{"gene":"CDK11B","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2008,"finding":"CDK11B (Cdc2l1) functions downstream of Smoothened (Smo) and upstream of Gli transcription factors in the Hedgehog (Hh) signaling pathway. It interacts with the negative regulator Suppressor of Fused (Sufu) and relieves its inhibition on Gli, providing a mechanism for Hh pathway activation. Knockdown abolished Hh signaling, while overexpression activated it, and zebrafish experiments confirmed in vivo activity.","method":"Kinome siRNA screen, genetic epistasis, co-immunoprecipitation with Sufu, overexpression rescue assays, zebrafish in vivo experiments","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding (Co-IP with Sufu), epistasis placement between Smo and Gli, replicated in vivo in zebrafish, multiple orthogonal methods in one study","pmids":["18827223"],"is_preprint":false},{"year":2014,"finding":"CDK11(p58) inhibits invasion and migration of ERα-positive breast cancer cells in a kinase-dependent manner by repressing integrin β3 expression through suppression of ERα signaling; CDK11(p58) inhibits the integrin β3 promoter via ERα repression.","method":"Transwell invasion assay, dual-luciferase reporter assay, qRT-PCR, siRNA knockdown of ERα, kinase-dead mutant analysis, TaqMan metastasis gene expression assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant used to establish kinase dependence, luciferase promoter assay, multiple methods but single lab","pmids":["25106495"],"is_preprint":false},{"year":2015,"finding":"CDK11(p58) inhibits breast cancer growth and angiogenesis in a kinase-activity-dependent manner by suppressing VEGF mRNA levels and VEGF promoter activity; kinase-dead mutant failed to inhibit VEGF, confirming kinase dependence.","method":"In vivo xenograft tumorigenicity assay, dual-luciferase reporter assay, real-time PCR, Western blot, kinase-dead mutant, immunohistochemistry","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant confirms catalytic requirement, in vivo and in vitro corroboration, single lab","pmids":["26470709"],"is_preprint":false},{"year":2017,"finding":"DNA methylation of the CDC2L1 gene promoter region in keloid fibroblasts suppresses CDK11p58 protein expression; treatment with the demethylating agent 5-aza-2'-deoxycytidine restored CDK11p58 expression in a dose-dependent manner and increased fibroblast apoptosis.","method":"Bisulfite sequencing, methylation-specific PCR, 5-aza-dC pharmacological demethylation, Western blot, apoptosis assay","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter methylation demonstrated by bisulfite sequencing with pharmacological reversal confirming functional consequence, single lab","pmids":["29204684"],"is_preprint":false},{"year":2020,"finding":"CDK11B promotes ubiquitin-proteasome-mediated degradation of the transcription factor SPDEF in hepatocellular carcinoma (HCC) stem cells. SPDEF degradation by CDK11B relieves SPDEF-dependent transcriptional activation of miR-448, which in turn suppresses DOT1L; this axis promotes self-renewal of HCC stem cells. Knockdown of CDK11B attenuated self-renewal and in vivo oncogenicity.","method":"Co-immunoprecipitation, ubiquitination-IP, ChIP assay, RT-qPCR, Western blot, sphere formation assay, colony formation assay, xenograft tumor model","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination-IP establish CDK11B-SPDEF interaction and ubiquitination, in vivo xenograft validation, but single lab","pmids":["33328586"],"is_preprint":false},{"year":2025,"finding":"USP22 deubiquitinates and stabilizes CDK11B protein in hepatocellular carcinoma cells; deubiquitination of CDK11B by USP22 promotes HCC cell proliferation, as demonstrated by flag affinity purification/mass spectrometry, co-immunoprecipitation, and ubiquitination assays.","method":"Flag affinity purification coupled with mass spectrometry, co-immunoprecipitation, ubiquitination assay, cellular proliferation assays, mouse tumor-bearing experiments","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay establish USP22 as deubiquitinase/stabilizer of CDK11B, in vivo validation, but single lab","pmids":["40341781"],"is_preprint":false},{"year":2026,"finding":"CDK11 inhibition by OTS964 induces G2/M cell cycle arrest and disrupts RNA splicing via SF3B1 dephosphorylation in rhabdoid tumor cells, ultimately triggering apoptosis through caspase-3 activation; CDK11B (but not CDK11A) was found upregulated in RTK.","method":"CDK11 inhibitor OTS964, flow cytometry for cell cycle, immunoblotting, RT-PCR for splicing, Sulforhodamine B cytotoxicity assay, xenograft mouse model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor with defined molecular readouts (SF3B1 