesis by Promoting Sinusoidal Endothelial Cell Survival and Regeneration.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32348770","citation_count":23,"is_preprint":false},{"pmid":"19478045","id":"PMC_19478045","title":"Cell-nonautonomous function of Id1 in the hematopoietic progenitor cell niche.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19478045","citation_count":23,"is_preprint":false},{"pmid":"30949224","id":"PMC_30949224","title":"Baicalein Inhibits Orthotopic Human Non-Small Cell Lung Cancer Xenografts via Src/Id1 Pathway.","date":"2019","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/30949224","citation_count":23,"is_preprint":false},{"pmid":"33428809","id":"PMC_33428809","title":"Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1-mediated EMT.","date":"2021","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/33428809","citation_count":23,"is_preprint":false},{"pmid":"18842581","id":"PMC_18842581","title":"Cyclooxygenase-2-derived prostaglandin E2 stimulates Id-1 transcription.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18842581","citation_count":22,"is_preprint":false},{"pmid":"15694377","id":"PMC_15694377","title":"CASK inhibits ECV304 cell growth and interacts with Id1.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15694377","citation_count":22,"is_preprint":false},{"pmid":"29721855","id":"PMC_29721855","title":"Id1 and Sonic Hedgehog Mediate Cell Cycle Reentry and Apoptosis Induced by Amyloid Beta-Peptide in Post-mitotic Cortical Neurons.","date":"2018","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29721855","citation_count":22,"is_preprint":false},{"pmid":"17412691","id":"PMC_17412691","title":"Protein kinase A-regulated nucleocytoplasmic shuttling of Id1 during angiogenesis.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17412691","citation_count":22,"is_preprint":false},{"pmid":"39939818","id":"PMC_39939818","title":"The AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes epidermal and immune homeostasis in atopic dermatitis-like skin inflammation.","date":"2025","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39939818","citation_count":21,"is_preprint":false},{"pmid":"33390793","id":"PMC_33390793","title":"Inhibition of USP1 induces apoptosis via ID1/AKT pathway in B-cell acute lymphoblastic leukemia cells.","date":"2021","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33390793","citation_count":21,"is_preprint":false},{"pmid":"20186495","id":"PMC_20186495","title":"Inhibitor of differentiation 1 (ID1) promotes cell survival and proliferation of prostate epithelial cells.","date":"2010","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/20186495","citation_count":21,"is_preprint":false},{"pmid":"35487890","id":"PMC_35487890","title":"Neuron-specific enolase promotes stem cell-like characteristics of small-cell lung cancer by downregulating NBL1 and activating the BMP2/Smad/ID1 pathway.","date":"2022","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/35487890","citation_count":21,"is_preprint":false},{"pmid":"31884068","id":"PMC_31884068","title":"Roles of Id1/HIF-1 and CDK5/HIF-1 in cell cycle reentry induced by amyloid-beta peptide in post-mitotic cortical neuron.","date":"2019","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31884068","citation_count":20,"is_preprint":false},{"pmid":"23948603","id":"PMC_23948603","title":"Serum regulation of Id1 expression by a BMP pathway and BMP responsive element.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23948603","citation_count":20,"is_preprint":false},{"pmid":"30535485","id":"PMC_30535485","title":"Overexpression of ID1 promotes tumor progression in penile squamous cell carcinoma.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/30535485","citation_count":20,"is_preprint":false},{"pmid":"20414347","id":"PMC_20414347","title":"Id1 promotes tumor cell migration in nonsmall cell lung cancers.","date":"2010","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20414347","citation_count":20,"is_preprint":false},{"pmid":"21053361","id":"PMC_21053361","title":"Id-1 induces cell invasiveness in immortalized epithelial cells by regulating cadherin switching and Rho GTPases.","date":"2011","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21053361","citation_count":20,"is_preprint":false},{"pmid":"15314144","id":"PMC_15314144","title":"Hyperresponse to T-cell receptor signaling and apoptosis of Id1 transgenic thymocytes.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15314144","citation_count":18,"is_preprint":false},{"pmid":"19014499","id":"PMC_19014499","title":"Id-1: regulator of EGFR and VEGF and potential target for colorectal cancer therapy.","date":"2008","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/19014499","citation_count":18,"is_preprint":false},{"pmid":"16184548","id":"PMC_16184548","title":"Id-1 gene downregulation by sulindac sulfide and its upregulation during tumor development in gastric cancer.","date":"2006","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16184548","citation_count":18,"is_preprint":false},{"pmid":"25938540","id":"PMC_25938540","title":"Overexpression of Id1 in transgenic mice promotes mammary basal stem cell activity and breast tumorigenesis.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25938540","citation_count":18,"is_preprint":false},{"pmid":"30618072","id":"PMC_30618072","title":"YAP1 influences differentiation of osteoblastic MC3T3-E1 cells through the regulation of ID1.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30618072","citation_count":18,"is_preprint":false},{"pmid":"9796921","id":"PMC_9796921","title":"Helix-loop-helix (E2-5, HEB, TAL1 and Id1) protein interaction with the TCRalphadelta enhancers.","date":"1998","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9796921","citation_count":18,"is_preprint":false},{"pmid":"26944543","id":"PMC_26944543","title":"Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin.","date":"2016","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/26944543","citation_count":18,"is_preprint":false},{"pmid":"37319434","id":"PMC_37319434","title":"The non-cell-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment.","date":"2023","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/37319434","citation_count":17,"is_preprint":false},{"pmid":"24920844","id":"PMC_24920844","title":"Id1 expression promotes T regulatory cell differentiation by facilitating TCR costimulation.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24920844","citation_count":17,"is_preprint":false},{"pmid":"16728343","id":"PMC_16728343","title":"Increasing expression of GST-pi MIF, and ID1 genes in chemoresistant prostate cancer cells.","date":"2006","source":"Archives of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/16728343","citation_count":17,"is_preprint":false},{"pmid":"22841831","id":"PMC_22841831","title":"OxLDL stimulates Id1 nucleocytoplasmic shuttling in endothelial cell angiogenesis via PI3K pathway.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22841831","citation_count":17,"is_preprint":false},{"pmid":"24434151","id":"PMC_24434151","title":"Inhibitory role of Id1 on TGF-β-induced collagen expression in human dermal fibroblasts.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24434151","citation_count":17,"is_preprint":false},{"pmid":"32730768","id":"PMC_32730768","title":"BMP9 attenuates occurrence of venous malformation by maintaining endothelial quiescence and strengthening vessel walls via SMAD1/5/ID1/α-SMA pathway.","date":"2020","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/32730768","citation_count":17,"is_preprint":false},{"pmid":"38643157","id":"PMC_38643157","title":"Trametinib sensitizes KRAS-mutant lung adenocarcinoma tumors to PD-1/PD-L1 axis blockade via Id1 downregulation.","date":"2024","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38643157","citation_count":16,"is_preprint":false},{"pmid":"37085918","id":"PMC_37085918","title":"TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37085918","citation_count":16,"is_preprint":false},{"pmid":"35605606","id":"PMC_35605606","title":"Therapeutic targeting of prenatal pontine ID1 signaling in diffuse midline glioma.","date":"2023","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35605606","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50434,"output_tokens":11275,"usd":0.160214,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22375,"output_tokens":10313,"usd":0.18485,"stage2_stop_reason":"end_turn"},"total_usd":0.345064,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Constitutive expression of Id1 in transgenic mice impairs B cell development at an early stage, reducing V(D)J recombination and expression of immunoglobulin, RAG-1, RAG-2, and lambda 5 genes, demonstrating that Id1 (as a dominant-negative inhibitor of bHLH transcription factors) blocks B lymphocyte differentiation.