{"gene":"CDK6","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1994,"finding":"CDK6 (PLSTIRE gene product) is a cyclin-dependent kinase that associates with cyclins D1, D2, and D3 in human cell lysates and is activated by coexpression with D-type cyclins in Sf9 insect cells. Endogenous CDK6 phosphorylates pRB (retinoblastoma protein) in vitro, and its kinase activity is activated during mid-G1 in phytohemagglutinin-stimulated T cells.","method":"Co-immunoprecipitation from human cell lysates, Sf9 insect cell coexpression, in vitro pRB phosphorylation assay, kinase activity timing in primary T cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with defined substrate (pRB), reconstitution in insect cells, multiple orthogonal methods, foundational study replicated by many subsequent labs","pmids":["8114739"],"is_preprint":false},{"year":1994,"finding":"CDK6 (PLSTIRE) and CDK4 (PSK-J3) form a distinct subset of CDKs that associate specifically with cyclin D1 in a squamous carcinoma cell line; in diploid fibroblasts, CDK2 and CDK5 can also co-precipitate with cyclin D1 alongside CDK4.","method":"Co-immunoprecipitation from tumor cell lines and human diploid fibroblasts","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in multiple cell types, independently confirming the cyclin D1-CDK6 interaction established in PMID:8114739","pmids":["8302605"],"is_preprint":false},{"year":1995,"finding":"CDK6 (PLSTIRE/p40cdk6) is the earliest inducible CDK in mitogen-stimulated human T lymphocytes. Cyclins D2 and D3 are the major associated cyclins, with D2 predominating in early G1. Kinase activity (measured by in vitro phosphorylation of recombinant truncated Rb) parallels protein accumulation and occurs independently of IL-2-mediated cell cycle progression.","method":"Immunoprecipitation/kinase assay with recombinant Rb substrate, co-immunoprecipitation of cyclin partners, cyclosporin A/FK506 treatment to dissect IL-2 dependence","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with defined substrate, pharmacological dissection, single lab but multiple orthogonal methods","pmids":["7759865"],"is_preprint":false},{"year":2001,"finding":"The CDK6-cyclin D3 complex uniquely evades inhibition by p27(KIP1) and p21(CIP1) compared with other cyclin D-CDK combinations, retaining kinase activity in anchorage-minus G1-arrested fibroblasts. Overexpression of both CDK6 and cyclin D3 confers resistance to serum starvation- and contact-inhibition-induced G1 arrest.","method":"Kinase activity assays in anchorage-independent conditions, overexpression in BALB/c 3T3 cells, comparison with other CDK-cyclin D combinations","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay and cell-based overexpression, single lab","pmids":["11360184"],"is_preprint":false},{"year":2007,"finding":"CDK6 binds to the runt domain of Runx1 (a hematopoietic transcription factor), interfering with Runx1 DNA binding and Runx1-C/EBPα interaction, thereby blocking myeloid differentiation. This function does not require CDK6 kinase activity.","method":"Co-immunoprecipitation (CDK6-Runx1 interaction), DNA-binding assays, kinase-dead CDK6 mutant overexpression, in vitro and in vivo differentiation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, kinase-dead mutant, multiple functional readouts in vitro and in vivo in single study","pmids":["17431401"],"is_preprint":false},{"year":2007,"finding":"CDK4 and CDK6 extend the replicative lifespan of human diploid fibroblasts through a mechanism requiring their kinase activity, as catalytically inactive versions fail to extend lifespan. This extension is independent of p16(INK4a) sequestration.","method":"Kinase-dead mutant expression, INK4a knockout fibroblasts, replicative lifespan assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant combined with genetic INK4a loss, single lab, two orthogonal approaches","pmids":["17420273"],"is_preprint":false},{"year":2011,"finding":"CDK6 kinase activity is required for early thymocyte development and HSC/progenitor function. Kinase-dead CDK6 (K43M knock-in) reduces thymocyte and LSK numbers and disrupts Notch-dependent survival/differentiation, including massive upregulation of CD25. INK4-insensitive hyperactive CDK6 (R31C) causes excess proliferation countered by increased apoptosis. CDK6 modulates Notch target gene expression