dephosphorylation, caspase-3), in vivo xenograft, but inhibitor used is not purely CDK11B-specific and single lab","pmids":["41595181"],"is_preprint":false},{"year":2004,"finding":"The CDC2L1 (Cdc2L1) gene promoter lacks TATA and CAAT boxes and is GC-rich; basal transcription requires the region from -152 to +11. Two Ets-1 sites and a Skn-1 site are critical for transcriptional activity; Ets-1 and Skn-1 transcription factors bind the endogenous promoter in vivo, as confirmed by ChIP.","method":"Deletion analysis, site-directed mutagenesis, transfection/luciferase reporter assays, chromatin immunoprecipitation (ChIP)","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms in vivo binding, mutagenesis identifies critical elements, single lab","pmids":["15656972"],"is_preprint":false},{"year":1998,"finding":"CDC2L1 and CDC2L2 (Cdc2L1/Cdc2L2) span ~140 kb on chromosome 1p36.3, are organized as a duplicated genomic region with adjacent MMP genes, and express >20 different transcripts from two promoter/5'UTR regions (CpG1 ubiquitous; CpG2 tissue/cell-line specific) encoding protein kinases with functions relevant to transcription/splicing regulation and apoptotic signaling.","method":"Genomic sequencing, Southern blotting, RT-PCR transcript mapping, VNTR analysis","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comprehensive genomic characterization establishing gene structure and transcript diversity, single study","pmids":["9750192"],"is_preprint":false},{"year":2015,"finding":"CDK11B knockdown reduces IFNβ production in response to viral RNA in RIG-I-like receptor (RLR) pathway activation, suggesting CDK11B positively regulates innate antiviral signaling; identified by RNAi knockdown screen with validated functional readout.","method":"RNAi knockdown, IFNβ production assay (ELISA/reporter), integrative genomics prediction followed by experimental validation","journal":"PLoS computational biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RNAi knockdown with phenotypic readout but no direct molecular mechanism or pathway placement established","pmids":["26485378"],"is_preprint":false}],"current_model":"CDK11B (CDC2L1) encodes a serine/threonine protein kinase that acts downstream of Smoothened and upstream of Gli in the Hedgehog pathway (by relieving Sufu-mediated repression), promotes ubiquitin-proteasome-dependent degradation of SPDEF to drive hepatocellular carcinoma stem cell self-renewal, is itself stabilized by USP22-mediated deubiquitination, inhibits breast cancer invasion/angiogenesis through kinase-dependent suppression of ERα/integrin β3 and VEGF signaling, regulates G2/M progression and RNA splicing (via SF3B1), and is transcriptionally controlled by Ets-1 and Skn-1 at its promoter; promoter methylation silences the gene and reduces apoptosis in keloid fibroblasts."},"narrative":{"mechanistic_narrative":"CDK11B (CDC2L1) encodes a serine/threonine protein kinase that operates across signal transduction, cell-cycle progression, RNA splicing, and protein turnover, with context-dependent roles in development and cancer [PMID:18827223, PMID:41595181]. In Hedgehog signaling it acts downstream of Smoothened and upstream of Gli, binding the negative regulator Suppressor of Fused (Sufu) and relieving its repression of Gli to activate the pathway in vivo [PMID:18827223]. As a catalytically active kinase it exerts tumor-suppressive functions in breast cancer, inhibiting invasion by repressing integrin β3 through suppression of ERα signaling [PMID:25106495] and limiting growth and angiogenesis by suppressing VEGF expression [PMID:26470709]; both effects require kinase activity. In hepatocellular carcinoma it instead drives malignancy by promoting ubiquitin-proteasome-dependent degradation of the transcription factor SPDEF, relieving the SPDEF–miR-448–DOT1L axis to sustain stem-cell self-renewal [PMID:33328586], and its own stability is controlled by USP22-mediated deubiquitination [PMID:40341781]. CDK11B regulates G2/M progression and RNA splicing via SF3B1 phosphorylation, and its inhibition triggers caspase-3–dependent apoptosis [PMID:41595181]. Transcriptionally, the gene is driven by a TATA-less GC-rich promoter requiring Ets-1 and Skn-1 binding sites [PMID:15656972], and promoter DNA methylation silences expression and reduces apoptosis in keloid fibroblasts [PMID:29204684].","teleology":[{"year":1998,"claim":"Before functional characterization, the genomic architecture and transcript diversity of the locus were unknown; this work established CDC2L1 as part of a duplicated 1p36.3 region producing many kinase isoforms from two promoters.","evidence":"Genomic sequencing, Southern blotting, RT-PCR transcript mapping in human genomic