\",\n      \"method\": \"Transgenic mouse model with constitutive Id1 expression; B cell phenotyping by flow cytometry and PCR\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo transgenic loss-of-function with defined cellular and molecular phenotype, replicated across multiple readouts\",\n      \"pmids\": [\"8001126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Id-1 suppresses mammary epithelial cell differentiation: stable Id-1 overexpression prevents beta-casein expression in response to differentiation signals and causes invasion of the basement membrane, while Id-1 antisense expression stabilizes differentiation, establishing Id-1 as an inhibitor of bHLH-driven mammary differentiation.\",\n      \"method\": \"Stable transfection of Id-1 expression and antisense vectors in SCp2 mammary epithelial cells; beta-casein expression, 3D culture morphology, and growth assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional (overexpression and antisense knockdown) in the same cellular system with multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"7760836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Targeted disruption of Id1 and Id3 in mice causes premature neuroblast withdrawal from the cell cycle, expression of neural differentiation markers, vascular malformations in the forebrain, and failure of tumor xenograft angiogenesis, establishing Id1 as required for timing of neuronal differentiation and vascular invasiveness.\",\n      \"method\": \"Id1/Id3 double-knockout mice; tumor xenograft implantation; histological and immunological analysis of neurogenesis and angiogenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal phenotypic readouts replicated across several tumor types\",\n      \"pmids\": [\"10537105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Id1 transcriptionally represses thrombospondin-1 (TSP-1): Id1-null mouse embryo fibroblasts secrete elevated TSP-1 that inhibits endothelial cell migration, and in vivo neovascularization defects in Id1-null mice are rescued by a TSP-1 neutralizing antibody, identifying TSP-1 as a major downstream effector through which Id1 promotes angiogenesis.\",\n      \"method\": \"PCR-select subtractive hybridization on wild-type vs. Id1 knockout MEFs; endothelial migration assay with TSP-1 depletion; in vivo Matrigel neovascularization assay with TSP-1 neutralizing antibody\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (subtractive hybridization, in vitro migration rescue, in vivo antibody rescue) in a single focused study\",\n      \"pmids\": [\"12498716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Id-1 promotes cell survival in prostate cancer cells via activation of the NF-κB signaling pathway: ectopic Id-1 increases nuclear translocation of p65/p50, upregulates Bcl-xL and ICAM-1, inactivates Bax and caspase 3, conferring resistance to TNFα-induced apoptosis; antisense Id-1 reduces nuclear p65/p50 and sensitizes cells to apoptosis.\",\n      \"method\": \"Stable Id-1 transfection in LNCaP cells; NF-κB reporter assays; Western blot for p65/p50 nuclear translocation; apoptosis assays; antisense knockdown in DU145 cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (overexpression and antisense) with multiple orthogonal assays (reporter, fractionation, apoptosis) in a single lab\",\n      \"pmids\": [\"12881706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BMP-2 increases Id1 expression, which in turn destabilizes Mash1 protein by shifting the E47/Id1 ratio: elevated Id1 promotes proteasomal degradation of Mash1, whereas E47 stabilizes Mash1; the E47/Id1 ratio also regulates CK2-mediated phosphorylation of Mash1 on Ser152, modulating Mash1-E47 heterodimer interaction.\",\n      \"method\": \"BMP-2 treatment of neuroendocrine lung carcinoma cells; Id1 overexpression and knockout; E47 overexpression; pulse-chase protein stability assays; phosphorylation analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (stability assays, genetic rescue with Id1-deficient cells, E47 overexpression, phosphorylation mapping) in a single rigorous study\",\n      \"pmids\": [\"15318167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Id1 is a downstream effector of the p53-dependent DNA damage response: DNA damage represses ID1 expression in a p53-dependent manner via the p53 target DEC1, which inhibits ID1 promoter activity; overexpression of ID1 promotes cell proliferation through inhibition of p21 and substantially decreases DNA damage-induced premature senescence.\",\n      \"method\": \"DNA damage treatment of cells; siRNA knockdown of DEC1; ID1 promoter deletion/mutation assays; ID1 overexpression with proliferation and senescence assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — promoter mapping, siRNA epistasis, and functional phenotype assays with multiple orthogonal methods in one study\",\n      \"pmids\": [\"18556654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"E12 and E47 physically interact with Id1 to stabilize it: cotransfection of E12 or E47 with Id1 markedly reduces Id1 degradation rate (t1/2 from ~1 h to ~8 h) and alters its subcellular localization, demonstrating that E-protein heterodimerization regulates Id1 protein stability via the ubiquitin-proteasome system.\",\n      \"method\": \"Co-transfection of E12/E47 with Id1 in non-muscle cells; pulse-chase degradation assays; NLS-mutant subcellular localization analysis; proteasome inhibitor experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (degradation kinetics, localization, NLS mutants) addressing the same mechanism in one focused study\",\n      \"pmids\": [\"16007194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ubiquitin-dependent degradation of Id1 and Id3 is mediated by the COP9 signalosome (CSN): Id1/Id3 (but not Id2/Id4) bind CSN subunit CSN5 in mammalian two-hybrid assays; Id3 physically interacts with the CSN complex and CSN5/CSN7; curcumin and emodin (CSN-associated kinase inhibitors) stimulate Id1/Id3 ubiquitination and proteasomal degradation; overexpression of CSN2 stabilizes Id3 protein.\",\n      \"method\": \"Mammalian two-hybrid analysis; pull-down and far-Western experiments; transfection with His-ubiquitin and Id3; pharmacological treatment with curcumin/emodin; CSN2 overexpression\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding demonstrated by multiple methods (two-hybrid, pulldown, far-Western) plus functional ubiquitination assay and rescue by CSN2 overexpression\",\n      \"pmids\": [\"15451666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Id1 protein undergoes PKA-regulated nucleocytoplasmic shuttling in endothelial cells: Id1 is nuclear in HUVECs on uncoated plates but translocates to the cytoplasm during capillary-like structure formation on Matrigel via CRM1/exportin-dependent nuclear export; PKA activation inhibits this export (Ser-5 phosphorylation implicated), suggesting nuclear Id1 function is controlled by localization during angiogenesis.