downstream of Notch signaling.","method":"Knock-in mice expressing kinase-dead (K43M) or INK4-insensitive (R31C) CDK6 alleles, hematopoietic phenotyping, Notch target gene expression analysis, CD25 knockout rescue experiment","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in mutant mice with specific alleles, genetic rescue (CD25 knockout), multiple phenotypic readouts","pmids":["21508411"],"is_preprint":false},{"year":2013,"finding":"CDK6 is part of a transcription complex that induces expression of VEGF-A (pro-angiogenic) and p16(INK4a) in lymphoid malignancy cells. This transcriptional function is independent of CDK6 kinase activity and is not shared by CDK4.","method":"Transcription complex identification, shRNA knockdown, kinase-dead CDK6 mutant, B-ALL mouse model with p185BCR-ABL+, VEGF-A and p16 promoter assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant combined with in vivo leukemia model and promoter analysis, single lab but multiple orthogonal approaches","pmids":["23948297"],"is_preprint":false},{"year":2013,"finding":"CDK6 binds to and promotes degradation of the EYA2 protein (a transcriptional activator/phosphatase involved in development), establishing a novel CDK6 interaction partner beyond the established pRB pathway.","method":"Co-immunoprecipitation (CDK6-EYA2), protein degradation assays","journal":"Cell cycle","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and degradation assay, single lab, limited mechanistic follow-up described in abstract","pmids":["24196439"],"is_preprint":false},{"year":2014,"finding":"CDK6 functions as part of a transcriptional complex in hematopoietic and leukemic stem cells, suppressing Egr1 transcription. CDK6-deficient HSCs fail to efficiently repopulate and are more susceptible to 5-FU treatment. In BCR-ABL(p210+) leukemic stem cells, CDK6 loss impairs disease induction, and Egr1 knockdown in CDK6-deficient LSKs rescues colony formation, establishing a CDK6-Egr1 axis.","method":"Cdk6-/- mice, competitive transplantation, 5-FU challenge, BCR-ABL transformation, transcriptional profiling, Egr1 shRNA knockdown rescue experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with epistasis rescue (Egr1 knockdown), multiple in vivo assays, replicated mechanistic concept across normal and leukemic stem cells","pmids":["25342715"],"is_preprint":false},{"year":2014,"finding":"CDK6 SUMOylation at Lys216 by UBC9 (mediated by CDK1 phosphorylation of UBC9 during mitosis) stabilizes CDK6 protein throughout the cell cycle. CDK6 SUMOylation at Lys216 blocks ubiquitination at Lys147, preventing ubiquitin-mediated CDK6 degradation. This mechanism operates in glioblastoma.","method":"SUMO1 modification identification, site-directed mutagenesis (K216 and K147), UBC9 co-immunoprecipitation, ubiquitination assays, CDK1 phosphorylation of UBC9 demonstrated","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of modification sites, identification of writer (UBC9/CDK1), competition between SUMO and ubiquitin pathways, multiple orthogonal biochemical methods in single study","pmids":["24953629"],"is_preprint":false},{"year":2014,"finding":"In MLL-rearranged AML, CDK6 is transcriptionally activated by mutant MLL and is required for maintaining the differentiation block. Depletion of CDK6 (but not CDK4) induces myeloid differentiation, and this is phenocopied by a selective CDK6 small-molecule inhibitor.","method":"shRNA knockdown (CDK6 vs CDK4 selectivity), MLL-AF9 mouse model, myeloid differentiation assays, CDK6 inhibitor treatment","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic selectivity (CDK6 vs CDK4 knockdown), in vivo mouse model, pharmacological confirmation, independent validation across multiple MLL fusion contexts","pmids":["24764564"],"is_preprint":false},{"year":2015,"finding":"CDK6 protein levels regulate quiescence exit kinetics in human HSC subsets. Long-term HSCs (LT-HSCs) lack CDK6 protein; short-term HSCs (ST-HSCs) contain high CDK6 protein and enter the cell cycle rapidly upon stimulation. Enforced CDK6 expression in LT-HSCs shortens quiescence exit and confers competitive advantage without impairing function.","method":"Western blotting for CDK6 protein in sorted human HSC subsets, lentiviral CDK6 overexpression, competitive transplantation, time-lapse imaging of cell cycle entry","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein quantification across sorted HSC subsets, gain-of-function with functional readout (competitive repopulation), computational modeling validation","pmids":["25704240"],"is_preprint":false},{"year":2017,"finding":"Cyclin D3-CDK6 kinase phosphorylates and inhibits two key glycolytic enzymes, 6-phosphofructokinase (PFKP) and pyruvate kinase M2 (PKM2), redirecting glycolytic intermediates into the pentose phosphate pathway and serine synthesis pathway. Inhibition of cyclin D3-CDK6 depletes NADPH and glutathione, increases reactive oxygen species, and causes apoptosis in tumor cells.","method":"In vitro kinase assays with 6-phosphofructokinase and PKM2 as substrates, patient-derived xenografts in mice, metabolic flux analysis, CDK6 inhibitor treatment","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay demonstrating phosphorylation of metabolic enzyme substrates, validated in vivo with xenografts, multiple orthogonal metabolic readouts","pmids":["28607489"],"is_preprint":false},{"year":2017,"finding":"Hedgehog signaling drives CDK6 expression through GLI2 binding to the Cdk6 promoter in medulloblastoma. CDK6 is identified as a direct transcriptional target of the Hedgehog/GLI2 pathway, and CDK6 promotes uncontrolled cell proliferation in Hh-associated medulloblastoma.","method":"Gli2-EGFP reporter knock-in mouse models of Hh-associated medulloblastoma, GLI2 ChIP on Cdk6 promoter, genetic and pharmacological CDK6 inhibition, survival analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct promoter binding, in vivo genetic models, pharmacological validation in two mouse models","pmids":["29202464"],"is_preprint":false},{"year":2017,"finding":"In Ph+ ALL cells, CDK6 is predominantly localized in the nucleus (whereas CDK4 is almost exclusively cytoplasmic), and CDK6 expression is required for Ph+ ALL cell growth through MYB-mediated transcriptional upregulation of CDK6, cyclin D3, and BCL2.","method":"Immunofluorescence/subcellular fractionation showing differential CDK6/CDK4 localization, MYB shRNA knockdown with rescue by CDK6 re-expression, pharmacological CDK6 inhibition in vitro and in vivo","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization by immunofluorescence with functional consequence, MYB-CDK6 transcriptional axis established by epistasis, single lab","pmids":["29233926"],"is_preprint":false},{"year":2018,"finding":"CDK6 kinase activity negatively regulates the conversion of white fat to beige fat (browning) by suppressing RUNX1. CDK6-null or kinase-dead (K43M) mice show increased beige fat formation and energy expenditure. Re-expression of CDK6 in CDK6-null cells or RUNX1 ablation in K43M cells reverses these phenotypes. RUNX1 binds to proximal promoter regions of Ucp-1 and Pgc1α.","method":"CDK6 knockout and kinase-dead knock-in mice, adipocyte-specific CDK6 re-expression, RUNX1 knockout, ChIP of RUNX1 on Ucp-1 and Pgc1α promoters, metabolic phenotyping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with CDK6 KO, kinase-dead KI, and RUNX1 KO rescue; ChIP validation; multiple metabolic readouts; single lab with orthogonal genetic approaches","pmids":["29523786"],"is_preprint":false},{"year":2018,"finding":"CDK6 kinase activity promotes a transcriptional program that antagonizes p53 responses in hematopoietic cells. CDK6 binds to promoters of p53 antagonists including Prmt5, Ppm1d, and Mdm4. Cells lacking CDK6 kinase function require TP53 mutation to achieve fully transformed immortalized state.","method":"CDK6 ChIP at promoters of p53 antagonist genes, kinase-dead CDK6 mouse models, immortalization assays, TP53 mutation frequency analysis in human tumors with low CDK6","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct CDK6 promoter binding, kinase-dead genetic model, human tumor correlation, multiple orthogonal approaches in single study","pmids":["29899063"],"is_preprint":false},{"year":2019,"finding":"CDK6 in JAK2V617F MPN coordinates NF-κB signaling, promotes cytokine production, and inhibits apoptosis in addition to regulating malignant stem cell quiescence. These effects are largely kinase-independent, as palbociclib (kinase inhibitor) does not mirror the effects of CDK6 absence.","method":"Cdk6-/- mice in JAK2V617F MPN model, palbociclib treatment comparison, NF-κB signaling assays, apoptosis and cytokine production