DNA","pmids":["9750192"],"confidence":"Medium","gaps":["Does not assign function to individual transcripts","Does not distinguish CDC2L1 from the adjacent paralog CDC2L2 functionally"]},{"year":2004,"claim":"It was unclear how CDC2L1 expression is controlled; this work mapped the basal promoter and identified the transcription factors that drive it.","evidence":"Deletion analysis, site-directed mutagenesis, luciferase reporters, and ChIP in cultured cells","pmids":["15656972"],"confidence":"Medium","gaps":["Does not connect promoter usage to physiological signals","Does not address isoform-specific regulation"]},{"year":2008,"claim":"The role of CDK11B in a defined signaling pathway was unknown; this work placed it between Smoothened and Gli in Hedgehog signaling via Sufu.","evidence":"Kinome siRNA screen, genetic epistasis, Co-IP with Sufu, overexpression rescue, and zebrafish in vivo assays","pmids":["18827223"],"confidence":"High","gaps":["Does not identify a direct phosphorylation substrate within the pathway","Mechanism by which Sufu inhibition is relieved not resolved at the molecular level"]},{"year":2014,"claim":"Whether CDK11B influences tumor cell behavior was unaddressed; this work showed kinase-dependent suppression of breast cancer invasion via ERα/integrin β3.","evidence":"Transwell invasion, dual-luciferase reporter, qRT-PCR, ERα siRNA, and kinase-dead mutant analysis in ERα-positive breast cancer cells","pmids":["25106495"],"confidence":"Medium","gaps":["Direct substrate linking kinase activity to ERα repression not identified","Single lab, in vitro emphasis"]},{"year":2015,"claim":"Building on the anti-invasion role, this work extended CDK11B's tumor-suppressive function to growth and angiogenesis through kinase-dependent VEGF suppression.","evidence":"Xenograft tumorigenicity, dual-luciferase reporter, real-time PCR, kinase-dead mutant, and IHC","pmids":["26470709"],"confidence":"Medium","gaps":["Mechanism linking kinase activity to VEGF transcription not defined","Single lab"]},{"year":2017,"claim":"It was unknown whether epigenetic silencing modulates CDK11p58 in disease; this work showed promoter methylation suppresses expression and reduces apoptosis in keloid fibroblasts.","evidence":"Bisulfite sequencing, methylation-specific PCR, 5-aza-dC demethylation, and apoptosis assays","pmids":["29204684"],"confidence":"Medium","gaps":["Does not define the apoptotic effectors downstream of CDK11p58","Single tissue context"]},{"year":2020,"claim":"In contrast to its breast-cancer tumor-suppressor role, this work revealed an oncogenic function in hepatocellular carcinoma via degradation of SPDEF.","evidence":"Co-IP, ubiquitination-IP, ChIP, sphere/colony formation, and xenograft assays in HCC stem cells","pmids":["33328586"],"confidence":"Medium","gaps":["Whether SPDEF degradation requires CDK11B kinase activity not established","Direct ubiquitin ligase recruited not identified"]},{"year":2025,"claim":"How CDK11B protein levels are maintained in HCC was unknown; this work identified USP22 as the deubiquitinase that stabilizes CDK11B to promote proliferation.","evidence":"Flag affinity purification/mass spectrometry, Co-IP, ubiquitination assay, proliferation assays, and tumor-bearing mouse experiments","pmids":["40341781"],"confidence":"Medium","gaps":["Specific ubiquitin sites on CDK11B not mapped","Single lab"]},{"year":2026,"claim":"The cell-cycle and splicing functions of CDK11B in tumors were unresolved; this work linked CDK11 inhibition to G2/M arrest, SF3B1 dephosphorylation, and apoptosis in rhabdoid tumor.","evidence":"OTS964 inhibitor, flow cytometry, immunoblotting, RT-PCR splicing readouts, and xenograft model","pmids":["41595181"],"confidence":"Medium","gaps":["Inhibitor OTS964 is not CDK11B-specific","Does not isolate CDK11B from CDK11A activity functionally"]},{"year":null,"claim":"It remains unresolved how CDK11B's opposing tumor-suppressive (breast) and oncogenic (liver) roles are determined, and what direct phosphorylation substrates connect its kinase activity to Hedgehog, splicing, and transcriptional outputs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying direct substrate identified across contexts","Context-dependent switch between tumor suppressor and oncogene unexplained","No structural model of kinase-substrate engagement"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["SUFU","SPDEF","USP22","SF3B1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P21127","full_name":"Cyclin-dependent kinase 11B","aliases":["Cell division cycle 2-like protein kinase 1","CLK-1","Cell division protein kinase 11B","Galactosyltransferase-associated protein kinase p58/GTA","PITSLRE serine/threonine-protein kinase