{"gene":"LIN9","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2004,"finding":"Human LIN9 (hLin-9) physically binds to pRB (retinoblastoma protein) and cooperates with pRB in flat cell formation and transactivation of an osteoblast-specific reporter gene. hLin-9 associates with partially penetrant pRB mutants that cannot bind E2F but retain transcriptional activation ability, indicating the LIN9-pRB interaction is distinct from E2F-pRB interaction. RNAi knockdown of LIN9 can substitute for loss of pRB in oncogenic transformation of human primary fibroblasts, demonstrating LIN9's tumor-suppressing activity is mediated through pRB.","method":"Co-immunoprecipitation, RNAi knockdown, reporter gene transactivation assays, flat cell formation assay in Saos-2 cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, functional rescue assays, multiple orthogonal methods in single focused study","pmids":["15538385"],"is_preprint":false},{"year":2000,"finding":"C. elegans lin-9 functions in an Rb-related pathway that antagonizes receptor tyrosine kinase/Ras signaling to control vulval induction, and is also required for gonadal sheath cell development and male spicule/ray/gonad development. lin-9 encodes a novel protein of 642-644 amino acids with conserved orthologs in Drosophila and vertebrates, founding a new protein family that functions in Rb-related pathways.","method":"Genetic epistasis analysis, loss-of-function mutant characterization, cDNA cloning and sequence analysis in C. elegans","journal":"Gene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in founding organism study, replicated across multiple developmental phenotypes","pmids":["10974557"],"is_preprint":false},{"year":2006,"finding":"Human LIN-9 is required for transcription of G2/M genes and for entry into mitosis. LIN-9 associates with B-MYB, and both LIN-9 and B-MYB bind directly to the promoters of G2/M-regulated genes as shown by chromatin immunoprecipitation. Depletion of LIN-9 by RNAi strongly impairs proliferation and delays G2-to-M progression. Depletion of B-MYB recapitulates the LIN-9 knockdown phenotype, indicating LIN-9 and B-MYB co-activate G2/M gene expression.","method":"RNAi knockdown, chromatin immunoprecipitation (ChIP), co-immunoprecipitation, proliferation assays, cell cycle analysis in human fibroblasts","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, co-IP, RNAi phenotype), replicated with B-MYB knockdown","pmids":["17159899"],"is_preprint":false},{"year":2009,"finding":"In F9 embryonal carcinoma cells, B-Myb is found in complexes with Lin-9 and other LINC constituents (but not pocket proteins, which only associate with LINC upon differentiation). B-Myb recruits Lin-9 to the Survivin promoter through multiple Myb-binding sites. Both B-Myb and Lin-9 are required for transcription of G2/M genes (Cyclin B1, Survivin). Loss of Lin-9 causes mitotic arrest in F9 cells.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, RNAi knockdown, reporter assays, cell cycle analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP showing B-Myb recruits Lin-9 to promoter, multiple orthogonal methods, independent replication of LINC complex concept","pmids":["19252525"],"is_preprint":false},{"year":2009,"finding":"Lin9 depletion in zebrafish embryos causes accumulation of cells in mitosis followed by apoptosis, particularly in the developing central nervous system. A cohort of Lin9-regulated mitotic genes required for mitotic entry, metaphase/anaphase transition, and cytokinesis was identified, establishing LIN9 as an essential regulator of mitosis in vertebrate development.","method":"Antisense morpholino knockdown in zebrafish, flow cytometry, confocal microscopy, gene expression profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with specific mitotic phenotype, gene target identification, replicated concept from human cell studies","pmids":["19278998"],"is_preprint":false},{"year":2010,"finding":"Lin9 is an essential core subunit of the mammalian DREAM complex. Genetic knockout of Lin9 is lethal in early embryonic development and in adult mice. Loss of Lin9 abolishes proliferation and causes multiple mitotic and cytokinesis defects due to loss of expression of mitotic genes including Plk1, Aurora A, and Kif20a. Lin9 heterozygous mice are more susceptible to oncogenic c-Raf-induced lung tumorigenesis, indicating haploinsufficient tumor suppressor function.","method":"Conditional and constitutive knockout mouse models, gene expression analysis, proliferation assays, tumor induction by oncogenic c-Raf","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with embryonic lethality, adult viability, and tumor susceptibility phenotypes; multiple orthogonal readouts","pmids":["20404087"],"is_preprint":false},{"year":2011,"finding":"Loss of LIN9 triggers premature senescence via upregulation of p16(INK4a) and p21(Waf1), implicating the pRB and p53 tumor suppressor pathways. SV40 large T antigen can overcome this senescence. LIN9-null cells that escape senescence exhibit chromosomal instability due to compromised mitotic fidelity, and SV40 LT-expressing LIN9-null cells grow anchorage-independently in soft agar.","method":"Gene knockout in mouse cells, immunoblotting for p16/p21, soft agar anchorage-independent growth assay, chromosomal instability analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined senescence pathway readouts (p16, p21), rescue by SV40 LT, multiple functional assays","pmids":["21860417"],"is_preprint":false},{"year":2011,"finding":"In hepatocellular carcinoma cells, LIN9 forms a complex with MYBL2 (B-Myb) termed LINC. The integrity of the MYBL2-LIN9 complex is required for survival of DNA-damaged p53-null