\",\n      \"method\": \"Live imaging of GFP-Id1 in HUVECs; leptomycin B treatment (CRM1 inhibitor); PKA activators (dbcAMP, forskolin) and inhibitors (H-89); Ser-5 mutagenesis of Id1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by live imaging with pharmacological and mutagenesis validation in a single focused mechanistic study\",\n      \"pmids\": [\"17412691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Id1 promotes the generation of endothelial progenitor cells (EPCs) in bone marrow by restraining expression of p21: Id1 knockout mice lack circulating EPCs and show increased p21 expression; genetic ablation of p21 in Id1-null mice rescues the EPC population, restores BM-derived angiogenesis, and normalizes tumor growth.\",\n      \"method\": \"Genetically modified mouse models (Id1-KO, p21-KO, Id1/p21 double-KO); flow cytometry for EPCs; tumor growth assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double-KO rescue) with multiple orthogonal in vivo functional readouts\",\n      \"pmids\": [\"18092003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Id1, but not Id3, is expressed in long-term repopulating hematopoietic stem cells (LT-HSCs) and is required for their maintenance: Id1-GFP knock-in marks LT-HSCs; Id1-deficient (but not Id3-deficient) bone marrow shows impaired engraftment in secondary transplantation assays, demonstrating a unique role for Id1 in LT-HSC self-renewal.\",\n      \"method\": \"Id1-GFP knock-in mouse model; serial bone marrow transplantation; flow cytometry for HSC populations\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in reporter plus functional transplantation assay with Id3-KO as internal negative control, single lab\",\n      \"pmids\": [\"17622570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Id1 overexpression inhibits BMP signaling by inducing Twist-1 degradation: Twist-1 inhibits BMP signaling by forming a complex with Smad4 and HDAC1; Id1 promotes Twist-1 degradation and thereby de-represses BMP target gene expression, establishing Id1 as a positive regulator of BMP signaling through a feedback loop.\",\n      \"method\": \"Co-immunoprecipitation in MC3T3-E1 cells; osteoblast differentiation assays; HDAC inhibitor (trichostatin) treatment; Id1 overexpression and Twist-1 stability assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP demonstrates complex; functional osteoblast readout; single lab, limited mutagenesis\",\n      \"pmids\": [\"17374642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"COX-2-derived PGE2 activates Id-1 transcription via the EP4 receptor → EGFR → ERK1/2 → Egr-1 pathway: PGE2 induces amphiregulin release to transactivate EGFR, leading to Egr-1 binding to the Id-1 promoter; this cascade increases Id-1 expression and mammary epithelial cell invasiveness.\",\n      \"method\": \"EP4 agonist treatment; EGFR/ERK inhibitor experiments; chromatin immunoprecipitation for Egr-1 at the Id-1 promoter; COX-2 siRNA silencing; cell migration/invasion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP identifies direct Egr-1 binding to Id-1 promoter; pathway established by pharmacological and siRNA dissection with multiple orthogonal methods\",\n      \"pmids\": [\"18842581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Id-1 activates the Akt pathway by inhibiting PTEN transcription through downregulation of p53: Id-1 reduces p53 binding to the PTEN promoter (confirmed by ChIP and serial promoter deletion); this activates Akt→ canonical Wnt signaling, leading to GSK-3β phosphorylation, β-catenin nuclear localization, and p27(Kip1) cytoplasmic sequestration.\",\n      \"method\": \"Id-1 overexpression in MCF7 cells; promoter deletion assays and ChIP for p53 at PTEN promoter; Western blot for Akt/β-catenin/p27 phosphorylation; TCF/LEF reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP plus promoter deletion identifies molecular mechanism; multiple downstream pathway readouts in one focused study\",\n      \"pmids\": [\"19079342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ID1 is a transcriptional target of JAK2-STAT5 signaling in erythroid cells: STAT5 binds and transactivates a downstream enhancer of ID1 (confirmed by ChIP); ID1 promotes survival of primary erythroid cells; ID1 expression correlates with JAK2V617F mutation in erythroid cells and polycythemia vera patients.\",\n      \"method\": \"Comparative genomics and chromatin immunoprecipitation for STAT5 at ID1 enhancer; ID1 knockdown and overexpression in primary fetal liver erythroid differentiation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct ChIP evidence of STAT5 binding plus functional validation by loss-/gain-of-function in primary cells\",\n      \"pmids\": [\"19571317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"High expression of Id1 identifies a rare population of B1-type adult neural stem cells (GFAP+ astrocytes) in the subventricular zone; Id1-high cells self-renew asymmetrically generating progeny with progressively lower Id1; Id genes are necessary for self-renewal capacity, demonstrated by loss-of-function.\",\n      \"method\": \"Id1-GFP knock-in reporter mouse; FACS isolation of Id1-high cells; neurosphere and in vivo transplantation assays; Id gene knockout\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in reporter for direct identification plus multiple functional stem cell assays and genetic knockout validation\",\n      \"pmids\": [\"19896442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Id1 has a non-cell-autonomous role in maintaining the hematopoietic progenitor cell niche: transplantation experiments show that Id1(-/-) microenvironment impairs normal hematopoietic development; Id1(-/-) stromal cells display altered cytokine production, demonstrating that Id1 regulates the niche rather than HSC intrinsic function.\",\n      \"method\": \"Reciprocal bone marrow transplantation between WT and Id1-KO mice; in vitro cytokine production assays of Id1-KO stromal cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean reciprocal transplantation epistasis experiment with cytokine mechanistic follow-up, single lab\",\n      \"pmids\": [\"19478045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Smurf2 is the E3 ubiquitin ligase that ubiquitinates Id1 and Id3: Smurf2-mediated ubiquitination and degradation of Id1 regulates p16 expression during cellular senescence, establishing a mechanistic link between Smurf2, Id1, and p16 in senescence.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assays; Smurf2 overexpression and knockdown; senescence assays; p16 expression analysis\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination assay with E3 ligase identification plus functional senescence/p16 readout, single lab with multiple methods\",\n      \"pmids\": [\"21933340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Id1 promotes breast cancer metastasis by interacting with TFAP2A to suppress S100A9 expression: ID1-TFAP2A interaction suppresses S100A9, which in turn permits elevated RhoC expression; reestablishment of S100A9 rescues the migratory/invasive and in vivo metastatic phenotypes induced by Id1.\",\n      \"method\": \"Co-immunoprecipitation of Id1 with TFAP2A; S100A9 knockdown/overexpression rescue; in vitro migration/invasion assays; in vivo metastasis assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP demonstrates Id1-TFAP2A interaction; epistasis rescue confirms S100A9 pathway; single lab\",\n      \"pmids\": [\"24948111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E47 and Id1 physically interact in mesenchymal breast carcinoma and MDCK-E47 EMT cells; ChIP demonstrates that E47 binds the endogenous E-cadherin promoter in a complex devoid of Id1; both E47 and Id1 are required to maintain the mesenchymal phenotype, operating through mechanisms independent of Id1 dominant-negative action on E-cadherin transcription.\",\n      \"method\": \"Co-immunoprecipitation of E47 and Id1; chromatin immunoprecipitation at E-cadherin promoter; Id1 knockdown in EMT cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP in the same system; single lab\",\n      \"pmids\": [\"23555842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p53 represses Id1 expression through BMP-Smad1-dependent and -independent mechanisms: p53 deficiency leads to elevated Smad1 and Id1 expression; Id1 upregulation contributes to both augmented NSC proliferation and accelerated neuronal differentiation in p53-null neural stem cells.