CDC2L1","p58 CLK-1"],"length_aa":795,"mass_kda":92.6,"function":"Cyclin-dependent protein kinase that acts as a regulator of transcription and pre-mRNA splicing (PubMed:12501247, PubMed:18216018, PubMed:32367068, PubMed:36104565). Acts as a key regulator of pre-mRNA splicing by mediating phosphorylation of SF3B1, enabling the association between SF3B1 and U5 and U6 snRNAs in the activated spliceosome, thereby promoting spliceosome assembly (PubMed:36104565, PubMed:38059508). Also acts as a regulator of transcription by phosphorylating 'Ser-2' of the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A (PubMed:32367068, PubMed:40858114). Involved in replication-dependent transcription of histone genes: binds to histone genes and phosphorylates POLR2A at 'Ser-2' of the CTD to specifically control transcriptional elongation of histones and recruitment of 3'-end processing factors (PubMed:32367068). Part of a transcription checkpoint upstream of CDK9, which regulates promoter-proximal pausing by RNA polymerase II, a transcription halt following transcription initiation, but prior to elongation (PubMed:40858114). Probably regulates promoter-proximal pausing by mediating phosphorylation of POLR2A at 'Ser-2' of the CTD (PubMed:40858114) Isoform expressed in a non-cell cycle-dependent manner Isoform specifically expressed during the G2-M phases of the cell cycle (PubMed:12082095, PubMed:2217177). Phosphorylates 'Ser-2' of the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A (PubMed:38019613). Promotes centromeric transcription to maintain centromeric cohesion during mitosis (PubMed:24436071, PubMed:38019613)","subcellular_location":"Nucleus; Chromosome, centromere","url":"https://www.uniprot.org/uniprotkb/P21127/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDK11B","classification":"Common Essential","n_dependent_lines":4,"n_total_lines":5,"dependency_fraction":0.8},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000248333","cell_line_id":"CID001144","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"CDC37","stoichiometry":10.0},{"gene":"CDK11B;CDK11A","stoichiometry":10.0},{"gene":"SAP30BP","stoichiometry":10.0},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001144","total_profiled":1310},"omim":[{"mim_id":"176873","title":"CYCLIN-DEPENDENT KINASE 11B; CDK11B","url":"https://www.omim.org/entry/176873"},{"mim_id":"116951","title":"CYCLIN-DEPENDENT KINASE 11A; CDK11A","url":"https://www.omim.org/entry/116951"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CDK11B"},"hgnc":{"alias_symbol":["CDK11-p110","CDK11-p58","CDK11-p46"],"prev_symbol":["CDC2L1"]},"alphafold":{"accession":"P21127","domains":[{"cath_id":"3.30.200.20","chopping":"436-519","consensus_level":"high","plddt":83.2711,"start":436,"end":519},{"cath_id":"1.10.510.10","chopping":"523-742","consensus_level":"high","plddt":89.996,"start":523,"end":742}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21127","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21127-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21127-F1-predicted_aligned_error_v6.png","plddt_mean":64.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDK11B","jax_strain_url":"https://www.jax.org/strain/search?query=CDK11B"},"sequence":{"accession":"P21127","fasta_url":"https://rest.uniprot.org/uniprotkb/P21127.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21127/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21127"}},"corpus_meta":[{"pmid":"11983916","id":"PMC_11983916","title":"Characterization 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40341781","citation_count":4,"is_preprint":false},{"pmid":"40368138","id":"PMC_40368138","title":"Proteomics and Phosphoproteomics Revealed Dysregulated Kinases and Potential Therapy for Liver Fibrosis.","date":"2025","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/40368138","citation_count":4,"is_preprint":false},{"pmid":"41595181","id":"PMC_41595181","title":"Targeting CDK11 in Rhabdoid Tumor of the Kidney.","date":"2026","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/41595181","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20142,"output_tokens":2652,"usd":0.050103,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9947,"output_tokens":3072,"usd":0.063268,"stage2_stop_reason":"end_turn"},"total_usd":0.113371,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"CDK11B (Cdc2l1) functions downstream of Smoothened (Smo) and upstream of Gli transcription factors in the Hedgehog (Hh) signaling pathway. It interacts with the negative regulator Suppressor of Fused (Sufu) and relieves its inhibition on Gli, providing a mechanism for Hh pathway activation. Knockdown abolished Hh signaling, while overexpression activated it, and zebrafish experiments confirmed in vivo activity.