{"gene":"DEPDC1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2007,"finding":"DEPDC1 protein localizes to the nucleus of bladder cancer cells, as detected by immunocytochemical staining, and siRNA-mediated knockdown of DEPDC1 significantly inhibits growth of bladder cancer cells.","method":"Immunocytochemical staining, siRNA knockdown with cell growth assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment and loss-of-function with defined phenotypic readout, single lab, two orthogonal methods","pmids":["17452976"],"is_preprint":false},{"year":2010,"finding":"DEPDC1 physically interacts with the zinc finger transcriptional repressor ZNF224 and colocalizes with it in the nucleus; this interaction suppresses transcription of A20 (TNFAIP3), an inhibitor of NF-κB signaling, and disrupting the DEPDC1-ZNF224 complex with a cell-permeable peptide triggers A20 transcriptional activation and apoptosis in bladder cancer cells.","method":"Co-immunoprecipitation, immunocytochemistry, cell-permeable peptide competition, in vitro and in vivo apoptosis assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, colocalization, functional rescue with competing peptide both in vitro and in vivo, single lab with multiple orthogonal methods","pmids":["20587513"],"is_preprint":false},{"year":2014,"finding":"In C. elegans, the DEPDC1 ortholog LET-99 acts upstream of the heterotrimeric G-protein alpha subunit GPA-11 to control activation of the stress kinase JNK-1 in response to microtubule-targeting drugs (vincristine); human DEPDC1 similarly promotes JNK-dependent phosphorylation and degradation of the anti-apoptotic BCL-2 family member MCL1, mediating anti-tubulin drug-induced apoptosis.","method":"RNAi-based screen in C. elegans, genetic epistasis, mammalian cell knockdown, western blot for MCL1 phosphorylation/degradation, JNK inhibitor experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established in vivo (C. elegans), human ortholog validated in mammalian cells with pathway placement, replicated across species with multiple orthogonal methods","pmids":["25064737"],"is_preprint":false},{"year":2015,"finding":"DEPDC1 expression peaks during mitosis in synchronized cells; siRNA-mediated knockdown causes mitotic arrest, multipolar spindle structures, and abnormal multinucleated cells, accompanied by upregulation of A20 and cell cycle genes CCNB1 and CCNB2, establishing a direct role for DEPDC1 in proper mitotic progression.","method":"Cell synchronization, immunofluorescence, siRNA knockdown with mitotic phenotype analysis, gene expression analysis","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific mitotic phenotype readout and gene expression changes, single lab, two orthogonal methods","pmids":["25902835"],"is_preprint":false},{"year":2017,"finding":"DEPDC1 isoform a (DEPDC1a) localizes to the centrosome in metaphase and is required for centrosome integrity and bipolar spindle organization; phosphorylation of DEPDC1 at Ser110 (identified by mass spectrometry) is essential for its centrosomal localization, and non-phosphorylatable Ser110 mutants fail to rescue centrosome disruption caused by DEPDC1 depletion. DEPDC1 isoform b localizes to the cell cortex during mitosis. Both isoforms are upregulated in mitosis and degraded upon mitotic exit.","method":"Mass spectrometry, immunofluorescence, site-directed mutagenesis, siRNA rescue experiments, subcellular fractionation/localization","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry identification of phosphosite, mutagenesis demonstrating functional necessity of Ser110 phosphorylation for localization and function, single lab with multiple orthogonal methods","pmids":["28602627"],"is_preprint":false},{"year":2017,"finding":"DEPDC1 interacts with the transcription factor E2F1, increasing its transcriptional activity, thereby activating E2F signaling and promoting G1-S phase cell cycle transition in prostate cancer cells.","method":"Co-immunoprecipitation, cell cycle analysis (flow cytometry), overexpression and knockdown with proliferation assays, in vivo xenograft","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, functional cell cycle phenotype confirmed in vitro and in vivo, single lab","pmids":["28634077"],"is_preprint":false},{"year":2017,"finding":"DEPDC1 depletion in nasopharyngeal carcinoma cells causes mitotic arrest with multipolar spindles and multiple nuclei, upregulates A20, and downregulates NF-κB downstream targets (c-Myc, BCL2, CCND1, CCNB1, CCNB2) as well as metastasis-associated genes (MMP2, MMP9, ICAM1, vimentin, Twist1), placing DEPDC1 upstream of NF-κB pathway regulation and cell motility.","method":"siRNA knockdown, immunofluorescence, gene expression analysis, migration/invasion assays, in vivo xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple defined phenotypic readouts and pathway gene expression changes, single lab","pmids":["28969015"],"is_preprint":false},{"year":2018,"finding":"miR-26b directly represses DEPDC1 expression, and DEPDC1 promotes cell proliferation and tumor growth in triple-negative breast cancer by increasing expression of the transcription factor FOXM1.","method":"miRNA overexpression/inhibition, DEPDC1 knockdown/overexpression, luciferase reporter assay (implied by direct repression), colony formation and tumor growth assays, western blot for FOXM1","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct target relationship and downstream FOXM1 induction shown with functional assays, single lab","pmids":["30419349"],"is_preprint":false},{"year":2019,"finding":"DEPDC1 knockdown in hepatocellular carcinoma cells significantly reduces expression of CCL20 and CCR6, and DEPDC1 drives HCC proliferation, invasion, and angiogenesis via the CCL20/CCR6 signaling pathway; CCL20 or CCR6 knockdown reverses the pro-angiogenic effects of DEPDC1 overexpression.","method":"siRNA knockdown, DNA microarray, qRT-PCR, western blot, invasion assay, tube formation assay, in vivo xenograft","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement via epistasis (CCL20/CCR6 knockdown rescues DEPDC1 overexpression phenotype), multiple orthogonal methods, single lab","pmids":["31322256"],"is_preprint":false},{"year":2019,"finding":"DEPDC1 promotes HCC cell viability and resistance to chemotherapy (oxaliplatin) through the JNK signaling pathway, as demonstrated by reversal of DEPDC1 pro-survival effects with the JNK-specific inhibitor SP600125.","method":"siRNA knockdown, overexpression, JNK inhibitor (SP600125) treatment, CCK-8 viability assay, flow cytometry, in vivo xenograft","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with JNK inhibitor, loss- and gain-of-function both tested, single lab","pmids":["31189746"],"is_preprint":false},{"year":2020,"finding":"DEPDC1 upregulates RAS expression and consequently enhances ERK1/2 activity in lung adenocarcinoma cells, through which DEPDC1 inhibits autophagy; knockdown of DEPDC1 impairs proliferation, migration, and invasion.","method":"siRNA knockdown, overexpression, western blot for RAS and phospho-ERK1/2, autophagy markers, cell functional assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — western blot pathway analysis with both knockdown and overexpression, single lab, consistent results across multiple cell lines","pmids":["33021072"],"is_preprint":false},{"year":2020,"finding":"NNK (tobacco carcinogen) stimulates DEPDC1 expression by promoting DNMT1-mediated methylation of the DEPDC1 gene body in OSCC cells; upregulated DEPDC1 in turn promotes OSCC cell proliferation by inhibiting CYP27B1 expression.","method":"In vitro NNK treatment, DNMT1 overexpression, DEPDC1 knockdown/overexpression, CYP27B1 expression analysis, in vivo tumor growth assay","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mechanistic chain established through gain- and loss-of-function experiments, DNMT1/methylation link shown, single lab","pmids":["32642287"],"is_preprint":false},{"year":2021,"finding":"ALPK2 directly interacts with DEPDC1A in bladder cancer cells, and DEPDC1A functions as a downstream effector of ALPK2; overexpression of DEPDC1A rescues the inhibitory effects of ALPK2 knockdown on bladder cancer cell proliferation, apoptosis, and migration.","method":"Co-immunoprecipitation (direct interaction), siRNA knockdown, overexpression rescue, in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct interaction, genetic epistasis via rescue experiment, single lab","pmids":["34210956"],"is_preprint":false},{"year":2021,"finding":"Linc-ROR acts as competing endogenous RNA to stabilize DEPDC1 mRNA and also regulates DEPDC1 mRNA stability by binding the RNA-binding protein HNRNPK, thereby promoting HCC progression and angiogenesis.","method":"lncRNA knockdown/overexpression, RNA pull-down/RIP for HNRNPK interaction, mRNA stability assay, functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA pull-down and RIP establish direct HNRNPK binding, mRNA stabilization mechanism shown, single lab","pmids":["34741030"],"is_preprint":false},{"year":2021,"finding":"DEPDC1 promotes HCC migration and invasion via activation of Wnt/β-catenin signaling and epithelial-mesenchymal transition, as demonstrated by downregulation of Wnt1 and β-catenin upon DEPDC1 reduction.","method":"Lentiviral DEPDC1 overexpression, in vitro migration/invasion assays, western blot for Wnt/β-catenin and EMT markers, in vivo bioluminescence metastasis model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional assays with pathway markers, single lab","pmids":["34268303"],"is_preprint":false},{"year":2022,"finding":"SIRT1 binds to the promoter of miR-20b-3p to repress its expression, thereby de-repressing DEPDC1 (a direct target of miR-20b-3p), and this SIRT1/miR-20b-3p/DEPDC1 axis mediates oxaliplatin resistance in colorectal cancer.","method":"ChIP (SIRT1 promoter binding), luciferase reporter assay (miR-20b-3p/DEPDC1 targeting), siRNA knockdown, drug resistance assays","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter establish direct regulatory relationships, functional drug resistance phenotype, single lab","pmids":["36200529"],"is_preprint":false},{"year":2022,"finding":"FOXO3a binds to the DEPDC1 promoter and represses its transcription; DEPDC1 in turn promotes nephroblastoma cell proliferation, invasion, and migration via activation of Wnt/β-catenin signaling (increasing phospho-GSK-3β, Wnt3a, and β-catenin); DEPDC1 overexpression reverses the inhibitory effects of FOXO3a overexpression.","method":"Co-immunoprecipitation, dual-luciferase reporter assay, siRNA/overexpression, western blot for Wnt/β-catenin pathway proteins, functional cellular assays","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding confirmed by luciferase reporter, IP, genetic epistasis, multiple orthogonal methods, single lab","pmids":["35795985"],"is_preprint":false},{"year":2022,"finding":"DEPDC1 interacts with FOXM1 (confirmed by Co-IP and immunofluorescence in OSCC cells) and facilitates Wnt/β-catenin signal transduction and nuclear β-catenin accumulation, thereby promoting OSCC pathogenesis.","method":"Co-immunoprecipitation, immunofluorescence, overexpression/knockdown, western blot for β-catenin, in vivo tumor model","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and colocalization establish physical interaction, downstream pathway activation shown, single lab","pmids":["36072787"],"is_preprint":false},{"year":2023,"finding":"DEPDC1 physically interacts with KIF4A (confirmed by Co-IP in osteosarcoma cells), and KIF4A overexpression partially reverses the effects of DEPDC1 knockdown on cell viability, proliferation, invasion, migration, and angiogenesis; DEPDC1 knockdown activates the Hippo pathway (increasing p-LATS1 and p-YAP), which is reversed by KIF4A upregulation.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, CCK-8, EdU staining, Transwell, wound healing, tube formation assay, western blot for Hippo pathway proteins","journal":"Journal of orthopaedic surgery and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes physical interaction, genetic epistasis via KIF4A rescue, Hippo pathway placement, single lab","pmids":["36849972"],"is_preprint":false},{"year":2023,"finding":"DEPDC1 promotes aerobic glycolysis, migration, and invasion in oral squamous cell carcinoma via the WNT/β-catenin pathway.","method":"siRNA knockdown, overexpression, functional migration/invasion assays, glycolysis assays, western blot for WNT/β-catenin pathway markers","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assays with pathway marker analysis, single lab, multiple readouts","pmids":["36768316"],"is_preprint":false},{"year":2023,"finding":"S100A16 directly binds DEPDC1 (confirmed by Co-IP), and DEPDC1 overexpression partially reverses the inhibitory effects of S100A16 knockdown on nephroblastoma cell proliferation, invasion, migration, and angiogenesis, acting through activation of the PI3K/Akt/mTOR pathway.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, western blot for PI3K/Akt/mTOR proteins, functional cellular assays","journal":"Polish journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes binding, epistasis rescue experiment, pathway protein analysis, single lab","pmids":["37955537"],"is_preprint":false},{"year":2024,"finding":"FOXM1 binds to the DEPDC1 promoter and transcriptionally induces DEPDC1 expression; in turn, DEPDC1 physically interacts with FOXM1, promotes its nuclear translocation, and reinforces its transcriptional activity, constituting a positive feedback loop that drives hepatocarcinogenesis.","method":"Chromatin immunoprecipitation (ChIP) for FOXM1 promoter binding, Co-immunoprecipitation for DEPDC1-FOXM1 interaction, nuclear fractionation, luciferase reporter assay, knockdown rescue experiments, in vivo HCC model","journal":"Cancer science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP establishes direct promoter binding, Co-IP establishes physical interaction, nuclear translocation assay, genetic epistasis, in vivo validation, multiple orthogonal methods in single study","pmids":["39004911"],"is_preprint":false},{"year":2024,"finding":"DEPDC1 knockdown reverses tyrosine kinase inhibitor (TKI) resistance in renal cell carcinoma cell lines; bulk RNA-seq and non-targeted metabolomics combined with