\",\n      \"method\": \"p53-knockout neural stem cells; in vivo BrdU labeling; Smad1 siRNA; Id1 overexpression; differentiation assays\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic knockout with functional differentiation readouts and siRNA epistasis; single lab\",\n      \"pmids\": [\"23199293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Serum induction of Id1 is mediated by a BMP-responsive element (BRE) in the Id1 promoter: BMP pathway inhibition (Smad4 siRNA, noggin, dorsomorphin) blocks serum induction of Id1; BMP2 alone is sufficient to induce Id1; the BRE is necessary and sufficient for serum responsiveness of Id1.\",\n      \"method\": \"Id1 promoter deletion/mapping in serum-stimulated fibroblasts; siRNA depletion of Smad4; BMP antagonist (noggin) and receptor inhibitor (dorsomorphin) treatment; BMP2 stimulation\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — promoter mapping identifies BRE as necessary and sufficient; multiple pathway inhibition approaches confirm mechanism; single lab\",\n      \"pmids\": [\"23948603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Id1 upregulation in response to tumour-derived TGFβ drives a switch from dendritic cell differentiation to myeloid-derived suppressor cell expansion: genetic inactivation of Id1 corrects the myeloid imbalance, and Id1 overexpression in the absence of tumour-derived factors re-creates immunosuppression and suppresses CD8 T-cell proliferation, identifying Id1 as a key mediator of tumour-induced immunosuppression.\",\n      \"method\": \"Id1 genetic inactivation and overexpression in mouse models; TGFβ stimulation; DC differentiation assays; CD8 T-cell proliferation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation with functional immune cell differentiation readouts; single lab\",\n      \"pmids\": [\"25924227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"COX-2-derived PGE2 induces Id1 in GBM cells via the EP4 receptor → ERK1/2 MAPK → Egr1 transcription factor pathway; this induction of Id1 is required for optimal GBM cell self-renewal and radiation resistance, demonstrated by siRNA and pharmacological pathway inhibition combined with chromatin immunoprecipitation.\",\n      \"method\": \"dmPGE2 stimulation of mouse and human GBM cells; siRNA knockdown and small molecule inhibitors of EP4, ERK1/2, Egr1; ChIP for Egr1 at Id1 promoter; sphere formation and radiation resistance assays\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP confirms direct Egr1 binding; multiple orthogonal pathway inhibitors; functional phenotype readout; single lab\",\n      \"pmids\": [\"27022132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ID1 suppresses CULLIN3 ubiquitin ligase in glioblastoma stem cells (GSCs): ID1 promotes GSC proliferation, self-renewal, and tumorigenicity by suppressing CULLIN3, leading to accumulation of CYCLIN E and CULLIN3 substrates GLI2 and DVL2 (confirmed by proteomics showing CULLIN3-GLI2/DVL2 interaction and ubiquitination); combined pharmacological inhibition of GLI2 and β-CATENIN diminishes GSC properties.\",\n      \"method\": \"ID1 knockdown/overexpression in human GSCs; proteomics analysis of CULLIN3 interactome; ubiquitination assays for GLI2/DVL2; combinatorial pharmacological inhibition; in vivo tumorigenicity assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proteomics interactome plus ubiquitination assay plus in vivo functional validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27477274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ID1 promotes resistance to etoposide-induced apoptosis through a c-Jun/c-Fos (AP-1)-dependent mechanism: AP-1 binding sites in the ID1 promoter mediate ID1 upregulation upon etoposide treatment; ablation of c-Jun/c-Fos or ID1 enhances etoposide-mediated apoptosis via caspase 3 activation and PARP cleavage.\",\n      \"method\": \"AP-1 site mutagenesis in ID1 promoter; c-Jun/c-Fos and ID1 siRNA knockdown; caspase 3 activity and PARP cleavage assays in esophageal cancer cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis defines AP-1 sites; functional apoptosis rescue; single lab\",\n      \"pmids\": [\"26858249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Id1 promotes obesity by suppressing brown adipose thermogenesis through two direct molecular interactions: (1) Id1 binds and suppresses PGC1α transcriptional activity to reduce UCP1 and thermogenic gene expression; (2) Id1 directly interacts with and suppresses Ebf2 transcriptional activity, reducing Prdm16 expression and brown/beige adipocyte fate determination.\",\n      \"method\": \"Adipose-specific Id1 transgenic mice; Id1-deficient mouse embryonic fibroblasts; co-immunoprecipitation of Id1 with PGC1α and Ebf2; chromatin/reporter assays; cold-exposure and HFD phenotype analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP demonstrates Id1-PGC1α and Id1-Ebf2 interactions; supported by in vivo transgenic and KO phenotypes; single lab with multiple methods\",\n      \"pmids\": [\"28270523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ID1 inhibits BMPR2 expression in glioblastoma stem cells through MYC-driven upregulation of miR-17 and miR-20a, thereby abrogating BMP differentiation signaling and promoting self-renewal; ID1 simultaneously activates WNT and SHH signaling by increasing MYC expression.\",\n      \"method\": \"ID1 overexpression and knockdown in GSCs; miRNA expression analysis; Western blotting for BMPR2; WNT/SHH inhibitor treatment; in vivo tumor survival assay\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — defined miRNA mechanism for BMPR2 suppression with functional in vivo validation; single lab\",\n      \"pmids\": [\"29208670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ID1 confers oxaliplatin resistance in hepatocellular carcinoma by activating the pentose phosphate pathway (PPP): ID1 induces G6PD promoter transcription and activates PPP through Wnt/β-catenin/c-MYC signaling, increasing NADPH and reducing ROS; ID1 knockdown decreases G6PD expression, blocks PPP, elevates ROS, and induces apoptosis.\",\n      \"method\": \"lentiviral shRNA knockdown of ID1 in oxaliplatin-resistant HCC cells; G6PD promoter luciferase assay; NADPH/ROS measurement; β-catenin/c-MYC inhibitor experiments; in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assay defines mechanistic target; metabolic readouts (NADPH, ROS) confirm pathway; single lab with multiple methods\",\n      \"pmids\": [\"29169374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hyaluronic acid–CD44 interactions promote BMP4/7-dependent Id1/3 expression: Co-IP demonstrates that CD44 physically associates with the BMP type II receptor ACVR2B; depletion of HA or CD44 reduces BMP4/7-driven Id1/3 expression; exogenous HA enhances it, linking pericellular matrix to Id1 regulation in melanoma.\",\n      \"method\": \"HA depletion by hyaluronidase and 4-MU; CD44 knockdown; exogenous HA treatment; Co-immunoprecipitation of CD44 with ACVR2B; Western blot for Id1/3\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifies CD44-ACVR2B interaction; functional Id1/3 regulation confirmed; single lab\",\n      \"pmids\": [\"30297743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Id1 ablation protects hematopoietic stem cells from stress-induced exhaustion: cytokine induction of Id1 drives HSC proliferation, mitochondrial biogenesis, and ROS production; Id1-/- HSCs are quiescent, accumulate less DNA damage, and display a blunted proliferative response to γ-irradiation, genotoxic stress, and aging.