\",\n      \"method\": \"Kinome siRNA screen, genetic epistasis, co-immunoprecipitation with Sufu, overexpression rescue assays, zebrafish in vivo experiments\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding (Co-IP with Sufu), epistasis placement between Smo and Gli, replicated in vivo in zebrafish, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18827223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDK11(p58) inhibits invasion and migration of ERα-positive breast cancer cells in a kinase-dependent manner by repressing integrin β3 expression through suppression of ERα signaling; CDK11(p58) inhibits the integrin β3 promoter via ERα repression.\",\n      \"method\": \"Transwell invasion assay, dual-luciferase reporter assay, qRT-PCR, siRNA knockdown of ERα, kinase-dead mutant analysis, TaqMan metastasis gene expression assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant used to establish kinase dependence, luciferase promoter assay, multiple methods but single lab\",\n      \"pmids\": [\"25106495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDK11(p58) inhibits breast cancer growth and angiogenesis in a kinase-activity-dependent manner by suppressing VEGF mRNA levels and VEGF promoter activity; kinase-dead mutant failed to inhibit VEGF, confirming kinase dependence.\",\n      \"method\": \"In vivo xenograft tumorigenicity assay, dual-luciferase reporter assay, real-time PCR, Western blot, kinase-dead mutant, immunohistochemistry\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant confirms catalytic requirement, in vivo and in vitro corroboration, single lab\",\n      \"pmids\": [\"26470709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DNA methylation of the CDC2L1 gene promoter region in keloid fibroblasts suppresses CDK11p58 protein expression; treatment with the demethylating agent 5-aza-2'-deoxycytidine restored CDK11p58 expression in a dose-dependent manner and increased fibroblast apoptosis.\",\n      \"method\": \"Bisulfite sequencing, methylation-specific PCR, 5-aza-dC pharmacological demethylation, Western blot, apoptosis assay\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter methylation demonstrated by bisulfite sequencing with pharmacological reversal confirming functional consequence, single lab\",\n      \"pmids\": [\"29204684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDK11B promotes ubiquitin-proteasome-mediated degradation of the transcription factor SPDEF in hepatocellular carcinoma (HCC) stem cells. SPDEF degradation by CDK11B relieves SPDEF-dependent transcriptional activation of miR-448, which in turn suppresses DOT1L; this axis promotes self-renewal of HCC stem cells. Knockdown of CDK11B attenuated self-renewal and in vivo oncogenicity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination-IP, ChIP assay, RT-qPCR, Western blot, sphere formation assay, colony formation assay, xenograft tumor model\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination-IP establish CDK11B-SPDEF interaction and ubiquitination, in vivo xenograft validation, but single lab\",\n      \"pmids\": [\"33328586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP22 deubiquitinates and stabilizes CDK11B protein in hepatocellular carcinoma cells; deubiquitination of CDK11B by USP22 promotes HCC cell proliferation, as demonstrated by flag affinity purification/mass spectrometry, co-immunoprecipitation, and ubiquitination assays.\",\n      \"method\": \"Flag affinity purification coupled with mass spectrometry, co-immunoprecipitation, ubiquitination assay, cellular proliferation assays, mouse tumor-bearing experiments\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay establish USP22 as deubiquitinase/stabilizer of CDK11B, in vivo validation, but single lab\",\n      \"pmids\": [\"40341781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CDK11 inhibition by OTS964 induces G2/M cell cycle arrest and disrupts RNA splicing via SF3B1 dephosphorylation in rhabdoid tumor cells, ultimately triggering apoptosis through caspase-3 activation; CDK11B (but not CDK11A) was found upregulated in RTK.\",\n      \"method\": \"CDK11 inhibitor OTS964, flow cytometry for cell cycle, immunoblotting, RT-PCR for splicing, Sulforhodamine B cytotoxicity assay, xenograft mouse model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor with defined molecular readouts (SF3B1 dephosphorylation, caspase-3), in vivo xenograft, but inhibitor used is not purely CDK11B-specific and single lab\",\n      \"pmids\": [\"41595181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The CDC2L1 (Cdc2L1) gene promoter lacks TATA and CAAT boxes and is GC-rich; basal transcription requires the region from -152 to +11. Two Ets-1 sites and a Skn-1 site are critical for transcriptional activity; Ets-1 and Skn-1 transcription factors bind the endogenous promoter in vivo, as confirmed by ChIP.