cells. Doxorubicin treatment causes LIN9 dissociation from MYBL2 in p53-positive cells (leading to p21(WAF1) upregulation) but increases MYBL2-LIN9 complexes in p53-null cells. siRNA-mediated silencing of MYBL2/LINC reduces proliferation and induces apoptosis.","method":"Co-immunoprecipitation, siRNA knockdown, proliferation assays, apoptosis assays, immunoblotting in HCC cell lines","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and siRNA in multiple cell lines with functional readouts, single lab","pmids":["21480327"],"is_preprint":false},{"year":2014,"finding":"Cyclin E1/Cdk3 phosphorylates LIN-9 on Threonine-96. Mutation of Thr-96 to alanine inhibits activation of cyclin A2 and B1 promoters, whereas a phosphomimetic Asp mutant strongly activates these promoters and triggers accelerated entry into G2/M phase. This establishes a role for cyclin E1 in S/G2 phase through LIN-9 phosphorylation to induce expression of subsequent cyclins.","method":"In vitro kinase assay, site-directed mutagenesis (T96A and T96D mutants), promoter reporter assays, cell cycle analysis in 293T cells","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional promoter validation, single lab but multiple orthogonal methods","pmids":["24475316"],"is_preprint":false},{"year":2017,"finding":"LIN9 is a direct transcriptional target of BET bromodomain proteins in triple-negative breast cancer cells. BET inhibition suppresses LIN9 expression, leading to prolonged mitotic progression and mitotic cell death (mitotic catastrophe). LIN9 mediates the effects of BET proteins on mitosis. The LIN9 gene lacks a super-enhancer but is amplified or overexpressed in the majority of TNBCs.","method":"Live cell imaging, BET inhibitor treatment, RNAi knockdown of LIN9, ChIP for BET proteins at LIN9 locus, gene expression analysis in TNBC cell lines","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live imaging plus ChIP plus genetic knockdown with defined mitotic phenotype, single lab but orthogonal methods","pmids":["28807940"],"is_preprint":false},{"year":2019,"finding":"LIN9 promotes paclitaxel resistance in triple-negative breast cancer cells at least in part by directly regulating the microtubule-binding protein CCSAP. LIN9 expression is elevated in paclitaxel-resistant TNBC cell lines. Knockdown of LIN9 or BETi treatment reduces LIN9 expression, promotes multinucleated cell formation, and restores paclitaxel sensitivity.","method":"qRT-PCR, Western blot, siRNA knockdown, MTS cell viability assay, flow cytometry for apoptosis in TNBC cell lines and resistant sublines","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — knockdown with functional readout and identification of downstream target CCSAP, single lab, limited mechanistic depth on LIN9-CCSAP interaction","pmids":["31420851"],"is_preprint":false},{"year":2020,"finding":"LIN9 transcriptionally regulates NEK2 (NIMA-related kinase 2) expression in taxane-resistant breast cancer cells. Elevated LIN9 in taxane-resistant cells sustains NEK2 expression and centrosome separation. Genetic or pharmacologic inhibition of LIN9 (via BET inhibitors) or NEK2 in combination with paclitaxel synergistically induces mitotic abnormalities in nearly 100% of cells and restores paclitaxel sensitivity in vitro and in vivo, including in patient-derived xenografts.","method":"Computational target identification, genetic knockdown, pharmacologic NEK2 inhibition, in vitro mitosis assays, in vivo TNBC xenograft and PDX models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockdown plus pharmacologic validation plus in vivo models including PDX; LIN9/NEK2 pathway independently validated by multiple approaches","pmids":["32054769"],"is_preprint":false},{"year":2024,"finding":"In vascular smooth muscle cells, IL-1β (downstream of NLRP3 activation) promotes BRD4 recruitment to the LIN9 locus, enhancing LIN9 expression. LIN9 then binds to the promoter region of AURKA, promoting its transcription and subsequently upregulating FOXM1, thereby mediating VSMC proliferation, migration, and paclitaxel resistance. JQ1 (BET inhibitor) inhibits BRD4-mediated LIN9 upregulation and shows synergy with PTX.","method":"RNA sequencing, ChIP assay (LIN9 binding to AURKA promoter, BRD4 binding to LIN9 locus), siRNA knockdown, in vivo rat restenosis model","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct LIN9 promoter binding at AURKA, upstream BRD4 recruitment shown by ChIP, in vivo validation, single lab but orthogonal methods","pmids":["39334121"],"is_preprint":false},{"year":2024,"finding":"E2F4 physically interacts with LIN9 in hepatocellular carcinoma cells, as demonstrated by co-immunoprecipitation, immunofluorescence co-localization, and bimolecular fluorescence complementation assays. E2F4 promotes HCC cell proliferation and SUMOylation via LIN9; rescue experiments showed LIN9 facilitates SUMOylation and proliferation driven by E2F4.","method":"Co-immunoprecipitation, immunofluorescence co-localization, bimolecular fluorescence complementation, soft agar assay, Transwell migration assay, Western blotting","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal co-localization/interaction methods, rescue experiment; single lab","pmids":["39239750"],"is_preprint":false},{"year":2025,"finding":"YARS (tyrosyl tRNA synthetase) binds to the LIN9 promoter and facilitates RNA polymerase II recruitment and phosphorylation, and deposition of activating epigenetic marks. YARS interacts with the Trim28 transcriptional regulator. During senescence escape, YARS activates LIN9 expression; both YARS and LIN9 are necessary for the proliferation of senescence-escaping cells.","method":"ChIP assay (YARS binding at LIN9 