protein-level analysis indicate that DEPDC1 regulates glycolysis via the AKT/mTOR/HIF1α pathway.","method":"scRNA-seq, siRNA knockdown, RNA-seq, non-targeted metabolomics, western blot for AKT/mTOR/HIF1α pathway proteins, drug resistance assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics approach with protein-level pathway validation and functional drug resistance reversal, single lab","pmids":["39068164"],"is_preprint":false},{"year":2024,"finding":"DEPDC1 upregulates RAS expression through TTK (phosphotyrosine-picked threonine tyrosine kinase), enhancing ERK activity, and thereby regulates glycolysis and autophagy in osteosarcoma cells; DEPDC1-TTK interaction is predicted by STRING and confirmed by co-immunoprecipitation.","method":"Co-immunoprecipitation, siRNA knockdown, western blot for RAS/ERK, glycolysis assays (ECAR, glucose uptake, lactate), autophagy markers","journal":"Anti-cancer drugs","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms interaction, pathway analysis with multiple metabolic readouts, single lab","pmids":["39016842"],"is_preprint":false},{"year":2024,"finding":"miR-130b-3p directly binds to the 3'UTR of DEPDC1 mRNA to suppress its expression; DEPDC1 levels affect NSCLC cell proliferation, migration, and apoptosis via TGF-β signaling pathway.","method":"Dual-luciferase reporter assay (3'UTR binding), miRNA overexpression/inhibition, DEPDC1 knockdown/overexpression, western blot for TGF-β pathway markers, functional assays","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirms direct 3'UTR binding, TGF-β pathway placement with epistasis, single lab","pmids":["38960258"],"is_preprint":false},{"year":2025,"finding":"The m6A methyltransferase METTL5 promotes DEPDC1 translation via m6A modification of 18S rRNA; METTL5 overexpression increases DEPDC1 protein levels and promotes lung squamous cell carcinoma tumorigenesis, while METTL5 knockdown inhibits proliferation and migration.","method":"Cell and animal experiments, overexpression/knockdown, western blot for DEPDC1 protein, in vivo tumor models","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mechanistic link between METTL5 m6A modification and DEPDC1 translation established, functional in vitro and in vivo validation, single lab","pmids":["40018408"],"is_preprint":false},{"year":2025,"finding":"DEPDC1 physically interacts with KIF20A (confirmed by Co-IP in liposarcoma cells), and KIF20A deletion partially mitigates the pro-malignant effects of DEPDC1 and suppresses PI3K/AKT/mTOR signaling pathway activation driven by DEPDC1.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, western blot for PI3K/AKT/mTOR pathway, functional cellular assays","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms physical interaction, genetic epistasis via KIF20A knockdown, pathway analysis, single lab","pmids":["40600015"],"is_preprint":false}],"current_model":"DEPDC1 is a nuclear/centrosomal protein that peaks in expression during mitosis, where its isoform a localizes to the centrosome in a Ser110 phosphorylation-dependent manner to maintain bipolar spindle integrity, while acting upstream of multiple oncogenic signaling pathways including NF-κB (via repression of A20 through interaction with ZNF224), E2F1 transcriptional activation, JNK-dependent MCL1 degradation, Wnt/β-catenin signaling, FOXM1 nuclear translocation (forming a positive feedback loop), and RAS-ERK-mediated autophagy inhibition, collectively promoting cancer cell proliferation, survival, invasion, and chemoresistance across multiple tumor types."},"narrative":{"mechanistic_narrative":"DEPDC1 is a cell-cycle-regulated nuclear and centrosomal protein whose expression peaks in mitosis and is required for proper mitotic progression and bipolar spindle organization [PMID:17452976, PMID:25902835, PMID:28602627]. Its isoform a localizes to the centrosome in metaphase in a manner dependent on phosphorylation at Ser110, with non-phosphorylatable mutants failing to rescue the centrosome disruption caused by DEPDC1 depletion, while isoform b localizes to the mitotic cell cortex; both isoforms are degraded upon mitotic exit [PMID:28602627]. Loss of DEPDC1 produces mitotic arrest, multipolar spindles, and multinucleated cells [PMID:25902835, PMID:28969015]. Beyond mitosis, DEPDC1 acts as a nuclear transcriptional co-regulator: it binds the zinc-finger repressor ZNF224 to suppress transcription of A20 (TNFAIP3), thereby de-repressing NF-κB signaling, and disrupting this complex with a competing peptide reactivates A20 and triggers apoptosis [PMID:20587513]. DEPDC1 engages the transcription factors E2F1, to drive the G1-S transition [PMID:28634077], and FOXM1, promoting its nuclear translocation in a positive feedback loop that reinforces FOXM1 transcriptional activity [PMID:39004911, PMID:36072787]. In response to anti-tubulin drugs, DEPDC1 promotes JNK-dependent phosphorylation and degradation of the anti-apoptotic factor MCL1, a function conserved with its C. elegans ortholog LET-99 acting upstream of G-protein/JNK signaling [PMID:25064737]. Across diverse tumor types DEPDC1 functions upstream of oncogenic pathways including Wnt/β-catenin [PMID:34268303, PMID:35795985], RAS-ERK with associated autophagy and glycolysis control [PMID:33021072, PMID:39016842], and PI3K/AKT/mTOR [PMID:37955537, PMID:40600015], collectively promoting proliferation, invasion, angiogenesis, and chemoresistance. DEPDC1 levels are tightly controlled post-transcriptionally by multiple microRNAs and RNA-binding factors [PMID:30419349, PMID:34741030, PMID:38960258].","teleology":[{"year":2007,"claim":"Established DEPDC1 as a nuclear protein required for cancer cell growth, defining it as a candidate proliferation driver.","evidence":"Immunocytochemistry and siRNA knockdown growth assay in bladder cancer cells","pmids":["17452976"],"confidence":"Medium","gaps":["No molecular mechanism for the growth requirement","Localization shown only in one cancer type"]},{"year":2010,"claim":"Identified the first molecular mechanism: DEPDC1 binds ZNF224 to repress A20 and sustain NF-κB signaling, with peptide disruption inducing apoptosis.","evidence":"Reciprocal Co-IP, colocalization, cell-permeable competing peptide, in vitro and in vivo apoptosis assays","pmids":["20587513"],"confidence":"High","gaps":["DNA-binding contribution of ZNF224 vs DEPDC1 not separated","Direct A20 promoter occupancy by the complex not shown"]},{"year":2014,"claim":"Placed DEPDC1 in a conserved JNK signaling axis controlling MCL1 turnover and anti-tubulin drug-induced apoptosis, using an ortholog to anchor pathway order.","evidence":"C. elegans RNAi screen, genetic epistasis with GPA-11/JNK-1, mammalian knockdown and MCL1 phosphorylation/degradation westerns","pmids":["25064737"],"confidence":"High","gaps":["Direct biochemical link between DEPDC1 and JNK activation not defined","Whether DEPDC1 acts via a GTPase-regulatory function unknown"]},{"year":2015,"claim":"Demonstrated DEPDC1 expression peaks in mitosis and is required for mitotic progression, connecting the proliferation phenotype to spindle integrity.","evidence":"Cell synchronization, immunofluorescence, siRNA