\",\n      \"method\": \"Deletion analysis, site-directed mutagenesis, transfection/luciferase reporter assays, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms in vivo binding, mutagenesis identifies critical elements, single lab\",\n      \"pmids\": [\"15656972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CDC2L1 and CDC2L2 (Cdc2L1/Cdc2L2) span ~140 kb on chromosome 1p36.3, are organized as a duplicated genomic region with adjacent MMP genes, and express >20 different transcripts from two promoter/5'UTR regions (CpG1 ubiquitous; CpG2 tissue/cell-line specific) encoding protein kinases with functions relevant to transcription/splicing regulation and apoptotic signaling.\",\n      \"method\": \"Genomic sequencing, Southern blotting, RT-PCR transcript mapping, VNTR analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive genomic characterization establishing gene structure and transcript diversity, single study\",\n      \"pmids\": [\"9750192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDK11B knockdown reduces IFNβ production in response to viral RNA in RIG-I-like receptor (RLR) pathway activation, suggesting CDK11B positively regulates innate antiviral signaling; identified by RNAi knockdown screen with validated functional readout.\",\n      \"method\": \"RNAi knockdown, IFNβ production assay (ELISA/reporter), integrative genomics prediction followed by experimental validation\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RNAi knockdown with phenotypic readout but no direct molecular mechanism or pathway placement established\",\n      \"pmids\": [\"26485378\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDK11B (CDC2L1) encodes a serine/threonine protein kinase that acts downstream of Smoothened and upstream of Gli in the Hedgehog pathway (by relieving Sufu-mediated repression), promotes ubiquitin-proteasome-dependent degradation of SPDEF to drive hepatocellular carcinoma stem cell self-renewal, is itself stabilized by USP22-mediated deubiquitination, inhibits breast cancer invasion/angiogenesis through kinase-dependent suppression of ERα/integrin β3 and VEGF signaling, regulates G2/M progression and RNA splicing (via SF3B1), and is transcriptionally controlled by Ets-1 and Skn-1 at its promoter; promoter methylation silences the gene and reduces apoptosis in keloid fibroblasts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDK11B (CDC2L1) encodes a serine/threonine protein kinase that operates across signal transduction, cell-cycle progression, RNA splicing, and protein turnover, with context-dependent roles in development and cancer [#0, #6]. In Hedgehog signaling it acts downstream of Smoothened and upstream of Gli, binding the negative regulator Suppressor of Fused (Sufu) and relieving its repression of Gli to activate the pathway in vivo [#0]. As a catalytically active kinase it exerts tumor-suppressive functions in breast cancer, inhibiting invasion by repressing integrin \\u03b23 through suppression of ER\\u03b1 signaling [#1] and limiting growth and angiogenesis by suppressing VEGF expression [#2]; both effects require kinase activity. In hepatocellular carcinoma it instead drives malignancy by promoting ubiquitin-proteasome-dependent degradation of the transcription factor SPDEF, relieving the SPDEF\\u2013miR-448\\u2013DOT1L axis to sustain stem-cell self-renewal [#4], and its own stability is controlled by USP22-mediated deubiquitination [#5]. CDK11B regulates G2/M progression and RNA splicing via SF3B1 phosphorylation, and its inhibition triggers caspase-3\\u2013dependent apoptosis [#6]. Transcriptionally, the gene is driven by a TATA-less GC-rich promoter requiring Ets-1 and Skn-1 binding sites [#7], and promoter DNA methylation silences expression and reduces apoptosis in keloid fibroblasts [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Before functional characterization, the genomic architecture and transcript diversity of the locus were unknown; this work established CDC2L1 as part of a duplicated 1p36.3 region producing many kinase isoforms from two promoters.\",\n      \"evidence\": \"Genomic sequencing, Southern blotting, RT-PCR transcript mapping in human genomic DNA\",\n      \"pmids\": [\"9750192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not assign function to individual transcripts\", \"Does not distinguish CDC2L1 from the adjacent paralog CDC2L2 functionally\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"It was unclear how CDC2L1 expression is controlled; this work mapped the basal promoter and identified the transcription factors that drive it.