measurements","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO vs pharmacological kinase inhibition comparison establishing kinase-independent function, in vivo MPN model, single lab","pmids":["30635286"],"is_preprint":false},{"year":2019,"finding":"In AML with FLT3-ITD mutations, CDK6 (but not CDK4) is overexpressed through a signaling pathway involving FLT3-ITD → SRC-family kinase HCK → CDK6. FLT3-ITD fails to transform primary hematopoietic progenitors from Cdk6-/- mice, establishing CDK6 as the primary target of CDK4/6 inhibitors in this AML subtype.","method":"Cdk6-/- mouse hematopoietic progenitor transformation assays, shRNA knockdown of CDK6 vs CDK4, HCK inhibition, FLT3-ITD signaling pathway dissection","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO transformation assay as epistasis, pharmacological pathway dissection, single lab","pmids":["27323399"],"is_preprint":false},{"year":2019,"finding":"In melanoma cells, CDK6 knockdown reduces VEGF-A expression and endothelial cell stimulation; this effect is associated with reduced CDK6 localization on the VEGF-A promoter, establishing a CDK6 transcriptional role in tumor angiogenesis in solid tumors.","method":"shRNA knockdown of CDK4 vs CDK6, CDK6 ChIP on VEGF-A promoter, xenotransplantation mouse model, endothelial cell growth stimulation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP evidence for CDK6 at VEGF-A promoter, in vivo xenograft validation, CDK4 vs CDK6 comparison, single lab","pmids":["30858922"],"is_preprint":false},{"year":2019,"finding":"UBE2N (ubiquitin-conjugating enzyme 2N) promotes CDK6 protein degradation through ubiquitination. miR-934 targets the 3'-UTR of UBE2N mRNA, downregulating UBE2N protein, which in turn attenuates CDK6 ubiquitination and promotes CDK6 protein accumulation in bladder cancer cells.","method":"miR-934 binding to UBE2N 3'-UTR confirmed by luciferase reporter assay, UBE2N knockdown/overexpression, CDK6 protein stability assays, xenograft tumor growth in vivo","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — UBE2N identified as E2 for CDK6 ubiquitination, luciferase validation of miR-UBE2N interaction, in vivo xenograft confirmation, single lab","pmids":["31373842"],"is_preprint":false},{"year":2020,"finding":"Cyclin D-CDK4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. Pharmacological CDK4/6 inhibition leads to rapid, TSC2-dependent reduction of mTORC1 activity in multiple cell lines including breast cancer cells, coupling cell growth to cell cycle progression.","method":"In vitro CDK4/6 phosphorylation of TSC2 (identifying specific phosphorylation sites), pharmacological inhibition in multiple cell lines, TSC2 genetic rescue experiments, mTORC1 activity readouts","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay identifying specific TSC2 phosphorylation sites, TSC2-dependent genetic rescue, multiple cell lines, single lab","pmids":["32294430"],"is_preprint":false},{"year":2017,"finding":"CDK6 contributes to cytoskeletal stability in erythrocytes through kinase-dependent and kinase-independent mechanisms. In erythroblasts, CDK6 is partly associated with the cytoskeleton. Mass spectrometry identified CDK6 interaction with proteins involved in cytoskeleton organization including gelsolin. CDK6-deficient erythroblasts show impaired F-actin formation and lower gelsolin levels.","method":"Mass spectrometry of CDK6 interaction partners, Cdk6-/- mouse erythrocytes, F-actin staining, cytoskeletal fractionation, mechanical stress assays","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry interactome with functional validation (F-actin, gelsolin), genetic KO phenotype, single lab","pmids":["28255017"],"is_preprint":false},{"year":2021,"finding":"Tumors expressing both CDK4 and CDK6 have increased reliance on CDK6 for cell cycle progression. CDK4/6 inhibitors and degraders potently bind and inhibit CDK6 selectively in tumors where CDK6 is highly thermounstable and strongly associated with the HSP90/CDC37 chaperone complex. In contrast, thermostable CDK6 (not associated with HSP90/CDC37) is resistant to CDK4/6i binding.","method":"Thermal stability assays (CETSA), Co-IP of CDK6 with HSP90/CDC37, CDK6 degrader treatment, CRISPR CDK4/CDK6 differential dependency analysis","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — thermal stability