promoter), co-immunoprecipitation (YARS-Trim28 interaction), RNA polymerase II phosphorylation analysis, epigenetic mark analysis, siRNA knockdown of YARS and LIN9","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at LIN9 promoter plus co-IP for YARS-Trim28, multiple orthogonal methods, single lab, single publication","pmids":["39756023"],"is_preprint":false}],"current_model":"LIN9 is a conserved core subunit of the DREAM multiprotein complex that in quiescent cells (G0/G1) represses cell cycle genes in association with pocket proteins (p130/p107) and E2F4, then switches in S/G2 phase to an activating LINC complex with B-MYB to drive transcription of a large set of G2/M mitotic genes (including Cyclin B1, Survivin, PLK1, Aurora A, Kif20a, NEK2, and AURKA); LIN9's transcriptional activity is modulated by Cyclin E1/Cdk3-mediated phosphorylation on Thr-96, by upstream BRD4/BET-dependent chromatin recruitment, and by YARS-mediated promoter activation, while its physical interaction with pRB mediates tumor-suppressive and differentiation functions distinct from E2F regulation; loss of LIN9 causes mitotic arrest, cytokinesis failure, genomic instability, and premature senescence, whereas overexpression sustains mitotic gene programs that promote taxane resistance in cancer."},"narrative":{"mechanistic_narrative":"LIN9 is a conserved core subunit of the DREAM/LINC transcriptional machinery that couples cell cycle gene expression to mitotic progression in vertebrate cells, functioning within Rb-related pathways first defined genetically in C. elegans [PMID:10974557, PMID:20404087]. As an activator, LIN9 partners with B-MYB (MYBL2) and is recruited to the promoters of G2/M genes such as Cyclin B1 and Survivin, where the two proteins co-activate transcription required for mitotic entry [PMID:17159899, PMID:19252525]. This activity is essential and dose-sensitive: genetic loss abolishes proliferation and produces mitotic and cytokinesis defects through failed expression of mitotic genes including Plk1, Aurora A, and Kif20a, is embryonic lethal in mice, and triggers premature p16/p21-dependent senescence and chromosomal instability, while Lin9 heterozygosity enhances tumorigenesis—establishing a haploinsufficient tumor suppressor function [PMID:19278998, PMID:20404087, PMID:21860417]. Independently of E2F regulation, LIN9 binds pRB and cooperates in transactivation and tumor suppression, such that LIN9 knockdown can substitute for pRB loss in transformation [PMID:15538385]. LIN9 transcriptional output is tuned by Cyclin E1/Cdk3 phosphorylation on Thr-96, which licenses activation of cyclin A2/B1 promoters and accelerates G2/M entry [PMID:24475316], and by upstream BET/BRD4-dependent chromatin recruitment that drives LIN9 expression [PMID:28807940, PMID:39334121]. In cancer, elevated LIN9 sustains mitotic gene programs—directly regulating CCSAP, NEK2, and AURKA/FOXM1—to promote taxane resistance, which BET inhibition reverses [PMID:31420851, PMID:32054769, PMID:39334121].","teleology":[{"year":2000,"claim":"Established LIN9 as the founding member of a conserved protein family acting in Rb-related pathways, answering whether this gene had a defined genetic role in growth control.","evidence":"Genetic epistasis and loss-of-function mutant analysis with cDNA cloning in C. elegans","pmids":["10974557"],"confidence":"High","gaps":["No biochemical mechanism or direct molecular partners defined","Vertebrate function inferred only by orthology at this stage"]},{"year":2004,"claim":"Defined a direct, E2F-independent LIN9-pRB interaction that mediates tumor suppression, distinguishing LIN9 function from classical E2F-pRB control.","evidence":"Co-IP, RNAi knockdown, and reporter/flat-cell transformation assays in human cells","pmids":["15538385"],"confidence":"High","gaps":["Mechanism by which LIN9-pRB suppresses transformation not resolved","Relationship to subsequent DREAM/LINC roles not addressed here"]},{"year":2006,"claim":"Identified LIN9-B-MYB co-activation of G2/M promoters as the mechanism linking LIN9 to mitotic entry, answering how LIN9 controls proliferation.","evidence":"ChIP, co-IP, and RNAi cell cycle/proliferation analysis in human fibroblasts","pmids":["17159899"],"confidence":"High","gaps":["Full subunit composition of the activating complex not enumerated","How LIN9 is recruited to chromatin not yet defined"]},{"year":2009,"claim":"Showed B-MYB recruits LIN9 to specific promoters (Survivin) and that this drives mitotic gene expression across cell types, refining the recruitment logic of the LINC complex.","evidence":"ChIP, reciprocal co-IP, RNAi, and reporter assays in F9 embryonal carcinoma cells; morpholino knockdown in zebrafish","pmids":["19252525","19278998"],"confidence":"High","gaps":["Switch between repressive (pocket protein) and activating states not mechanistically dissected","In vivo target set defined by expression profiling without direct binding for all genes"]},{"year":2010,"claim":"Demonstrated LIN9 is an essential DREAM core subunit and haploinsufficient tumor suppressor in vivo, establishing physiological essentiality and cancer relevance.","evidence":"Conditional/constitutive knockout mice, expression analysis, and c-Raf tumor induction","pmids":["20404087"],"confidence":"High","gaps":["Tissue-specific contributions of LIN9 loss not separated","Mechanism of haploinsufficient tumor susceptibility not fully resolved"]},{"year":2011,"claim":"Connected LIN9 loss to defined senescence and genomic instability pathways and showed LINC integrity supports survival of p53-null damaged cells, clarifying tumor-suppressive versus pro-survival outputs.","evidence":"Gene knockout with p16/p21 immunoblotting and soft-agar