\",\n      \"method\": \"Id1 genetic ablation; serial bone marrow transplantation; BrdU proliferation assay; ROS measurement; mitochondrial biogenesis assay; γ-irradiation model\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (proliferation, ROS, DNA damage, transplantation) in a defined genetic model; replicated across multiple stress conditions\",\n      \"pmids\": [\"30082068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ID1 expression is selected for in pancreatic ductal adenocarcinoma to escape TGFβ-induced tumor suppression: ID1 uncouples TGFβ-induced EMT from apoptosis by preventing the imbalance of SOX4 and KLF5 that normally triggers cell death; AKT signaling converges on ID1 to preserve its expression, and TGFβ-mediated repression of ID1 is evaded during PDA progression.\",\n      \"method\": \"Genetic loss-of-function and gain-of-function of ID1 in pancreatic progenitor cells; TGFβ treatment; apoptosis and EMT assays; analysis of PDA patient samples for ID1 genetic/epigenetic alterations; AKT inhibitor experiments\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation in multiple systems with mechanistic pathway dissection; supported by clinical genomics; single lab\",\n      \"pmids\": [\"31582374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRISPR-mediated knockout of ID1 in glioblastoma, breast adenocarcinoma, and melanoma cells dramatically reduces tumor progression through transcriptional downregulation of EGF, resulting in decreased EGFR phosphorylation; ID1-positive cells are enriched by temozolomide chemotherapy and drive tumor recurrence.\",\n      \"method\": \"CRISPR-Cas9 knockout of ID1 in three cancer cell lines; EGF/EGFR expression and phosphorylation analysis; in vivo tumor growth assays; temozolomide treatment and recurrence tracking\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO replicated across three independent cancer systems with mechanistic EGF/EGFR downstream link\",\n      \"pmids\": [\"31292163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Salt-inducible kinase 1 (SIK1) negatively regulates Id1 expression in osteoblasts by phosphorylating CRTC1, preventing CRTC1 from enhancing CREB transcriptional activity at osteogenic genes including Id1; BMP2 suppresses SIK1 via PKA to permit Id1 expression and osteogenesis.\",\n      \"method\": \"SIK1 gene knockdown in primary preosteoblasts; SIK1-KO mice; CRTC1 phosphorylation assays; osteoblast differentiation and bone mineralization assays; BMP2/PKA pathway inhibitor experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assay and KO mice with functional osteogenesis readout; single lab with multiple methods\",\n      \"pmids\": [\"31672960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ID1 confers cancer cell chemoresistance through a STAT3/ATF6-mediated induction of autophagy: ID1 activates NF-κB p65 nuclear translocation, which increases IL-6 secretion, activating STAT3 (Y705 phosphorylation), which transcriptionally upregulates ATF6 to induce ER stress-dependent autophagy and resistance to cisplatin/paclitaxel.\",\n      \"method\": \"ID1 overexpression/siRNA in ovarian cancer cells; luciferase assays for NF-κB and STAT3/ATF6 promoters; IL-6 ELISA; phosphorylation Western blot; autophagy assays; clinical correlation in 1104 HGSOC samples\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequential pathway dissection with multiple reporter assays, phosphorylation analysis, and functional autophagy/chemoresistance readouts; single lab\",\n      \"pmids\": [\"32080166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Id1-/-Id3-/- sinusoidal endothelial cells (SECs) undergo increased apoptosis due to reduced Bcl2-family gene expression, and show increased p21/p27 expression and impaired proliferation; reduced E2-2 expression rescues proliferation, demonstrating that Id1/Id3 maintain BM SEC survival and regeneration by suppressing E-protein activity.\",\n      \"method\": \"Conditional Id1/Id3 deletion in adult ECs; SEC apoptosis assays; Bcl2 family gene expression; p21/p27 analysis; E2-2 knockdown rescue; irradiation survival model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic model with mechanistic E2-2 rescue and multiple cellular readouts; single lab\",\n      \"pmids\": [\"32348770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BMP signaling controls id1 expression in neural stem cells through conserved Smad1/5 and Smad4 binding motifs in a cis-regulatory module (CRM): deletion mapping and mutation of these binding sites in stable transgenic zebrafish reveal that BMP-Smad signaling is required for id1 expression in radial glial NSCs under both homeostatic and regenerative neurogenesis.\",\n      \"method\": \"Systematic CRM deletion mapping in stable transgenic zebrafish; Smad binding site mutation; pharmacological BMP pathway inhibition; transcriptome analysis of injured/uninjured telencephala\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct cis-regulatory mapping with binding site mutagenesis in stable transgenics plus pharmacological and transcriptomic validation\",\n      \"pmids\": [\"32246536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"rHDL-apoE3 promotes endothelial cell migration through ID1-mediated activation of ERK1/2 and AKT: siRNA silencing of ID1 markedly reduces rHDL-apoE3-triggered EC migration and inhibits phosphorylation of ERK1/2 and AKT, placing ID1 upstream of MEK1/2 and PI3K pathways in EC migration.\",\n      \"method\": \"siRNA-mediated ID1 knockdown in HCAEC and EA.hy926 cells; wound healing and transwell migration assays; Western blot for phospho-ERK1/2, AKT, eNOS, p38 MAPK; pathway inhibitors PD98059 and LY294002\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA epistasis with phosphorylation readouts and functional migration assay; single lab\",\n      \"pmids\": [\"34875308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ID1 in tumor-associated macrophages (TAMs) interacts with STAT1 to promote its cytoplasmic distribution, inhibiting STAT1-mediated transcription of SerpinB2 and CCL4, two secretory factors that suppress cancer stemness and recruit CD8+ T cells; reducing ID1 in TAMs ameliorates CRC progression and improves immunotherapy sensitivity.\",\n      \"method\": \"Co-immunoprecipitation of ID1 with STAT1; STAT1 subcellular localization assays; SerpinB2/CCL4 promoter analysis; ID1 knockdown in TAMs; CD8+ T cell infiltration measurement; in vivo CRC tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrates ID1-STAT1 interaction; localization assay links to function; mechanistic transcriptional target identification; in vivo validation; single lab with multiple methods\",\n      \"pmids\": [\"37996458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ID1 in bone marrow mesenchymal stem cells promotes AML progression through a non-cell-autonomous mechanism: ID1 interacts with RNF4 (E3 ubiquitin ligase), reducing SP1 ubiquitination; preserved SP1 drives Angptl7 expression in the microenvironment, which supports AML cell proliferation.\",\n      \"method\": \"ID1-interactome analysis by proteomics; Co-IP of ID1 with RNF4; SP1 ubiquitination assays; ID1 truncation to disrupt ID1-RNF4 interaction; AML co-culture and mouse model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proteomics interactome, direct Co-IP, ubiquitination assay, and truncation mutant; in vivo validation; single lab\",\n      \"pmids\": [\"37319434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CASK physically interacts with Id1: yeast two-hybrid screening identified Id1 as a novel CASK-interacting protein, confirmed by endogenous co-immunoprecipitation from ECV304 cells; mammalian two-hybrid assays show differential CASK binding to Id1 and its alternative splicing variant.