assay distinguishing CDK6 conformational states, Co-IP identifying HSP90/CDC37 complex, multiple cell lines, CDK6-selective degraders validating mechanism","pmids":["34568836"],"is_preprint":false},{"year":2012,"finding":"The lncRNA gadd7, induced by UV irradiation, directly binds TDP-43 and interferes with the TDP-43-CDK6 mRNA interaction, resulting in CDK6 mRNA degradation and G1/S checkpoint enforcement. This establishes TDP-43 as an RNA-binding protein that stabilizes Cdk6 mRNA.","method":"RNA pull-down (gadd7-TDP-43 interaction), Co-IP (TDP-43-CDK6 mRNA RIP), UV irradiation, CDK6 mRNA stability assays, G1/S checkpoint analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA pulldown, RIP demonstrating displacement of TDP-43 from CDK6 mRNA, mRNA stability assays, functional checkpoint readout in single study","pmids":["23103768"],"is_preprint":false},{"year":2014,"finding":"In BCR-ABL(p210+) leukemogenesis, CDK6-deficient Cdk4 becomes more susceptible to p16(INK4a) binding (sequestration), whereas cells with both CDK4 R24C and CDK6 R31C (INK4-insensitive) alleles show accelerated disease. This demonstrates that CDK6 normally sequesters INK4 proteins away from CDK4.","method":"Cdk6 R31C knock-in mice, double Cdk4 R24C/Cdk6 R31C knock-in, BCR-ABL transformation assays, INK4 binding co-immunoprecipitation, hematopoietic transplantation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with two INK4-insensitive alleles, Co-IP of p16INK4a with CDK4, single lab","pmids":["25157181"],"is_preprint":false},{"year":2022,"finding":"CDK6 increases glycolysis and suppresses autophagy in cervical cancer cells through an mTORC1-HK2 (hexokinase 2) pathway. CDK6 knockout in HeLa cells inhibits mTORC1 and HK2 expression, reduces glycolysis, and induces autophagy and apoptosis.","method":"CRISPR/CDK6 knockout in cervical cancer cell lines, mTORC1 activity assays, HK2 expression analysis, glycolysis measurement (glucose consumption, lactate/ATP production), autophagy markers","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple metabolic readouts, consistent with complementary mechanism established in PMID:28607489, single lab","pmids":["35167417"],"is_preprint":false},{"year":2024,"finding":"Kinase-inactivated CDK6 (CDK6 K43M knock-in) in mouse HSCs enhances long-term repopulation and homing compared with CDK6-null HSCs. Transcriptome analysis identifies MAZ (myc-associated zinc finger protein) and NFY-A (nuclear transcription factor Y subunit alpha) as critical CDK6 interactors regulating HSC quiescence and self-renewal. Pharmacological CDK4/6 kinase inhibition in murine and human HSCs increases repopulation capability, validating kinase-independent CDK6 function in HSC fitness.","method":"CDK6 K43M and CDK6-/- knock-in/knockout mouse models, serial transplantation, RNA-seq, CDK6 interactor identification (MAZ, NFY-A), palbociclib treatment of human HSCs","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinase-dead vs null genetic comparison distinguishing kinase-independent function, transcriptome plus interactor identification, pharmacological validation in human HSCs, single lab with multiple orthogonal approaches","pmids":["38684032"],"is_preprint":false},{"year":2023,"finding":"CDK6 binds to and regulates the activity of GSK3β in a noncanonical (kinase-independent) pathway, leading to activation of Wnt/β-catenin signaling in lenvatinib-resistant hepatocellular carcinoma. CDK6 upregulation in this context is mediated by ERK/YAP1 signaling.","method":"Co-IP (CDK6-GSK3β interaction), CDK6 knockdown/inhibition with GSK3β activity readout, Wnt/β-catenin reporter assays, ERK/YAP1 pathway inhibition, chemical biology kinase profiling (XO44 probe)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of CDK6-GSK3β, pathway epistasis, single lab; noncanonical pathway requires further independent replication","pmids":["37872167"],"is_preprint":false},{"year":2022,"finding":"p16INK4A and p18INK4C protect CDK6 from PROTAC-mediated degradation: CDK6 complexes containing these INK4 proteins are resistant to BSJ-03-123-mediated degradation, and INK4 protein levels define the proliferative response to CDK6 degradation in AML subtypes.","method":"CDK6-specific PROTAC (BSJ-03-123) treatment in AML cell lines with different INK4 levels, Co-IP demonstrating INK4-CDK6 complex protection from degradation, INK4 