assays; co-IP and siLINC in HCC lines with apoptosis readouts","pmids":["21860417","21480327"],"confidence":"High","gaps":["Context-dependence of LIN9 as suppressor versus survival factor not unified","HCC co-IP/siRNA findings are single-lab and Medium confidence"]},{"year":2014,"claim":"Identified Cyclin E1/Cdk3 phosphorylation of LIN9 at Thr-96 as a regulatory switch driving G2/M promoter activation, answering how LIN9 transcriptional activity is timed.","evidence":"In vitro kinase assay, T96A/T96D mutagenesis, promoter reporters, and cell cycle analysis in 293T cells","pmids":["24475316"],"confidence":"High","gaps":["Phosphorylation not validated at endogenous LIN9 in vivo","Effect on complex composition or DNA binding not shown"]},{"year":2017,"claim":"Placed LIN9 downstream of BET bromodomain proteins, showing chromatin-level control of LIN9 expression governs mitotic fidelity in cancer cells.","evidence":"Live imaging, BET inhibitor treatment, ChIP for BET proteins at LIN9, and RNAi in TNBC lines","pmids":["28807940"],"confidence":"High","gaps":["Direct vs indirect BET regulation of additional LIN9 targets not parsed","No structural basis for BET occupancy at the LIN9 locus"]},{"year":2020,"claim":"Defined LIN9-driven transcription of mitotic kinases (CCSAP, NEK2) as a mechanism of taxane resistance, providing actionable combination targets.","evidence":"Knockdown, pharmacologic NEK2/BET inhibition, and in vitro/in vivo TNBC and PDX models","pmids":["31420851","32054769"],"confidence":"High","gaps":["Direct LIN9 binding at CCSAP promoter not fully established (Medium confidence)","Resistance mechanism beyond mitotic gene output not explored"]},{"year":2024,"claim":"Extended the BRD4-LIN9 axis to vascular smooth muscle and identified direct LIN9 binding at the AURKA promoter upstream of FOXM1, generalizing the pathway beyond breast cancer.","evidence":"RNA-seq, ChIP (LIN9 at AURKA; BRD4 at LIN9), siRNA, and in vivo rat restenosis model","pmids":["39334121"],"confidence":"High","gaps":["Whether AURKA/FOXM1 regulation requires B-MYB not tested","Single-lab finding in one disease context"]},{"year":2024,"claim":"Revealed a LIN9-E2F4 interaction promoting HCC proliferation and SUMOylation, adding a repressive-complex partner to LIN9's interactome in cancer.","evidence":"Co-IP, IF co-localization, BiFC, and rescue with soft-agar/migration assays in HCC cells","pmids":["39239750"],"confidence":"Medium","gaps":["Mechanism linking LIN9 to SUMOylation machinery unresolved","Single-lab Medium-confidence interaction"]},{"year":2025,"claim":"Identified YARS as a transcriptional activator of LIN9 during senescence escape, linking a tRNA synthetase to LIN9-dependent proliferation.","evidence":"ChIP at LIN9 promoter, YARS-Trim28 co-IP, Pol II phosphorylation and epigenetic mark analysis, siRNA of YARS/LIN9","pmids":["39756023"],"confidence":"Medium","gaps":["Direct vs indirect YARS promoter function not fully distinguished","Single-lab Medium-confidence; physiological generality unknown"]},{"year":null,"claim":"How the repressive DREAM and activating LINC states of LIN9 are molecularly switched, and how upstream regulators (phosphorylation, BET/BRD4, YARS) coordinate to set this balance in normal versus malignant cells, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of LIN9 within DREAM/LINC","Integration of Thr-96 phosphorylation, BET recruitment, and partner switching not mechanistically unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,3,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,13]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,4,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,12]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6]}],"complexes":["DREAM complex","LINC complex"],"partners":["MYBL2","RB1","E2F4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5TKA1","full_name":"Protein lin-9 homolog","aliases":["Beta subunit-associated regulator of apoptosis","TUDOR gene similar protein","Type I interferon receptor beta chain-associated protein","pRB-associated protein"],"length_aa":542,"mass_kda":61.9,"function":"Acts as a tumor suppressor. Inhibits DNA synthesis. Its ability to inhibit oncogenic transformation is mediated through its association with RB1. Plays a role in the expression of genes required for the G1/S transition","subcellular_location":"Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q5TKA1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LIN9","classification":"Not Classified","n_dependent_lines":133,"n_total_lines":1208,"dependency_fraction":0.11009933774834436},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LIN9","total_profiled":1310},"omim":[{"mim_id":"621288","title":"LIN52 DREAM MUVB CORE COMPLEX COMPONENT; LIN52","url":"https://www.omim.org/entry/621288"},{"mim_id":"621287","title":"LIN37 DREAM MUVB CORE COMPLEX COMPONENT; LIN37","url":"https://www.omim.org/entry/621287"},{"mim_id":"617207","title":"ENCEPHALOPATHY, PROGRESSIVE, WITH AMYOTROPHY AND OPTIC ATROPHY; PEAMO","url":"https://www.omim.org/entry/617207"},{"mim_id":"613367","title":"LIN54, C. ELEGANS, HOMOLOG OF; LIN54","url":"https://www.omim.org/entry/613367"},{"mim_id":"609375","title":"LIN9 DREAM MUVB CORE COMPLEX COMPONENT; LIN9","url":"https://www.omim.org/entry/609375"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LIN9"},"hgnc":{"alias_symbol":["TGS"],"prev_symbol":[]},"alphafold":{"accession":"Q5TKA1","domains":[{"cath_id":"2.30.30.140","chopping":"188-287","consensus_level":"high","plddt":87.4783,"start":188,"end":287},{"cath_id":"-","chopping":"427-526","consensus_level":"high","plddt":80.5461,"start":427,"end":526},{"cath_id":"1.20.120","chopping":"335-417","consensus_level":"high","plddt":87.7494,"start":335,"end":417}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TKA1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TKA1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TKA1-F1-predicted_aligned_error_v6.png","plddt_mean":70.