with mitotic phenotype and CCNB1/CCNB2/A20 expression analysis","pmids":["25902835"],"confidence":"Medium","gaps":["Mechanism linking DEPDC1 to spindle bipolarity not resolved","Causal order between A20 upregulation and arrest unclear"]},{"year":2017,"claim":"Resolved isoform-specific localization and showed Ser110 phosphorylation is necessary for centrosomal targeting and centrosome integrity, providing the first structural-functional handle.","evidence":"Mass spectrometry phosphosite mapping, site-directed mutagenesis, siRNA rescue, immunofluorescence","pmids":["28602627"],"confidence":"High","gaps":["Kinase responsible for Ser110 phosphorylation unknown","Centrosomal binding partners not identified"]},{"year":2017,"claim":"Expanded DEPDC1's transcriptional reach by showing it potentiates E2F1 activity to drive G1-S transition and confirming NF-κB axis upstream control across additional tumor types.","evidence":"Co-IP, flow cytometry cell cycle analysis, gain/loss-of-function with xenografts (E2F1); siRNA with pathway gene expression and invasion assays (NF-κB)","pmids":["28634077","28969015"],"confidence":"Medium","gaps":["Direct vs indirect effect on E2F1 target promoters not dissected","Whether E2F1 and NF-κB effects share a common mechanism unclear"]},{"year":2019,"claim":"Extended DEPDC1 oncogenic output to chemokine (CCL20/CCR6) and JNK-mediated chemoresistance programs in hepatocellular carcinoma.","evidence":"siRNA/overexpression, microarray, epistatic rescue, JNK inhibitor SP600125, tube formation and viability assays, xenografts","pmids":["31322256","31189746"],"confidence":"Medium","gaps":["Direct molecular targets of DEPDC1 within these pathways not defined","Connection to mitotic/centrosomal function unexplored"]},{"year":2021,"claim":"Defined upstream regulators (ALPK2, Linc-ROR/HNRNPK) and a Wnt/β-catenin output, framing DEPDC1 as both a regulated node and a driver of EMT-associated invasion.","evidence":"Co-IP (ALPK2), RNA pull-down/RIP and mRNA stability assays (Linc-ROR/HNRNPK), overexpression with Wnt/β-catenin and EMT markers, metastasis models","pmids":["34210956","34741030","34268303"],"confidence":"Medium","gaps":["Whether ALPK2 phosphorylates DEPDC1 not tested","Direct molecular link from DEPDC1 to Wnt pathway components missing"]},{"year":2022,"claim":"Mapped multilayered transcriptional and epigenetic control of DEPDC1 (FOXO3a repression, SIRT1/miR-20b-3p axis) and consolidated FOXM1 as a physical partner promoting Wnt signaling.","evidence":"ChIP, dual-luciferase reporter, Co-IP and immunofluorescence, drug-resistance and functional assays","pmids":["35795985","36200529","36072787"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of DEPDC1-FOXM1 interaction unknown","Integration of competing regulators in a single cell context not shown"]},{"year":2023,"claim":"Identified kinesin partners (KIF4A) and Hippo, PI3K/AKT/mTOR, and glycolytic outputs, linking DEPDC1 to cytoskeletal motors and metabolic reprogramming.","evidence":"Co-IP, KIF4A/S100A16 rescue epistasis, western blots for Hippo and PI3K/Akt/mTOR proteins, glycolysis and angiogenesis assays","pmids":["36849972","37955537","36768316"],"confidence":"Medium","gaps":["Whether kinesin binding relates to mitotic spindle function untested","Causal hierarchy among the multiple downstream pathways unresolved"]},{"year":2024,"claim":"Established a FOXM1-DEPDC1 positive feedback loop and additional RAS-ERK (via TTK), AKT/mTOR/HIF1α, and TGF-β mechanisms underlying tumorigenesis and TKI resistance.","evidence":"ChIP, Co-IP, nuclear fractionation, luciferase, multi-omics, drug-resistance assays and in vivo models","pmids":["39004911","39016842","39068164","38960258"],"confidence":"High","gaps":["How a single protein coordinates so many distinct pathways mechanistically unclear","Whether these reflect direct biochemical activities or indirect transcriptional effects undefined"]},{"year":2025,"claim":"Defined translational and motor-protein control of DEPDC1 (METTL5/m6A 18S rRNA, KIF20A), reinforcing post-transcriptional regulation and PI3K/AKT/mTOR coupling.","evidence":"Overexpression/knockdown with DEPDC1 protein westerns, Co-IP, pathway analysis, in vivo tumor models","pmids":["40018408","40600015"],"confidence":"Medium","gaps":["Specificity of METTL5 effect on DEPDC1 versus global translation not isolated","KIF20A-DEPDC1 functional relationship to spindle biology untested"]},{"year":null,"claim":"The core biochemical activity of DEPDC1 — whether it acts enzymatically, as a scaffold, or as a GTPase regulator via its DEP domain — remains undefined, leaving open how a mitotic centrosomal protein controls such diverse cytoplasmic and transcriptional pathways.","evidence":"No timeline discovery assigns a catalytic or defined molecular activity to DEPDC1","pmids":[],"confidence":"Low","gaps":["No structural model or domain-function map","No reconstituted biochemical activity","Mechanism unifying mitotic, transcriptional, and signaling roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,5,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,21]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,14,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,15,22]}],"complexes":[],"partners":["ZNF224","E2F1","FOXM1","ALPK2","KIF4A","KIF20A","TTK","S100A16"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5TB30","full_name":"DEP domain-containing protein 1A","aliases":[],"length_aa":811,"mass_kda":93.0,"function":"May be involved in transcriptional regulation as a transcriptional corepressor. The DEPDC1A-ZNF224 complex may play a critical role in bladder carcinogenesis by repressing the transcription of the A20 gene, leading to transport of NF-KB protein into the nucleus, resulting in suppression of apoptosis of bladder cancer cells","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q5TB30/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DEPDC1","classification":"Not Classified","n_dependent_lines":173,"n_total_lines":1208,"dependency_fraction":0.14321192052980133},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DEPDC1","total_profiled":1310},"omim":[{"mim_id":"612002","title":"DEP DOMAIN-CONTAINING PROTEIN 1; DEPDC1","url":"https://www.omim.org/entry/612002"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":4.7},{"tissue":"lymphoid tissue","ntpm":7.5},{"tissue":"testis","ntpm":7.5}],"url":"https://www.proteinatlas.org/search/DEPDC1"},"hgnc":{"alias_symbol":["DEP.8","FLJ20354","SDP35","DEPDC1A"],"prev_symbol":[]},"alphafold":{"accession":"Q5TB30","domains":[{"cath_id":"1.10.10.10","chopping":"13-106","consensus_level":"high","plddt":88.1331,"start":13,"end":106},{"cath_id":"1.10.555.10","chopping":"184-310_592-703","consensus_level":"medium","plddt":85.9687,"start":184,"end":703},{"cath_id":"-","chopping":"728-788","consensus_level":"high","plddt":81.1149,"start":728,"end":788}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TB30","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TB30-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TB30-F1-predicted_aligned_error_v6.png","plddt_mean":60.