protein quantification","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical demonstration that INK4-CDK6 complexes resist PROTAC degradation, functional proliferation readout, single lab","pmids":["35326705"],"is_preprint":false},{"year":2013,"finding":"Overexpression of CDK6 together with cyclin D1 (but not CDK6 alone) in chondrocytes inhibits chondrocyte maturation and causes p53-dependent apoptosis through dysregulation of E2F target genes, requiring CDK6 kinase activity. Kinase-negative CDK6 with cyclin D1 abolishes these effects.","method":"Chondrocyte-specific Cdk6 and Ccnd1 transgenic mice, kinase-dead CDK6 rescue, p53 knockout rescue, BrdU incorporation, TUNEL assay, E2F target gene expression analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic mouse models combined with kinase-dead rescue and p53 KO rescue, multiple phenotypic readouts, epistasis established","pmids":["23624920"],"is_preprint":false},{"year":2005,"finding":"p38 MAPK signaling pathway mediates downregulation of CDK6 mRNA/protein during chondrocyte differentiation. Inhibition of p38 MAPK (but not ERK or PI3K) blocks CDK6 reduction during ATDC5 differentiation. Enforced CDK6 expression blocks chondrocyte differentiation without affecting proliferation, through a mechanism largely independent of cell cycle regulation.","method":"p38 MAPK, ERK, PI3K inhibitors in differentiating ATDC5 prechondrocytes, CDK6 mRNA/protein analysis, CDK6 overexpression in differentiation assays, proteasome inhibitor controls","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection identifying p38 MAPK as upstream regulator, CDK6 overexpression with differentiation readout, single lab","pmids":["15795936"],"is_preprint":false},{"year":2018,"finding":"p27(Kip1) inhibits formation of the CDK6/cyclin D1 (CCND1) complex without directly affecting CDK6 or CCND1 expression levels, thereby blocking cell cycle progression. CCND1 does not regulate the cell cycle independently but functions together with CDK6.","method":"Co-immunoprecipitation of CDK6/CCND1 complex in presence/absence of p27, immunofluorescence co-localization, flow cytometry cell cycle analysis, MTT proliferation assay","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP showing p27 disrupts CDK6/CCND1 complex formation, single lab, limited mechanistic follow-up","pmids":["30317923"],"is_preprint":false},{"year":2023,"finding":"The HOXB9/PBX2 transcription factor heterodimer transcriptionally upregulates CDK6 in gastric cancer, downstream of E2F1-induced HOXB9 expression. CDK6 knockdown phenocopies HOXB9 depletion (G1 arrest, cytoskeletal effects).","method":"ChIP (HOXB9/PBX2 at CDK6 promoter), Co-IP (HOXB9-PBX2 heterodimer), CDK6 knockdown phenocopy of HOXB9 knockdown, CDK6 rescue of HOXB9 depletion","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP establishing transcription factor complex at CDK6 promoter, CDK6 rescue epistasis, single lab","pmids":["37272544"],"is_preprint":false},{"year":2023,"finding":"CDK6 deficiency or inhibition increases endogenous DNA damage levels, which triggers the cGAS-STING signaling pathway to activate type I interferon responses in tumor cells. Sting knockout reverses the anti-tumor effect of Cdk4 or Cdk6 deficiency.","method":"Cdk4 and Cdk6 genetic deletion in tumor cells, DNA damage quantification, cGAS-STING pathway activation assays, Sting knockout epistasis, in vivo tumor growth","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Sting KO rescue of CDK6 KO phenotype), DNA damage and IFN pathway readouts, single lab","pmids":["37833461"],"is_preprint":false},{"year":2022,"finding":"YTHDC1-mediated m6A methylation of CDK6 mRNA regulates CDK6 expression in retinal vascular endothelial cells through mRNA decay in the nucleus. YTHDC1 also inhibits CDK6 nuclear export. In vivo, CDK6 overexpression reverses the protective effects of YTHDC1 knockdown on STZ-induced retinal tissue damage.","method":"m6A-IP-qPCR (m6A modification on CDK6 mRNA), YTHDC1 overexpression/knockdown, CDK6 mRNA nuclear/cytoplasmic fractionation, in vivo STZ diabetic retinopathy model with rescue by CDK6 overexpression","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-IP identifying CDK6 mRNA as m6A target, nuclear export assay, in vivo rescue, single lab","pmids":["38978074"],"is_preprint":false}],"current_model":"CDK6 is a cyclin D1/D2/D3-activated kinase that phosphorylates pRB to drive G1-to-S phase progression, but also functions kinase-independently as a transcriptional regulator (promoting VEGF-A, suppressing Egr1 and p53 target genes by binding gene promoters), phosphorylates metabolic enzymes (6-phosphofructokinase, PKM2, TSC2) to couple cell metabolism and growth to the cell cycle, is stabilized by SUMO1 modification at Lys216 (which blocks ubiquitination at Lys147), and plays specialized roles in hematopoietic and leukemic stem cell activation, differentiation control (via Runx1 and RUNX1 binding), and cytoskeletal organization in erythrocytes."