\",\n      \"method\": \"Yeast two-hybrid screening; co-immunoprecipitation of endogenous CASK and Id1; mammalian two-hybrid interaction assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP confirmation; no functional mechanism established beyond growth correlation\",\n      \"pmids\": [\"15694377\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ID1 is a dominant-negative HLH protein that lacks a DNA-binding domain and acts primarily by heterodimerizing with bHLH transcription factors (E-proteins, tissue-specific bHLH factors) to inhibit their DNA binding and transcriptional activity, thereby suppressing differentiation across multiple lineages (B cells, neural, mammary, muscle, adipose); its transcription is directly induced by BMP-Smad1/4/5 signaling through a conserved BRE in its promoter, as well as by PGE2-EP4-ERK1/2-Egr1 and JAK2V617F-STAT5 pathways; ID1 protein stability and localization are regulated by ubiquitin-proteasome degradation (via Smurf2 E3 ligase and the COP9 signalosome), by heterodimerization with E-proteins that stabilize it, and by PKA-regulated CRM1-dependent nuclear export during angiogenesis; downstream, ID1 promotes cell survival and proliferation by activating NF-κB, suppressing PTEN transcription to activate Akt/Wnt signaling, restraining p21 expression, transcriptionally repressing TSP-1 (promoting angiogenesis) and STAT1-mediated target genes (promoting immunosuppression), suppressing CULLIN3 to stabilize oncogenic substrates, and activating the pentose phosphate pathway; in stem cells, ID1 maintains quiescence and self-renewal in LT-HSCs and adult neural stem cells, and its loss or gain dictates cell fate in hematopoietic, neural, and adipose progenitor compartments.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ID1 is a dominant-negative helix-loop-helix protein that controls the balance between differentiation, proliferation, and survival across hematopoietic, neural, mammary, endothelial, and adipose lineages, acting as a downstream node of BMP and other growth-factor signals [#0, #2, #16]. By heterodimerizing with bHLH E-proteins (E12/E47), ID1 sequesters them from DNA and blocks lineage differentiation programs—impairing V(D)J recombination and B cell development, preventing beta-casein induction in mammary epithelium, and destabilizing the proneural factor Mash1 by shifting the E47/Id1 ratio [#0, #1, #5]; reciprocally, E-protein binding stabilizes ID1 protein and alters its localization [#7]. Beyond E-protein antagonism, ID1 engages additional transcriptional partners directly—binding TFAP2A to suppress S100A9, PGC1\\u03b1 and Ebf2 to suppress brown-adipose thermogenic programs, and STAT1 in tumor-associated macrophages to drive its cytoplasmic retention and silence SerpinB2/CCL4 [#19, #27, #39]. ID1 transcription is induced through a BMP-responsive element bound by Smad1/5 and Smad4, and through parallel PGE2-EP4-ERK1/2-Egr1 and JAK2-STAT5 cascades, while it is repressed by p53 acting via DEC1 and BMP-Smad1 [#22, #37, #13, #24, #15, #6, #21]. ID1 abundance is set by ubiquitin-proteasome degradation through the COP9 signalosome and the Smurf2 E3 ligase, and its nuclear export is controlled by PKA-regulated CRM1-dependent shuttling during angiogenesis [#8, #18, #9]. Functionally, ID1 promotes survival and proliferation by activating NF-\\u03baB, suppressing PTEN to engage Akt/Wnt signaling, restraining p21/p27, repressing thrombospondin-1 to enable angiogenesis, suppressing CULLIN3 to stabilize GLI2/DVL2, and activating the pentose phosphate pathway to lower ROS [#4, #14, #10, #3, #25, #29]. In stem-cell compartments ID1 maintains long-term HSC and adult neural stem cell self-renewal and dictates their proliferative versus quiescent state, with its loss protecting HSCs from stress-induced exhaustion [#11, #16, #31]. These activities make ID1 a recurrent driver of tumor progression, chemoresistance, metastasis, and immunosuppression across multiple cancers [#23, #33, #35, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that ID1 functions in vivo as a dominant-negative inhibitor of bHLH factors that blocks lineage differentiation, using B lymphopoiesis as the first defined system.\",\n      \"evidence\": \"Constitutive Id1 expression in transgenic mice with B cell phenotyping\",\n      \"pmids\": [\"8001126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the specific bHLH partners sequestered in B cells\", \"Did not address whether the same mechanism operates in other lineages\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed ID1 inhibits differentiation bidirectionally in epithelial cells and promotes invasive behavior, generalizing its anti-differentiation role beyond hematopoiesis.\",\n      \"evidence\": \"Overexpression and antisense knockdown in SCp2 mammary epithelial cells with beta-casein and 3D morphology readouts\",\n      \"pmids\": [\"7760836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners mediating beta-casein suppression not defined\", \"Mechanism of basement-membrane invasion not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Genetic loss-of-function established ID1 (with ID3) as required for proper timing of neuronal differentiation and for tumor angiogenesis/vascular invasion in vivo.\",\n      \"evidence\": \"Id1/Id3 double-knockout mice with neurogenesis and xenograft angiogenesis analysis\",\n      \"pmids\": [\"10537105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy between Id1 and Id3 not separated\", \"Downstream angiogenic effectors not yet identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified thrombospondin-1 as a major downstream effector through which ID1 promotes angiogenesis, providing the first molecular target explaining the vascular phenotype.\",\n      \"evidence\": \"Subtractive hybridization on Id1-null MEFs plus in vitro and in vivo TSP-1 neutralization rescue\",\n      \"pmids\": [\"12498716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ID1 represses TSP-1 transcriptionally not defined\", \"Cell type in which repression is most relevant not pinned down\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined a survival mechanism in which ID1 activates NF-\\u03baB to confer apoptosis resistance, linking ID1 to anti-apoptotic signaling in cancer.\",\n      \"evidence\": \"Bidirectional Id1 manipulation in prostate cancer cells with NF-\\u03baB reporter, fractionation, and apoptosis assays\",\n      \"pmids\": [\"12881706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between ID1 and NF-\\u03baB activation not established\", \"Whether effect is transcription-factor sequestration or another route unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected ID1 to proliferation/senescence control by showing DNA damage represses ID1 via p53/DEC1 and that ID1 overexpression restrains p21 and blunts senescence.\",\n      \"evidence\": \"DNA damage, DEC1 siRNA, ID1 promoter mapping, and proliferation/senescence assays\",\n      \"pmids\": [\"18556654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ID1 represses p21 mechanistically not resolved\", \"Direct p53/DEC1 binding kinetics on ID1 promoter not detailed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that ID1 controls proneural factor stability by shifting the E47/Id1 ratio to degrade Mash1, mechanistically tying ID1 dosage to neural differentiation output.\",\n      \"evidence\": \"BMP-2 treatment, Id1 gain/loss, E47 overexpression, and pulse-chase stability assays in neuroendocrine cells\",\n      \"pmids\": [\"15318167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase degrading Mash1 not identified\", \"Relevance to normal neurogenesis vs. carcinoma not separated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that E-protein heterodimerization is itself a stability switch for ID1, showing partner binding controls ID1 half-life and localization.\",\n      \"evidence\": \"Co-transfection of E12/E47 with Id1, pulse-chase degradation kinetics, NLS-mutant localization, and proteasome inhibition\",\n      \"pmids\": [\"16007194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ligase governing free vs. bound ID1 not identified here\", \"How localization change maps to function not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the COP9 signalosome as a regulator of ID1/ID3 ubiquitin-dependent degradation, distinguishing ID1/ID3 from ID2/ID4 at the level of turnover.\",\n      \"evidence\": \"Two-hybrid, pulldown and far-Western with CSN5, His-ubiquitin assays, and CSN-kinase inhibitor treatment\",\n      \"pmids\": [\"15451666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The cognate E3 ligase acting with CSN not defined here\", \"Physiological contexts where CSN sets ID1 levels not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed ID1 localization is dynamically regulated by PKA-controlled CRM1-dependent nuclear export during capillary morphogenesis, adding spatial control to ID1 function.