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DEPDC1","jax_strain_url":"https://www.jax.org/strain/search?query=DEPDC1"},"sequence":{"accession":"Q5TB30","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5TB30.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5TB30/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TB30"}},"corpus_meta":[{"pmid":"17452976","id":"PMC_17452976","title":"Involvement 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progenitors","date":"2024-07-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.23.604718","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23034,"output_tokens":6432,"usd":0.082791,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15543,"output_tokens":4360,"usd":0.093357,"stage2_stop_reason":"end_turn"},"total_usd":0.176148,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"DEPDC1 protein localizes to the nucleus of bladder cancer cells, as detected by immunocytochemical staining, and siRNA-mediated knockdown of DEPDC1 significantly inhibits growth of bladder cancer cells.\",\n      \"method\": \"Immunocytochemical staining, siRNA knockdown with cell growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment and loss-of-function with defined phenotypic readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"17452976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DEPDC1 physically interacts with the zinc finger transcriptional repressor ZNF224 and colocalizes with it in the nucleus; this interaction suppresses transcription of A20 (TNFAIP3), an inhibitor of NF-κB signaling, and disrupting the DEPDC1-ZNF224 complex with a cell-permeable peptide triggers A20 transcriptional activation and apoptosis in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, immunocytochemistry, cell-permeable peptide competition, in vitro and in vivo apoptosis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, colocalization, functional rescue with competing peptide both in vitro and in vivo, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20587513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In C. elegans, the DEPDC1 ortholog LET-99 acts upstream of the heterotrimeric G-protein alpha subunit GPA-11 to control activation of the stress kinase JNK-1 in response to microtubule-targeting drugs (vincristine); human DEPDC1 similarly promotes JNK-dependent phosphorylation and degradation of the anti-apoptotic BCL-2 family member MCL1, mediating anti-tubulin drug-induced apoptosis.\",\n      \"method\": \"RNAi-based screen in C. elegans, genetic epistasis, mammalian cell knockdown, western blot for MCL1 phosphorylation/degradation, JNK inhibitor experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established in vivo (C. elegans), human ortholog validated in mammalian cells with pathway placement, replicated across species with multiple orthogonal methods\",\n      \"pmids\": [\"25064737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DEPDC1 expression peaks during mitosis in synchronized cells; siRNA-mediated knockdown causes mitotic arrest, multipolar spindle structures, and abnormal multinucleated cells, accompanied by upregulation of A20 and cell cycle genes CCNB1 and CCNB2, establishing a direct role for DEPDC1 in proper mitotic progression.\",\n      \"method\": \"Cell synchronization, immunofluorescence, siRNA knockdown with mitotic phenotype analysis, gene expression analysis\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific mitotic phenotype readout and gene expression changes, single lab, two orthogonal methods\",\n      \"pmids\": [\"25902835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DEPDC1 isoform a (DEPDC1a) localizes to the centrosome in metaphase and is required for centrosome integrity and bipolar spindle organization; phosphorylation of DEPDC1 at Ser110 (identified by mass spectrometry) is essential for its centrosomal localization, and non-phosphorylatable Ser110 mutants fail to rescue centrosome disruption caused by DEPDC1 depletion. DEPDC1 isoform b localizes to the cell cortex during mitosis. Both isoforms are upregulated in mitosis and degraded upon mitotic exit.\",\n      \"method\": \"Mass spectrometry, immunofluorescence, site-directed mutagenesis, siRNA rescue experiments, subcellular fractionation/localization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry identification of phosphosite, mutagenesis demonstrating functional necessity of Ser110 phosphorylation for localization and function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28602627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DEPDC1 interacts with the transcription factor E2F1, increasing its transcriptional activity, thereby activating E2F signaling and promoting G1-S phase cell cycle transition in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, cell cycle analysis (flow cytometry), overexpression and knockdown with proliferation assays, in vivo xenograft\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, functional cell cycle phenotype confirmed in vitro and in vivo, single lab\",\n      \"pmids\": [\"28634077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DEPDC1 depletion in nasopharyngeal carcinoma cells causes mitotic arrest with multipolar spindles and multiple nuclei, upregulates A20, and downregulates NF-κB downstream targets (c-Myc, BCL2, CCND1, CCNB1, CCNB2) as well as metastasis-associated genes (MMP2, MMP9, ICAM1, vimentin, Twist1), placing DEPDC1 upstream of NF-κB pathway regulation and cell motility.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, gene expression analysis, migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple defined phenotypic readouts and pathway gene expression changes, single lab\",\n      \"pmids\": [\"28969015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-26b directly represses DEPDC1 expression, and DEPDC1 promotes cell proliferation and tumor growth in triple-negative breast cancer by increasing expression of the transcription factor FOXM1.\",\n      \"method\": \"miRNA overexpression/inhibition, DEPDC1 knockdown/overexpression, luciferase reporter assay (implied by direct repression), colony formation and tumor growth assays, western blot for FOXM1\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct target relationship and downstream FOXM1 induction shown with functional assays, single lab\",\n      \"pmids\": [\"30419349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DEPDC1 knockdown in hepatocellular carcinoma cells significantly reduces expression of CCL20 and CCR6, and DEPDC1 drives HCC proliferation, invasion, and angiogenesis via the CCL20/CCR6 signaling pathway; CCL20 or CCR6 knockdown reverses the pro-angiogenic effects of DEPDC1 overexpression.\",\n      \"method\": \"siRNA knockdown, DNA microarray, qRT-PCR, western blot, invasion assay, tube formation assay, in vivo xenograft\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement via epistasis (CCL20/CCR6 knockdown rescues DEPDC1 overexpression phenotype), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31322256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DEPDC1 promotes HCC cell viability and resistance to chemotherapy (oxaliplatin) through the JNK signaling pathway, as demonstrated by reversal of DEPDC1 pro-survival effects with the JNK-specific inhibitor SP600125.