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LIN9","jax_strain_url":"https://www.jax.org/strain/search?query=LIN9"},"sequence":{"accession":"Q5TKA1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5TKA1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5TKA1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TKA1"}},"corpus_meta":[{"pmid":"17159899","id":"PMC_17159899","title":"The human synMuv-like protein LIN-9 is required for transcription of G2/M genes and for entry into mitosis.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17159899","citation_count":104,"is_preprint":false},{"pmid":"23381944","id":"PMC_23381944","title":"A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α.","date":"2013","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23381944","citation_count":88,"is_preprint":false},{"pmid":"19252525","id":"PMC_19252525","title":"A Lin-9 complex is recruited by B-Myb to activate transcription of G2/M genes in undifferentiated embryonal carcinoma cells.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19252525","citation_count":79,"is_preprint":false},{"pmid":"26565975","id":"PMC_26565975","title":"TGS-TB: Total Genotyping Solution for Mycobacterium tuberculosis Using Short-Read Whole-Genome 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interaction is distinct from E2F-pRB interaction. RNAi knockdown of LIN9 can substitute for loss of pRB in oncogenic transformation of human primary fibroblasts, demonstrating LIN9's tumor-suppressing activity is mediated through pRB.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, reporter gene transactivation assays, flat cell formation assay in Saos-2 cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, functional rescue assays, multiple orthogonal methods in single focused study\",\n      \"pmids\": [\"15538385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"C. elegans lin-9 functions in an Rb-related pathway that antagonizes receptor tyrosine kinase/Ras signaling to control vulval induction, and is also required for gonadal sheath cell development and male spicule/ray/gonad development. lin-9 encodes a novel protein of 642-644 amino acids with conserved orthologs in Drosophila and vertebrates, founding a new protein family that functions in Rb-related pathways.\",\n      \"method\": \"Genetic epistasis analysis, loss-of-function mutant characterization, cDNA cloning and sequence analysis in C. elegans\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in founding organism study, replicated across multiple developmental phenotypes\",\n      \"pmids\": [\"10974557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human LIN-9 is required for transcription of G2/M genes and for entry into mitosis. LIN-9 associates with B-MYB, and both LIN-9 and B-MYB bind directly to the promoters of G2/M-regulated genes as shown by chromatin immunoprecipitation. Depletion of LIN-9 by RNAi strongly impairs proliferation and delays G2-to-M progression. Depletion of B-MYB recapitulates the LIN-9 knockdown phenotype, indicating LIN-9 and B-MYB co-activate G2/M gene expression.\",\n      \"method\": \"RNAi knockdown, chromatin immunoprecipitation (ChIP), co-immunoprecipitation, proliferation assays, cell cycle analysis in human fibroblasts\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, co-IP, RNAi phenotype), replicated with B-MYB knockdown\",\n      \"pmids\": [\"17159899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In F9 embryonal carcinoma cells, B-Myb is found in complexes with Lin-9 and other LINC constituents (but not pocket proteins, which only associate with LINC upon differentiation). B-Myb recruits Lin-9 to the Survivin promoter through multiple Myb-binding sites. Both B-Myb and Lin-9 are required for transcription of G2/M genes (Cyclin B1, Survivin). Loss of Lin-9 causes mitotic arrest in F9 cells.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, RNAi knockdown, reporter assays, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP showing B-Myb recruits Lin-9 to promoter, multiple orthogonal methods, independent replication of LINC complex concept\",\n      \"pmids\": [\"19252525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Lin9 depletion in zebrafish embryos causes accumulation of cells in mitosis followed by apoptosis, particularly in the developing central nervous system. A cohort of Lin9-regulated mitotic genes required for mitotic entry, metaphase/anaphase transition, and cytokinesis was identified, establishing LIN9 as an essential regulator of mitosis in vertebrate development.\",\n      \"method\": \"Antisense morpholino knockdown in zebrafish, flow cytometry, confocal microscopy, gene expression profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with specific mitotic phenotype, gene target identification, replicated concept from human cell studies\",\n      \"pmids\": [\"19278998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Lin9 is an essential core subunit of the mammalian DREAM complex. Genetic knockout of Lin9 is lethal in early embryonic development and in adult mice. Loss of Lin9 abolishes proliferation and causes multiple mitotic and cytokinesis defects due to loss of expression of mitotic genes including Plk1, Aurora A, and Kif20a. Lin9 heterozygous mice are more susceptible to oncogenic c-Raf-induced lung tumorigenesis, indicating haploinsufficient tumor suppressor function.