\",\n      \"evidence\": \"Live GFP-Id1 imaging in HUVECs, leptomycin B, PKA modulators, and Ser-5 mutagenesis\",\n      \"pmids\": [\"17412691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of cytoplasmic ID1 not directly demonstrated\", \"Export receptor binding site not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed ID1 upstream of p21 in endothelial progenitor cell generation, with genetic p21 ablation rescuing the Id1-null EPC and angiogenesis defects.\",\n      \"evidence\": \"Id1-KO, p21-KO, and double-KO mice with EPC flow cytometry and tumor growth assays\",\n      \"pmids\": [\"18092003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ID1 restrains p21 in EPCs mechanistically not defined\", \"Cell-autonomy of the EPC defect not fully separated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined a non-redundant, Id3-independent requirement for ID1 in long-term HSC self-renewal, distinguishing ID family members functionally in hematopoiesis.\",\n      \"evidence\": \"Id1-GFP knock-in and serial bone marrow transplantation with Id3-KO control\",\n      \"pmids\": [\"17622570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"bHLH partners ID1 sequesters in LT-HSCs not identified\", \"Whether the role is intrinsic vs. niche not resolved here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a non-cell-autonomous niche role for ID1 in hematopoiesis through altered stromal cytokine production, complicating the intrinsic-stem-cell view.\",\n      \"evidence\": \"Reciprocal WT/Id1-KO bone marrow transplantation and stromal cytokine assays\",\n      \"pmids\": [\"19478045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific cytokines and their bHLH-dependent regulation not defined\", \"Reconciliation with intrinsic LT-HSC role not provided\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed ID1 acts as a positive feedback amplifier of BMP signaling by promoting Twist-1 degradation to de-repress BMP targets.\",\n      \"evidence\": \"Co-IP in MC3T3-E1 cells, Twist-1 stability assays, and osteoblast differentiation readouts\",\n      \"pmids\": [\"17374642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect promotion of Twist-1 degradation not distinguished\", \"E3 ligase involved not identified\", \"Single lab, limited mutagenesis\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped a PGE2-EP4-EGFR-ERK1/2-Egr1 cascade that transcriptionally induces ID1, linking inflammatory eicosanoid signaling to ID1 in epithelial invasion.\",\n      \"evidence\": \"EP4 agonist, EGFR/ERK inhibitors, COX-2 siRNA, and ChIP for Egr-1 at the Id-1 promoter\",\n      \"pmids\": [\"18842581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the cascade beyond mammary cells not tested here\", \"Other Egr-1 cofactors at the promoter not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined an ID1\\u2192p53\\u2192PTEN\\u2192Akt/Wnt axis, showing ID1 activates proliferative signaling by transcriptionally suppressing PTEN.\",\n      \"evidence\": \"Id1 overexpression in MCF7, ChIP and promoter deletion for p53 at the PTEN promoter, and pathway/reporter readouts\",\n      \"pmids\": [\"19079342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ID1 downregulates p53 not mechanistically resolved\", \"In vivo relevance not addressed in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified ID1 as a JAK2-STAT5 transcriptional target supporting erythroid survival, linking ID1 to myeloproliferative disease driven by JAK2V617F.\",\n      \"evidence\": \"ChIP for STAT5 at an ID1 enhancer plus ID1 gain/loss in primary erythroid differentiation\",\n      \"pmids\": [\"19571317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"bHLH targets of ID1 in erythroid survival not defined\", \"Causal role in PV pathogenesis not directly tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed Id1-high marks self-renewing adult neural stem cells and that Id genes are required for asymmetric self-renewal capacity.\",\n      \"evidence\": \"Id1-GFP knock-in reporter, FACS, neurosphere/transplantation assays, and Id knockout\",\n      \"pmids\": [\"19896442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking Id1 dosage to asymmetric division not defined\", \"Partner factors in NSCs not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a partner-mediated metastasis pathway: ID1 binds TFAP2A to suppress S100A9 and elevate RhoC, providing a transcriptional route to invasion.\",\n      \"evidence\": \"Co-IP of Id1-TFAP2A and S100A9 rescue in migration/invasion and in vivo metastasis assays\",\n      \"pmids\": [\"24948111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ID1-TFAP2A interaction interface not mapped\", \"Single lab; reciprocal validation limited\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated ID1 and E47 cooperate to maintain a mesenchymal EMT phenotype through mechanisms beyond classic dominant-negative repression of E-cadherin.\",\n      \"evidence\": \"Reciprocal Co-IP of E47 and Id1, ChIP at E-cadherin promoter, and Id1 knockdown in EMT cells\",\n      \"pmids\": [\"23555842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The non-dominant-negative mechanism not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed p53 represses ID1 via BMP-Smad1-dependent and -independent routes, with ID1 controlling both proliferation and differentiation in neural stem cells.\",\n      \"evidence\": \"p53-KO NSCs, Smad1 siRNA, BrdU labeling, and differentiation assays\",\n      \"pmids\": [\"23199293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The Smad1-independent repression mechanism not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the BMP-responsive element as necessary and sufficient for ID1 induction by serum, anchoring BMP-Smad as the principal upstream activator.\",\n      \"evidence\": \"ID1 promoter mapping, Smad4 siRNA, noggin/dorsomorphin, and BMP2 stimulation in fibroblasts\",\n      \"pmids\": [\"23948603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Smad cofactors at the BRE not enumerated\", \"Cell-type specificity of BRE usage not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified ID1 as a key mediator of tumor-induced immunosuppression by switching dendritic cell differentiation toward myeloid-derived suppressor cell expansion downstream of TGF\\u03b2.\",\n      \"evidence\": \"Bidirectional Id1 genetic manipulation in mice with DC differentiation and CD8 T-cell proliferation assays\",\n      \"pmids\": [\"25924227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets in myeloid cells not defined here\", \"Link to later STAT1 mechanism not made\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed PGE2-EP4-ERK1/2-Egr1 induction of ID1 is required for glioblastoma stem-cell self-renewal and radiation resistance, extending the eicosanoid-ID1 axis to brain cancer.\",\n      \"evidence\": \"dmPGE2 with EP4/ERK/Egr1 inhibitors and siRNA, ChIP for Egr1, and sphere/radiation assays\",\n      \"pmids\": [\"27022132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"bHLH effectors of self-renewal downstream of ID1 not identified\", \"Mechanism of radiation resistance not detailed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined an ID1\\u2192CULLIN3 suppression mechanism stabilizing GLI2/DVL2 and CYCLIN E to drive glioblastoma stem-cell tumorigenicity.\",\n      \"evidence\": \"ID1 gain/loss in GSCs, CULLIN3 interactome proteomics, ubiquitination assays, and in vivo tumorigenicity\",\n      \"pmids\": [\"27477274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ID1 suppresses CULLIN3 transcriptionally/post-transcriptionally not resolved\", \"Direct vs. indirect link unproven\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed AP-1 (c-Jun/c-Fos) drives ID1 induction upon genotoxic stress to confer apoptosis resistance, adding a stress-responsive transcriptional input to ID1.