\",\n      \"method\": \"siRNA knockdown, overexpression, JNK inhibitor (SP600125) treatment, CCK-8 viability assay, flow cytometry, in vivo xenograft\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with JNK inhibitor, loss- and gain-of-function both tested, single lab\",\n      \"pmids\": [\"31189746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DEPDC1 upregulates RAS expression and consequently enhances ERK1/2 activity in lung adenocarcinoma cells, through which DEPDC1 inhibits autophagy; knockdown of DEPDC1 impairs proliferation, migration, and invasion.\",\n      \"method\": \"siRNA knockdown, overexpression, western blot for RAS and phospho-ERK1/2, autophagy markers, cell functional assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — western blot pathway analysis with both knockdown and overexpression, single lab, consistent results across multiple cell lines\",\n      \"pmids\": [\"33021072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NNK (tobacco carcinogen) stimulates DEPDC1 expression by promoting DNMT1-mediated methylation of the DEPDC1 gene body in OSCC cells; upregulated DEPDC1 in turn promotes OSCC cell proliferation by inhibiting CYP27B1 expression.\",\n      \"method\": \"In vitro NNK treatment, DNMT1 overexpression, DEPDC1 knockdown/overexpression, CYP27B1 expression analysis, in vivo tumor growth assay\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mechanistic chain established through gain- and loss-of-function experiments, DNMT1/methylation link shown, single lab\",\n      \"pmids\": [\"32642287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ALPK2 directly interacts with DEPDC1A in bladder cancer cells, and DEPDC1A functions as a downstream effector of ALPK2; overexpression of DEPDC1A rescues the inhibitory effects of ALPK2 knockdown on bladder cancer cell proliferation, apoptosis, and migration.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction), siRNA knockdown, overexpression rescue, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct interaction, genetic epistasis via rescue experiment, single lab\",\n      \"pmids\": [\"34210956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Linc-ROR acts as competing endogenous RNA to stabilize DEPDC1 mRNA and also regulates DEPDC1 mRNA stability by binding the RNA-binding protein HNRNPK, thereby promoting HCC progression and angiogenesis.\",\n      \"method\": \"lncRNA knockdown/overexpression, RNA pull-down/RIP for HNRNPK interaction, mRNA stability assay, functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA pull-down and RIP establish direct HNRNPK binding, mRNA stabilization mechanism shown, single lab\",\n      \"pmids\": [\"34741030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DEPDC1 promotes HCC migration and invasion via activation of Wnt/β-catenin signaling and epithelial-mesenchymal transition, as demonstrated by downregulation of Wnt1 and β-catenin upon DEPDC1 reduction.\",\n      \"method\": \"Lentiviral DEPDC1 overexpression, in vitro migration/invasion assays, western blot for Wnt/β-catenin and EMT markers, in vivo bioluminescence metastasis model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional assays with pathway markers, single lab\",\n      \"pmids\": [\"34268303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT1 binds to the promoter of miR-20b-3p to repress its expression, thereby de-repressing DEPDC1 (a direct target of miR-20b-3p), and this SIRT1/miR-20b-3p/DEPDC1 axis mediates oxaliplatin resistance in colorectal cancer.\",\n      \"method\": \"ChIP (SIRT1 promoter binding), luciferase reporter assay (miR-20b-3p/DEPDC1 targeting), siRNA knockdown, drug resistance assays\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter establish direct regulatory relationships, functional drug resistance phenotype, single lab\",\n      \"pmids\": [\"36200529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXO3a binds to the DEPDC1 promoter and represses its transcription; DEPDC1 in turn promotes nephroblastoma cell proliferation, invasion, and migration via activation of Wnt/β-catenin signaling (increasing phospho-GSK-3β, Wnt3a, and β-catenin); DEPDC1 overexpression reverses the inhibitory effects of FOXO3a overexpression.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter assay, siRNA/overexpression, western blot for Wnt/β-catenin pathway proteins, functional cellular assays\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding confirmed by luciferase reporter, IP, genetic epistasis, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35795985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DEPDC1 interacts with FOXM1 (confirmed by Co-IP and immunofluorescence in OSCC cells) and facilitates Wnt/β-catenin signal transduction and nuclear β-catenin accumulation, thereby promoting OSCC pathogenesis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, overexpression/knockdown, western blot for β-catenin, in vivo tumor model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and colocalization establish physical interaction, downstream pathway activation shown, single lab\",\n      \"pmids\": [\"36072787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DEPDC1 physically interacts with KIF4A (confirmed by Co-IP in osteosarcoma cells), and KIF4A overexpression partially reverses the effects of DEPDC1 knockdown on cell viability, proliferation, invasion, migration, and angiogenesis; DEPDC1 knockdown activates the Hippo pathway (increasing p-LATS1 and p-YAP), which is reversed by KIF4A upregulation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, CCK-8, EdU staining, Transwell, wound healing, tube formation assay, western blot for Hippo pathway proteins\",\n      \"journal\": \"Journal of orthopaedic surgery and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes physical interaction, genetic epistasis via KIF4A rescue, Hippo pathway placement, single lab\",\n      \"pmids\": [\"36849972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DEPDC1 promotes aerobic glycolysis, migration, and invasion in oral squamous cell carcinoma via the WNT/β-catenin pathway.