\",\n      \"method\": \"Conditional and constitutive knockout mouse models, gene expression analysis, proliferation assays, tumor induction by oncogenic c-Raf\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with embryonic lethality, adult viability, and tumor susceptibility phenotypes; multiple orthogonal readouts\",\n      \"pmids\": [\"20404087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of LIN9 triggers premature senescence via upregulation of p16(INK4a) and p21(Waf1), implicating the pRB and p53 tumor suppressor pathways. SV40 large T antigen can overcome this senescence. LIN9-null cells that escape senescence exhibit chromosomal instability due to compromised mitotic fidelity, and SV40 LT-expressing LIN9-null cells grow anchorage-independently in soft agar.\",\n      \"method\": \"Gene knockout in mouse cells, immunoblotting for p16/p21, soft agar anchorage-independent growth assay, chromosomal instability analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined senescence pathway readouts (p16, p21), rescue by SV40 LT, multiple functional assays\",\n      \"pmids\": [\"21860417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In hepatocellular carcinoma cells, LIN9 forms a complex with MYBL2 (B-Myb) termed LINC. The integrity of the MYBL2-LIN9 complex is required for survival of DNA-damaged p53-null cells. Doxorubicin treatment causes LIN9 dissociation from MYBL2 in p53-positive cells (leading to p21(WAF1) upregulation) but increases MYBL2-LIN9 complexes in p53-null cells. siRNA-mediated silencing of MYBL2/LINC reduces proliferation and induces apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, proliferation assays, apoptosis assays, immunoblotting in HCC cell lines\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and siRNA in multiple cell lines with functional readouts, single lab\",\n      \"pmids\": [\"21480327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cyclin E1/Cdk3 phosphorylates LIN-9 on Threonine-96. Mutation of Thr-96 to alanine inhibits activation of cyclin A2 and B1 promoters, whereas a phosphomimetic Asp mutant strongly activates these promoters and triggers accelerated entry into G2/M phase. This establishes a role for cyclin E1 in S/G2 phase through LIN-9 phosphorylation to induce expression of subsequent cyclins.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (T96A and T96D mutants), promoter reporter assays, cell cycle analysis in 293T cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional promoter validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24475316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LIN9 is a direct transcriptional target of BET bromodomain proteins in triple-negative breast cancer cells. BET inhibition suppresses LIN9 expression, leading to prolonged mitotic progression and mitotic cell death (mitotic catastrophe). LIN9 mediates the effects of BET proteins on mitosis. The LIN9 gene lacks a super-enhancer but is amplified or overexpressed in the majority of TNBCs.\",\n      \"method\": \"Live cell imaging, BET inhibitor treatment, RNAi knockdown of LIN9, ChIP for BET proteins at LIN9 locus, gene expression analysis in TNBC cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus ChIP plus genetic knockdown with defined mitotic phenotype, single lab but orthogonal methods\",\n      \"pmids\": [\"28807940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LIN9 promotes paclitaxel resistance in triple-negative breast cancer cells at least in part by directly regulating the microtubule-binding protein CCSAP. LIN9 expression is elevated in paclitaxel-resistant TNBC cell lines. Knockdown of LIN9 or BETi treatment reduces LIN9 expression, promotes multinucleated cell formation, and restores paclitaxel sensitivity.\",\n      \"method\": \"qRT-PCR, Western blot, siRNA knockdown, MTS cell viability assay, flow cytometry for apoptosis in TNBC cell lines and resistant sublines\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — knockdown with functional readout and identification of downstream target CCSAP, single lab, limited mechanistic depth on LIN9-CCSAP interaction\",\n      \"pmids\": [\"31420851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LIN9 transcriptionally regulates NEK2 (NIMA-related kinase 2) expression in taxane-resistant breast cancer cells. Elevated LIN9 in taxane-resistant cells sustains NEK2 expression and centrosome separation. Genetic or pharmacologic inhibition of LIN9 (via BET inhibitors) or NEK2 in combination with paclitaxel synergistically induces mitotic abnormalities in nearly 100% of cells and restores paclitaxel sensitivity in vitro and in vivo, including in patient-derived xenografts.\",\n      \"method\": \"Computational target identification, genetic knockdown, pharmacologic NEK2 inhibition, in vitro mitosis assays, in vivo TNBC xenograft and PDX models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockdown plus pharmacologic validation plus in vivo models including PDX; LIN9/NEK2 pathway independently validated by multiple approaches\",\n      \"pmids\": [\"32054769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In vascular smooth muscle cells, IL-1β (downstream of NLRP3 activation) promotes BRD4 recruitment to the LIN9 locus, enhancing LIN9 expression. LIN9 then binds to the promoter region of AURKA, promoting its transcription and subsequently upregulating FOXM1, thereby mediating VSMC proliferation, migration, and paclitaxel resistance. JQ1 (BET inhibitor) inhibits BRD4-mediated LIN9 upregulation and shows synergy with PTX.