\",\n      \"evidence\": \"Deletion analysis, site-directed mutagenesis, luciferase reporters, and ChIP in cultured cells\",\n      \"pmids\": [\"15656972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not connect promoter usage to physiological signals\", \"Does not address isoform-specific regulation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The role of CDK11B in a defined signaling pathway was unknown; this work placed it between Smoothened and Gli in Hedgehog signaling via Sufu.\",\n      \"evidence\": \"Kinome siRNA screen, genetic epistasis, Co-IP with Sufu, overexpression rescue, and zebrafish in vivo assays\",\n      \"pmids\": [\"18827223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify a direct phosphorylation substrate within the pathway\", \"Mechanism by which Sufu inhibition is relieved not resolved at the molecular level\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether CDK11B influences tumor cell behavior was unaddressed; this work showed kinase-dependent suppression of breast cancer invasion via ER\\u03b1/integrin \\u03b23.\",\n      \"evidence\": \"Transwell invasion, dual-luciferase reporter, qRT-PCR, ER\\u03b1 siRNA, and kinase-dead mutant analysis in ER\\u03b1-positive breast cancer cells\",\n      \"pmids\": [\"25106495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate linking kinase activity to ER\\u03b1 repression not identified\", \"Single lab, in vitro emphasis\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Building on the anti-invasion role, this work extended CDK11B's tumor-suppressive function to growth and angiogenesis through kinase-dependent VEGF suppression.\",\n      \"evidence\": \"Xenograft tumorigenicity, dual-luciferase reporter, real-time PCR, kinase-dead mutant, and IHC\",\n      \"pmids\": [\"26470709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking kinase activity to VEGF transcription not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"It was unknown whether epigenetic silencing modulates CDK11p58 in disease; this work showed promoter methylation suppresses expression and reduces apoptosis in keloid fibroblasts.\",\n      \"evidence\": \"Bisulfite sequencing, methylation-specific PCR, 5-aza-dC demethylation, and apoptosis assays\",\n      \"pmids\": [\"29204684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the apoptotic effectors downstream of CDK11p58\", \"Single tissue context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In contrast to its breast-cancer tumor-suppressor role, this work revealed an oncogenic function in hepatocellular carcinoma via degradation of SPDEF.\",\n      \"evidence\": \"Co-IP, ubiquitination-IP, ChIP, sphere/colony formation, and xenograft assays in HCC stem cells\",\n      \"pmids\": [\"33328586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SPDEF degradation requires CDK11B kinase activity not established\", \"Direct ubiquitin ligase recruited not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"How CDK11B protein levels are maintained in HCC was unknown; this work identified USP22 as the deubiquitinase that stabilizes CDK11B to promote proliferation.\",\n      \"evidence\": \"Flag affinity purification/mass spectrometry, Co-IP, ubiquitination assay, proliferation assays, and tumor-bearing mouse experiments\",\n      \"pmids\": [\"40341781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ubiquitin sites on CDK11B not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The cell-cycle and splicing functions of CDK11B in tumors were unresolved; this work linked CDK11 inhibition to G2/M arrest, SF3B1 dephosphorylation, and apoptosis in rhabdoid tumor.\",\n      \"evidence\": \"OTS964 inhibitor, flow cytometry, immunoblotting, RT-PCR splicing readouts, and xenograft model\",\n      \"pmids\": [\"41595181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibitor OTS964 is not CDK11B-specific\", \"Does not isolate CDK11B from CDK11A activity functionally\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CDK11B's opposing tumor-suppressive (breast) and oncogenic (liver) roles are determined, and what direct phosphorylation substrates connect its kinase activity to Hedgehog, splicing, and transcriptional outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying direct substrate identified across contexts\", \"Context-dependent switch between tumor suppressor and oncogene unexplained\", \"No structural model of kinase-substrate engagement\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SUFU\", \"SPDEF\", \"USP22\", \"SF3B1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}