},"narrative":{"mechanistic_narrative":"CDK6 is a cyclin D-dependent kinase that couples mitogenic signaling to cell cycle entry, phosphorylating the retinoblastoma protein during mid-G1 in association with cyclins D1, D2, and D3 [PMID:8114739, PMID:8302605, PMID:7759865]. Its kinase activity extends well beyond pRB: cyclin D3-CDK6 phosphorylates the glycolytic enzymes 6-phosphofructokinase (PFKP) and PKM2 to redirect carbon flux into the pentose phosphate and serine synthesis pathways, sustaining NADPH/glutathione and limiting reactive oxygen species [PMID:28607489], and CDK4/6 phosphorylates TSC2 to activate mTORC1, thereby linking cell growth to division [PMID:32294430]. In parallel, CDK6 acts kinase-independently as a chromatin-associated transcriptional regulator, occupying gene promoters to induce VEGF-A [PMID:23948297, PMID:30858922], suppress Egr1 in hematopoietic and leukemic stem cells [PMID:25342715], and repress p53-antagonist genes including Prmt5, Ppm1d, and Mdm4 [PMID:29899063]. CDK6 has prominent specialized roles in the hematopoietic system, where its protein level governs HSC quiescence-exit kinetics and self-renewal [PMID:25704240, PMID:38684032], it sustains the differentiation block in MLL-rearranged and other leukemias [PMID:24764564], and it binds the runt domain of Runx1 to block myeloid differentiation independent of catalysis [PMID:17431401]. CDK6 abundance and inhibitor sensitivity are set post-translationally: SUMOylation at Lys216 by UBC9 blocks ubiquitination at Lys147 to stabilize the protein [PMID:24953629], UBE2N-mediated ubiquitination drives its degradation [PMID:31373842], and association with the HSP90/CDC37 chaperone defines a thermounstable conformer selectively targeted by CDK4/6 inhibitors and degraders [PMID:34568836].","teleology":[{"year":1994,"claim":"Established CDK6's foundational identity as a D-type cyclin-activated kinase that phosphorylates pRB and is activated during G1, defining its place in cell cycle entry.","evidence":"Co-IP from human lysates, reconstitution in Sf9 cells, in vitro pRB kinase assays, and activity timing in mitogen-stimulated T cells","pmids":["8114739","8302605","7759865"],"confidence":"High","gaps":["Did not resolve which downstream pRB targets are CDK6-specific versus CDK4-redundant","Did not address non-pRB substrates"]},{"year":2001,"claim":"Revealed that CDK6-cyclin D3 is uniquely refractory to CIP/KIP inhibitors and can override growth-arrest signals, distinguishing CDK6 complexes from other cyclin D-CDKs.","evidence":"Kinase assays under anchorage-independent conditions and overexpression in 3T3 fibroblasts","pmids":["11360184"],"confidence":"Medium","gaps":["Structural basis of p27/p21 evasion not defined","Single lab"]},{"year":2007,"claim":"Demonstrated a kinase-independent transcriptional/differentiation function, showing CDK6 binds Runx1's runt domain to block myeloid differentiation, decoupling part of CDK6 biology from catalysis.","evidence":"Reciprocal Co-IP, DNA-binding assays, and kinase-dead mutant in differentiation assays in vitro and in vivo","pmids":["17431401"],"confidence":"High","gaps":["Did not map CDK6 binding interface on Runx1","Generality across other transcription factors unknown at the time"]},{"year":2011,"claim":"Used knock-in alleles to dissect kinase-dependent from inhibitor-resistant CDK6 functions in hematopoiesis, showing kinase activity is required for thymocyte and HSC/progenitor function downstream of Notch.","evidence":"K43M kinase-dead and R31C INK4-insensitive knock-in mice with Notch target analysis and CD25-knockout rescue","pmids":["21508411"],"confidence":"High","gaps":["Direct CDK6 substrate(s) in Notch axis not identified","Mechanism