\",\n      \"method\": \"RNA sequencing, ChIP assay (LIN9 binding to AURKA promoter, BRD4 binding to LIN9 locus), siRNA knockdown, in vivo rat restenosis model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct LIN9 promoter binding at AURKA, upstream BRD4 recruitment shown by ChIP, in vivo validation, single lab but orthogonal methods\",\n      \"pmids\": [\"39334121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E2F4 physically interacts with LIN9 in hepatocellular carcinoma cells, as demonstrated by co-immunoprecipitation, immunofluorescence co-localization, and bimolecular fluorescence complementation assays. E2F4 promotes HCC cell proliferation and SUMOylation via LIN9; rescue experiments showed LIN9 facilitates SUMOylation and proliferation driven by E2F4.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, bimolecular fluorescence complementation, soft agar assay, Transwell migration assay, Western blotting\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal co-localization/interaction methods, rescue experiment; single lab\",\n      \"pmids\": [\"39239750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YARS (tyrosyl tRNA synthetase) binds to the LIN9 promoter and facilitates RNA polymerase II recruitment and phosphorylation, and deposition of activating epigenetic marks. YARS interacts with the Trim28 transcriptional regulator. During senescence escape, YARS activates LIN9 expression; both YARS and LIN9 are necessary for the proliferation of senescence-escaping cells.\",\n      \"method\": \"ChIP assay (YARS binding at LIN9 promoter), co-immunoprecipitation (YARS-Trim28 interaction), RNA polymerase II phosphorylation analysis, epigenetic mark analysis, siRNA knockdown of YARS and LIN9\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at LIN9 promoter plus co-IP for YARS-Trim28, multiple orthogonal methods, single lab, single publication\",\n      \"pmids\": [\"39756023\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LIN9 is a conserved core subunit of the DREAM multiprotein complex that in quiescent cells (G0/G1) represses cell cycle genes in association with pocket proteins (p130/p107) and E2F4, then switches in S/G2 phase to an activating LINC complex with B-MYB to drive transcription of a large set of G2/M mitotic genes (including Cyclin B1, Survivin, PLK1, Aurora A, Kif20a, NEK2, and AURKA); LIN9's transcriptional activity is modulated by Cyclin E1/Cdk3-mediated phosphorylation on Thr-96, by upstream BRD4/BET-dependent chromatin recruitment, and by YARS-mediated promoter activation, while its physical interaction with pRB mediates tumor-suppressive and differentiation functions distinct from E2F regulation; loss of LIN9 causes mitotic arrest, cytokinesis failure, genomic instability, and premature senescence, whereas overexpression sustains mitotic gene programs that promote taxane resistance in cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LIN9 is a conserved core subunit of the DREAM/LINC transcriptional machinery that couples cell cycle gene expression to mitotic progression in vertebrate cells, functioning within Rb-related pathways first defined genetically in C. elegans [#1, #5]. As an activator, LIN9 partners with B-MYB (MYBL2) and is recruited to the promoters of G2/M genes such as Cyclin B1 and Survivin, where the two proteins co-activate transcription required for mitotic entry [#2, #3]. This activity is essential and dose-sensitive: genetic loss abolishes proliferation and produces mitotic and cytokinesis defects through failed expression of mitotic genes including Plk1, Aurora A, and Kif20a, is embryonic lethal in mice, and triggers premature p16/p21-dependent senescence and chromosomal instability, while Lin9 heterozygosity enhances tumorigenesis—establishing a haploinsufficient tumor suppressor function [#4, #5, #6]. Independently of E2F regulation, LIN9 binds pRB and cooperates in transactivation and tumor suppression, such that LIN9 knockdown can substitute for pRB loss in transformation [#0]. LIN9 transcriptional output is tuned by Cyclin E1/Cdk3 phosphorylation on Thr-96, which licenses activation of cyclin A2/B1 promoters and accelerates G2/M entry [#8], and by upstream BET/BRD4-dependent chromatin recruitment that drives LIN9 expression [#9, #12]. In cancer, elevated LIN9 sustains mitotic gene programs—directly regulating CCSAP, NEK2, and AURKA/FOXM1—to promote taxane resistance, which BET inhibition reverses [#10, #11, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established LIN9 as the founding member of a conserved protein family acting in Rb-related pathways, answering whether this gene had a defined genetic role in growth control.\",\n      \"evidence\": \"Genetic epistasis and loss-of-function mutant analysis with cDNA cloning in C. elegans\",\n      \"pmids\": [\"10974557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No biochemical mechanism or direct molecular partners defined\", \"Vertebrate function inferred only by orthology at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a direct, E2F-independent LIN9-pRB interaction that mediates tumor suppression, distinguishing LIN9 function from classical E2F-pRB control.\",\n      \"evidence\": \"Co-IP, RNAi knockdown, and reporter/flat-cell transformation assays in human cells\",\n      \"pmids\": [\"15538385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which LIN9-pRB suppresses transformation not resolved\", \"Relationship to subsequent DREAM/LINC roles not addressed here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified LIN9-B-MYB co-activation of G2/M promoters as the mechanism linking LIN9 to mitotic entry, answering how LIN9 controls proliferation.