\",\n      \"evidence\": \"AP-1 site mutagenesis in the ID1 promoter, c-Jun/c-Fos/ID1 knockdown, and caspase 3/PARP assays\",\n      \"pmids\": [\"26858249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AP-1 binding by ChIP not shown here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified direct ID1 binding to PGC1\\u03b1 and Ebf2 to suppress brown/beige adipose thermogenesis, expanding ID1's partner repertoire to metabolic transcription factors.\",\n      \"evidence\": \"Adipose-specific Id1 transgenic and Id1-deficient models with Co-IP and thermogenic phenotype analysis\",\n      \"pmids\": [\"28270523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interaction interfaces and stoichiometry not mapped\", \"Whether suppression is HLH-dependent not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined an ID1\\u2192MYC\\u2192miR-17/20a axis suppressing BMPR2 to block BMP differentiation signaling while activating WNT/SHH in glioblastoma stem cells.\",\n      \"evidence\": \"ID1 gain/loss in GSCs, miRNA/BMPR2 analysis, WNT/SHH inhibitors, and in vivo survival\",\n      \"pmids\": [\"29208670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ID1 increases MYC not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked ID1 to metabolic chemoresistance by showing it activates the pentose phosphate pathway via G6PD/Wnt/c-MYC to lower ROS.\",\n      \"evidence\": \"ID1 shRNA in oxaliplatin-resistant HCC, G6PD promoter luciferase, NADPH/ROS measurement, and xenografts\",\n      \"pmids\": [\"29169374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect G6PD promoter regulation not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected pericellular matrix to ID1 regulation, showing hyaluronic acid-CD44 association with the BMP receptor ACVR2B enhances BMP4/7-driven Id1/3 expression.\",\n      \"evidence\": \"HA/CD44 depletion, exogenous HA, and Co-IP of CD44 with ACVR2B in melanoma cells\",\n      \"pmids\": [\"30297743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CD44-ACVR2B interaction is direct not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed ID1 drives stress-induced HSC exhaustion: cytokine-induced ID1 promotes proliferation, mitochondrial biogenesis and ROS, while Id1 loss enforces protective quiescence.\",\n      \"evidence\": \"Id1 genetic ablation with serial transplantation, BrdU, ROS, mitochondrial assays, and irradiation/aging stress\",\n      \"pmids\": [\"30082068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"bHLH targets enforcing quiescence not identified\", \"How ID1 induces mitochondrial biogenesis not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined ID1 as the factor selected during pancreatic cancer to uncouple TGF\\u03b2-driven EMT from apoptosis by preventing SOX4/KLF5 imbalance, with AKT preserving ID1 expression.\",\n      \"evidence\": \"ID1 gain/loss in pancreatic progenitors with TGF\\u03b2 treatment, apoptosis/EMT assays, AKT inhibition, and patient genomics\",\n      \"pmids\": [\"31582374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ID1 maintains SOX4/KLF5 balance mechanistically not detailed\", \"Direct ID1 partners in this context not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CRISPR knockout across three cancer types showed ID1 sustains tumor progression through transcriptional EGF upregulation and EGFR phosphorylation, and that ID1+ cells drive chemotherapy recurrence.\",\n      \"evidence\": \"CRISPR-Cas9 ID1 KO in glioblastoma, breast, and melanoma cells with EGF/EGFR analysis and in vivo growth/temozolomide tracking\",\n      \"pmids\": [\"31292163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ID1 upregulates EGF transcriptionally not defined\", \"Direct promoter mechanism not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped an ID1\\u2192NF-\\u03baB\\u2192IL-6\\u2192STAT3\\u2192ATF6 cascade inducing autophagy to confer platinum/taxane chemoresistance in ovarian cancer.\",\n      \"evidence\": \"ID1 gain/loss with NF-\\u03baB/STAT3/ATF6 reporters, IL-6 ELISA, autophagy assays, and clinical HGSOC correlation\",\n      \"pmids\": [\"32080166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from ID1 to NF-\\u03baB activation not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed Id1/Id3 maintain bone marrow sinusoidal endothelial cell survival and regeneration by suppressing E-protein E2-2 activity, with E2-2 knockdown rescuing proliferation.\",\n      \"evidence\": \"Conditional Id1/Id3 deletion in adult ECs with apoptosis, Bcl2-family, p21/p27 analysis, and E2-2 rescue\",\n      \"pmids\": [\"32348770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct E2-2 targets driving Bcl2/p21/p27 not enumerated\", \"Relative contribution of Id1 vs Id3 not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed BMP-Smad1/5/Smad4 binding motifs in a conserved cis-regulatory module drive id1 expression in radial glial neural stem cells in vivo across homeostatic and regenerative neurogenesis.\",\n      \"evidence\": \"CRM deletion/mutation in stable transgenic zebrafish with BMP inhibition and transcriptomics\",\n      \"pmids\": [\"32246536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Smad-associated cofactors at the CRM not defined\", \"Conservation of this CRM in mammals not tested here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed ID1 upstream of ERK1/2 and AKT in endothelial migration triggered by rHDL-apoE3, extending ID1's role to lipoprotein-stimulated angiogenic signaling.\",\n      \"evidence\": \"ID1 siRNA in HCAEC/EA.hy926 with migration assays and phospho-ERK/AKT readouts plus pathway inhibitors\",\n      \"pmids\": [\"34875308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ID1 activates ERK/AKT mechanistically not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified ID1-STAT1 interaction in tumor-associated macrophages as a driver of immunosuppression by promoting STAT1 cytoplasmic retention to silence SerpinB2 and CCL4.\",\n      \"evidence\": \"Co-IP of ID1 with STAT1, STAT1 localization assays, target promoter analysis, and in vivo CRC immunotherapy model\",\n      \"pmids\": [\"37996458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ID1-STAT1 interaction interface not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a niche mechanism whereby ID1 in mesenchymal stem cells interacts with the E3 ligase RNF4 to stabilize SP1 and drive Angptl7, promoting AML in a non-cell-autonomous manner.\",\n      \"evidence\": \"ID1 interactome proteomics, Co-IP with RNF4, SP1 ubiquitination assays, truncation mutants, and AML mouse model\",\n      \"pmids\": [\"37319434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ID1 inhibits RNF4 catalytically not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Despite extensive partner and pathway mapping, the structural basis and partner-selection rules governing which bHLH and non-bHLH factors ID1 sequesters in a given lineage, and how its many context-specific transcriptional outputs are coordinated, remain unresolved.\",\n      \"evidence\": \"No timeline discovery provides a structural model or systematic partner-affinity hierarchy\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ID1-partner complexes in the corpus\", \"Rules dictating lineage-specific partner choice undefined\", \"Integration of competing transcriptional outputs not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 5, 19, 27, 39]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 12, 19, 27, 39, 40]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [22, 14, 13, 24, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 5, 19, 27, 39]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 16, 11, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 23, 39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [25, 32, 33, 35]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 8, 18, 25, 40]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"E47\", \"E12\", \"TFAP2A\", \"PGC1A\", \"EBF2\", \"STAT1\", \"RNF4\", \"CUL3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}