\",\n      \"method\": \"siRNA knockdown, overexpression, functional migration/invasion assays, glycolysis assays, western blot for WNT/β-catenin pathway markers\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assays with pathway marker analysis, single lab, multiple readouts\",\n      \"pmids\": [\"36768316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"S100A16 directly binds DEPDC1 (confirmed by Co-IP), and DEPDC1 overexpression partially reverses the inhibitory effects of S100A16 knockdown on nephroblastoma cell proliferation, invasion, migration, and angiogenesis, acting through activation of the PI3K/Akt/mTOR pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, western blot for PI3K/Akt/mTOR proteins, functional cellular assays\",\n      \"journal\": \"Polish journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes binding, epistasis rescue experiment, pathway protein analysis, single lab\",\n      \"pmids\": [\"37955537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXM1 binds to the DEPDC1 promoter and transcriptionally induces DEPDC1 expression; in turn, DEPDC1 physically interacts with FOXM1, promotes its nuclear translocation, and reinforces its transcriptional activity, constituting a positive feedback loop that drives hepatocarcinogenesis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for FOXM1 promoter binding, Co-immunoprecipitation for DEPDC1-FOXM1 interaction, nuclear fractionation, luciferase reporter assay, knockdown rescue experiments, in vivo HCC model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP establishes direct promoter binding, Co-IP establishes physical interaction, nuclear translocation assay, genetic epistasis, in vivo validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"39004911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DEPDC1 knockdown reverses tyrosine kinase inhibitor (TKI) resistance in renal cell carcinoma cell lines; bulk RNA-seq and non-targeted metabolomics combined with protein-level analysis indicate that DEPDC1 regulates glycolysis via the AKT/mTOR/HIF1α pathway.\",\n      \"method\": \"scRNA-seq, siRNA knockdown, RNA-seq, non-targeted metabolomics, western blot for AKT/mTOR/HIF1α pathway proteins, drug resistance assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics approach with protein-level pathway validation and functional drug resistance reversal, single lab\",\n      \"pmids\": [\"39068164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DEPDC1 upregulates RAS expression through TTK (phosphotyrosine-picked threonine tyrosine kinase), enhancing ERK activity, and thereby regulates glycolysis and autophagy in osteosarcoma cells; DEPDC1-TTK interaction is predicted by STRING and confirmed by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, western blot for RAS/ERK, glycolysis assays (ECAR, glucose uptake, lactate), autophagy markers\",\n      \"journal\": \"Anti-cancer drugs\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms interaction, pathway analysis with multiple metabolic readouts, single lab\",\n      \"pmids\": [\"39016842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-130b-3p directly binds to the 3'UTR of DEPDC1 mRNA to suppress its expression; DEPDC1 levels affect NSCLC cell proliferation, migration, and apoptosis via TGF-β signaling pathway.\",\n      \"method\": \"Dual-luciferase reporter assay (3'UTR binding), miRNA overexpression/inhibition, DEPDC1 knockdown/overexpression, western blot for TGF-β pathway markers, functional assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirms direct 3'UTR binding, TGF-β pathway placement with epistasis, single lab\",\n      \"pmids\": [\"38960258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The m6A methyltransferase METTL5 promotes DEPDC1 translation via m6A modification of 18S rRNA; METTL5 overexpression increases DEPDC1 protein levels and promotes lung squamous cell carcinoma tumorigenesis, while METTL5 knockdown inhibits proliferation and migration.\",\n      \"method\": \"Cell and animal experiments, overexpression/knockdown, western blot for DEPDC1 protein, in vivo tumor models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mechanistic link between METTL5 m6A modification and DEPDC1 translation established, functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"40018408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DEPDC1 physically interacts with KIF20A (confirmed by Co-IP in liposarcoma cells), and KIF20A deletion partially mitigates the pro-malignant effects of DEPDC1 and suppresses PI3K/AKT/mTOR signaling pathway activation driven by DEPDC1.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, western blot for PI3K/AKT/mTOR pathway, functional cellular assays\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms physical interaction, genetic epistasis via KIF20A knockdown, pathway analysis, single lab\",\n      \"pmids\": [\"40600015\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DEPDC1 is a nuclear/centrosomal protein that peaks in expression during mitosis, where its isoform a localizes to the centrosome in a Ser110 phosphorylation-dependent manner to maintain bipolar spindle integrity, while acting upstream of multiple oncogenic signaling pathways including NF-κB (via repression of A20 through interaction with ZNF224), E2F1 transcriptional activation, JNK-dependent MCL1 degradation, Wnt/β-catenin signaling, FOXM1 nuclear translocation (forming a positive feedback loop), and RAS-ERK-mediated autophagy inhibition, collectively promoting cancer cell proliferation, survival, invasion, and chemoresistance across multiple tumor types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DEPDC1 is a cell-cycle-regulated nuclear and centrosomal protein whose expression peaks in mitosis and is required for proper mitotic progression and bipolar spindle organization [#0, #3, #4]. Its isoform a localizes to the centrosome in metaphase in a manner dependent on phosphorylation at Ser110, with non-phosphorylatable mutants failing to rescue the centrosome disruption caused by DEPDC1 depletion, while isoform b localizes to the mitotic cell cortex; both isoforms are degraded upon mitotic exit [#4]. Loss of DEPDC1 produces mitotic arrest, multipolar spindles, and multinucleated cells [#3, #6]. Beyond mitosis, DEPDC1 acts as a nuclear transcriptional co-regulator: it binds the zinc-finger repressor ZNF224 to suppress transcription of A20 (TNFAIP3), thereby de-repressing NF-\\u03baB signaling, and disrupting this complex with a competing peptide reactivates A20 and triggers apoptosis [#1]. DEPDC1 engages the transcription factors E2F1, to drive the G1-S transition [#5], and FOXM1, promoting its nuclear translocation in a positive feedback loop that reinforces FOXM1 transcriptional activity [#21, #17]. In response to anti-tubulin drugs, DEPDC1 promotes JNK-dependent phosphorylation and degradation of the anti-apoptotic factor MCL1, a function conserved with its C. elegans ortholog LET-99 acting upstream of G-protein/JNK signaling [#2]. Across diverse tumor types DEPDC1 functions upstream of oncogenic pathways including Wnt/\\u03b2-catenin [#14, #16], RAS-ERK with associated autophagy and glycolysis control [#10, #23], and PI3K/AKT/mTOR [#20, #26], collectively promoting proliferation, invasion, angiogenesis, and chemoresistance. DEPDC1 levels are tightly controlled post-transcriptionally by multiple microRNAs and RNA-binding factors [#7, #13, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established DEPDC1 as a nuclear protein required for cancer cell growth, defining it as a candidate proliferation driver.\",\n      \"evidence\": \"Immunocytochemistry and siRNA knockdown growth assay in bladder cancer cells\",\n      \"pmids\": [\"17452976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for the growth requirement\", \"Localization shown only in one cancer type\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the first molecular mechanism: DEPDC1 binds ZNF224 to repress A20 and sustain NF-\\u03baB signaling, with peptide disruption inducing apoptosis.