\",\n      \"evidence\": \"ChIP, co-IP, and RNAi cell cycle/proliferation analysis in human fibroblasts\",\n      \"pmids\": [\"17159899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full subunit composition of the activating complex not enumerated\", \"How LIN9 is recruited to chromatin not yet defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed B-MYB recruits LIN9 to specific promoters (Survivin) and that this drives mitotic gene expression across cell types, refining the recruitment logic of the LINC complex.\",\n      \"evidence\": \"ChIP, reciprocal co-IP, RNAi, and reporter assays in F9 embryonal carcinoma cells; morpholino knockdown in zebrafish\",\n      \"pmids\": [\"19252525\", \"19278998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Switch between repressive (pocket protein) and activating states not mechanistically dissected\", \"In vivo target set defined by expression profiling without direct binding for all genes\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated LIN9 is an essential DREAM core subunit and haploinsufficient tumor suppressor in vivo, establishing physiological essentiality and cancer relevance.\",\n      \"evidence\": \"Conditional/constitutive knockout mice, expression analysis, and c-Raf tumor induction\",\n      \"pmids\": [\"20404087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions of LIN9 loss not separated\", \"Mechanism of haploinsufficient tumor susceptibility not fully resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected LIN9 loss to defined senescence and genomic instability pathways and showed LINC integrity supports survival of p53-null damaged cells, clarifying tumor-suppressive versus pro-survival outputs.\",\n      \"evidence\": \"Gene knockout with p16/p21 immunoblotting and soft-agar assays; co-IP and siLINC in HCC lines with apoptosis readouts\",\n      \"pmids\": [\"21860417\", \"21480327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependence of LIN9 as suppressor versus survival factor not unified\", \"HCC co-IP/siRNA findings are single-lab and Medium confidence\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Cyclin E1/Cdk3 phosphorylation of LIN9 at Thr-96 as a regulatory switch driving G2/M promoter activation, answering how LIN9 transcriptional activity is timed.\",\n      \"evidence\": \"In vitro kinase assay, T96A/T96D mutagenesis, promoter reporters, and cell cycle analysis in 293T cells\",\n      \"pmids\": [\"24475316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation not validated at endogenous LIN9 in vivo\", \"Effect on complex composition or DNA binding not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed LIN9 downstream of BET bromodomain proteins, showing chromatin-level control of LIN9 expression governs mitotic fidelity in cancer cells.\",\n      \"evidence\": \"Live imaging, BET inhibitor treatment, ChIP for BET proteins at LIN9, and RNAi in TNBC lines\",\n      \"pmids\": [\"28807940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect BET regulation of additional LIN9 targets not parsed\", \"No structural basis for BET occupancy at the LIN9 locus\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined LIN9-driven transcription of mitotic kinases (CCSAP, NEK2) as a mechanism of taxane resistance, providing actionable combination targets.\",\n      \"evidence\": \"Knockdown, pharmacologic NEK2/BET inhibition, and in vitro/in vivo TNBC and PDX models\",\n      \"pmids\": [\"31420851\", \"32054769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct LIN9 binding at CCSAP promoter not fully established (Medium confidence)\", \"Resistance mechanism beyond mitotic gene output not explored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the BRD4-LIN9 axis to vascular smooth muscle and identified direct LIN9 binding at the AURKA promoter upstream of FOXM1, generalizing the pathway beyond breast cancer.\",\n      \"evidence\": \"RNA-seq, ChIP (LIN9 at AURKA; BRD4 at LIN9), siRNA, and in vivo rat restenosis model\",\n      \"pmids\": [\"39334121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AURKA/FOXM1 regulation requires B-MYB not tested\", \"Single-lab finding in one disease context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a LIN9-E2F4 interaction promoting HCC proliferation and SUMOylation, adding a repressive-complex partner to LIN9's interactome in cancer.\",\n      \"evidence\": \"Co-IP, IF co-localization, BiFC, and rescue with soft-agar/migration assays in HCC cells\",\n      \"pmids\": [\"39239750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking LIN9 to SUMOylation machinery unresolved\", \"Single-lab Medium-confidence interaction\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified YARS as a transcriptional activator of LIN9 during senescence escape, linking a tRNA synthetase to LIN9-dependent proliferation.\",\n      \"evidence\": \"ChIP at LIN9 promoter, YARS-Trim28 co-IP, Pol II phosphorylation and epigenetic mark analysis, siRNA of YARS/LIN9\",\n      \"pmids\": [\"39756023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect YARS promoter function not fully distinguished\", \"Single-lab Medium-confidence; physiological generality unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the repressive DREAM and activating LINC states of LIN9 are molecularly switched, and how upstream regulators (phosphorylation, BET/BRD4, YARS) coordinate to set this balance in normal versus malignant cells, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of LIN9 within DREAM/LINC\", \"Integration of Thr-96 phosphorylation, BET recruitment, and partner switching not mechanistically unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 3, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"DREAM complex\", \"LINC complex\"],\n    \"partners\": [\"MYBL2\", \"RB1\", \"E2F4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}