\",\n      \"evidence\": \"Reciprocal Co-IP, colocalization, cell-permeable competing peptide, in vitro and in vivo apoptosis assays\",\n      \"pmids\": [\"20587513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA-binding contribution of ZNF224 vs DEPDC1 not separated\", \"Direct A20 promoter occupancy by the complex not shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed DEPDC1 in a conserved JNK signaling axis controlling MCL1 turnover and anti-tubulin drug-induced apoptosis, using an ortholog to anchor pathway order.\",\n      \"evidence\": \"C. elegans RNAi screen, genetic epistasis with GPA-11/JNK-1, mammalian knockdown and MCL1 phosphorylation/degradation westerns\",\n      \"pmids\": [\"25064737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between DEPDC1 and JNK activation not defined\", \"Whether DEPDC1 acts via a GTPase-regulatory function unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated DEPDC1 expression peaks in mitosis and is required for mitotic progression, connecting the proliferation phenotype to spindle integrity.\",\n      \"evidence\": \"Cell synchronization, immunofluorescence, siRNA with mitotic phenotype and CCNB1/CCNB2/A20 expression analysis\",\n      \"pmids\": [\"25902835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking DEPDC1 to spindle bipolarity not resolved\", \"Causal order between A20 upregulation and arrest unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved isoform-specific localization and showed Ser110 phosphorylation is necessary for centrosomal targeting and centrosome integrity, providing the first structural-functional handle.\",\n      \"evidence\": \"Mass spectrometry phosphosite mapping, site-directed mutagenesis, siRNA rescue, immunofluorescence\",\n      \"pmids\": [\"28602627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Ser110 phosphorylation unknown\", \"Centrosomal binding partners not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded DEPDC1's transcriptional reach by showing it potentiates E2F1 activity to drive G1-S transition and confirming NF-\\u03baB axis upstream control across additional tumor types.\",\n      \"evidence\": \"Co-IP, flow cytometry cell cycle analysis, gain/loss-of-function with xenografts (E2F1); siRNA with pathway gene expression and invasion assays (NF-\\u03baB)\",\n      \"pmids\": [\"28634077\", \"28969015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effect on E2F1 target promoters not dissected\", \"Whether E2F1 and NF-\\u03baB effects share a common mechanism unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended DEPDC1 oncogenic output to chemokine (CCL20/CCR6) and JNK-mediated chemoresistance programs in hepatocellular carcinoma.\",\n      \"evidence\": \"siRNA/overexpression, microarray, epistatic rescue, JNK inhibitor SP600125, tube formation and viability assays, xenografts\",\n      \"pmids\": [\"31322256\", \"31189746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets of DEPDC1 within these pathways not defined\", \"Connection to mitotic/centrosomal function unexplored\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined upstream regulators (ALPK2, Linc-ROR/HNRNPK) and a Wnt/\\u03b2-catenin output, framing DEPDC1 as both a regulated node and a driver of EMT-associated invasion.\",\n      \"evidence\": \"Co-IP (ALPK2), RNA pull-down/RIP and mRNA stability assays (Linc-ROR/HNRNPK), overexpression with Wnt/\\u03b2-catenin and EMT markers, metastasis models\",\n      \"pmids\": [\"34210956\", \"34741030\", \"34268303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ALPK2 phosphorylates DEPDC1 not tested\", \"Direct molecular link from DEPDC1 to Wnt pathway components missing\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped multilayered transcriptional and epigenetic control of DEPDC1 (FOXO3a repression, SIRT1/miR-20b-3p axis) and consolidated FOXM1 as a physical partner promoting Wnt signaling.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, Co-IP and immunofluorescence, drug-resistance and functional assays\",\n      \"pmids\": [\"35795985\", \"36200529\", \"36072787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of DEPDC1-FOXM1 interaction unknown\", \"Integration of competing regulators in a single cell context not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified kinesin partners (KIF4A) and Hippo, PI3K/AKT/mTOR, and glycolytic outputs, linking DEPDC1 to cytoskeletal motors and metabolic reprogramming.\",\n      \"evidence\": \"Co-IP, KIF4A/S100A16 rescue epistasis, western blots for Hippo and PI3K/Akt/mTOR proteins, glycolysis and angiogenesis assays\",\n      \"pmids\": [\"36849972\", \"37955537\", \"36768316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether kinesin binding relates to mitotic spindle function untested\", \"Causal hierarchy among the multiple downstream pathways unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a FOXM1-DEPDC1 positive feedback loop and additional RAS-ERK (via TTK), AKT/mTOR/HIF1\\u03b1, and TGF-\\u03b2 mechanisms underlying tumorigenesis and TKI resistance.\",\n      \"evidence\": \"ChIP, Co-IP, nuclear fractionation, luciferase, multi-omics, drug-resistance assays and in vivo models\",\n      \"pmids\": [\"39004911\", \"39016842\", \"39068164\", \"38960258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single protein coordinates so many distinct pathways mechanistically unclear\", \"Whether these reflect direct biochemical activities or indirect transcriptional effects undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined translational and motor-protein control of DEPDC1 (METTL5/m6A 18S rRNA, KIF20A), reinforcing post-transcriptional regulation and PI3K/AKT/mTOR coupling.\",\n      \"evidence\": \"Overexpression/knockdown with DEPDC1 protein westerns, Co-IP, pathway analysis, in vivo tumor models\",\n      \"pmids\": [\"40018408\", \"40600015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity of METTL5 effect on DEPDC1 versus global translation not isolated\", \"KIF20A-DEPDC1 functional relationship to spindle biology untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The core biochemical activity of DEPDC1 — whether it acts enzymatically, as a scaffold, or as a GTPase regulator via its DEP domain — remains undefined, leaving open how a mitotic centrosomal protein controls such diverse cytoplasmic and transcriptional pathways.\",\n      \"evidence\": \"No timeline discovery assigns a catalytic or defined molecular activity to DEPDC1\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model or domain-function map\", \"No reconstituted biochemical activity\", \"Mechanism unifying mitotic, transcriptional, and signaling roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 5, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 14, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 15, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ZNF224\", \"E2F1\", \"FOXM1\", \"ALPK2\", \"KIF4A\", \"KIF20A\", \"TTK\", \"S100A16\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}