of CD25 upregulation unresolved"]},{"year":2013,"claim":"Defined CDK6 as a chromatin-bound transcriptional regulator (VEGF-A, p16) and uncovered a degradation partner (EYA2), expanding CDK6 beyond the pRB pathway.","evidence":"Transcription complex identification, kinase-dead mutants, promoter assays, B-ALL model; separate Co-IP/degradation assay for EYA2","pmids":["23948297","24196439"],"confidence":"High","gaps":["Composition of the CDK6 transcription complex incompletely defined","EYA2 finding rests on single Co-IP/degradation assay (Low confidence)"]},{"year":2014,"claim":"Established CDK6 as a master regulator of stem-cell activation across normal and leukemic hematopoiesis, operating through transcriptional axes (Egr1) and as a sequestrator of INK4 proteins away from CDK4.","evidence":"Cdk6-/- mice, competitive transplantation, BCR-ABL models with Egr1-knockdown epistasis, MLL-AF9 models, and R31C/R24C INK4-insensitive knock-ins","pmids":["25342715","24764564","25157181"],"confidence":"High","gaps":["How CDK6 selects target promoters not defined","Relative contribution of INK4 sequestration vs transcriptional roles unresolved"]},{"year":2014,"claim":"Resolved how CDK6 protein levels are set post-translationally, showing SUMOylation at K216 blocks K147 ubiquitination to stabilize CDK6 in a cell-cycle-regulated manner.","evidence":"SUMO1 site mutagenesis (K216/K147), UBC9 Co-IP, ubiquitination assays, and CDK1-dependent UBC9 phosphorylation in glioblastoma","pmids":["24953629"],"confidence":"High","gaps":["Identity of the K147 E3 ligase not established here","Whether SUMO/Ub switch operates outside glioblastoma untested"]},{"year":2015,"claim":"Showed CDK6 protein abundance is the rate-limiting determinant of quiescence-exit kinetics in human HSC subsets, providing a molecular basis for HSC heterogeneity.","evidence":"Western blotting of sorted HSC subsets, lentiviral overexpression, competitive transplantation, and time-lapse imaging","pmids":["25704240"],"confidence":"High","gaps":["Whether the quiescence effect is kinase-dependent not fully separated here","Upstream control of differential CDK6 levels unresolved"]},{"year":2017,"claim":"Connected CDK6 kinase activity directly to metabolism, identifying glycolytic enzymes PFKP and PKM2 as substrates and explaining redox vulnerability upon CDK6 inhibition; also linked CDK6 to erythrocyte cytoskeletal integrity.","evidence":"In vitro kinase assays with PFKP/PKM2, PDX metabolic flux analysis; separate mass-spec interactome (gelsolin) and Cdk6-/- erythroblast F-actin phenotyping","pmids":["28607489","28255017"],"confidence":"High","gaps":["In vivo stoichiometry of metabolic enzyme phosphorylation not quantified","Cytoskeletal mechanism (gelsolin) is correlative interactome plus KO phenotype, single lab"]},{"year":2017,"claim":"Identified upstream transcriptional drivers and differential subcellular localization of CDK6 in cancers, placing it downstream of Hedgehog/GLI2 and MYB and showing nuclear CDK6 (vs cytoplasmic CDK4) in Ph+ ALL.","evidence":"GLI2 ChIP and Gli2 reporter medulloblastoma models; subcellular fractionation/IF and MYB-knockdown rescue in Ph+ ALL","pmids":["29202464","29233926"],"confidence":"Medium","gaps":["Determinants of CDK6 nuclear localization not defined","Generality of GLI2/MYB regulation across tumor types untested"]},{"year":2018,"claim":"Extended kinase-dependent and kinase-independent CDK6 functions to p53 antagonism, white-to-beige fat conversion (via RUNX1), and p53-dependent apoptosis in chondrocytes.","evidence":"CDK6 ChIP at p53-antagonist promoters with kinase-dead models; CDK6 KO/K43M and RUNX1-KO fat browning with ChIP; chondrocyte transgenics with kinase-dead and p53-KO rescue","pmids":["29899063","29523786","23624920"],"confidence":"High","gaps":["Direct CDK6 substrate driving the p53-antagonist transcriptional program not identified","How kinase activity gates promoter occupancy unresolved"]},{"year":2019,"claim":"Reinforced largely kinase-independent oncogenic roles of CDK6 in myeloid neoplasms (NF-kB/cytokine/apoptosis in JAK2V617F MPN; FLT3-ITD→HCK→CDK6 in AML) and a transcriptional angiogenic role in melanoma, while identifying UBE2N as the E2 driving CDK6 degradation.","evidence":"Cdk6-/- MPN and AML transformation models with palbociclib comparison and HCK dissection; CDK6 ChIP at VEGF-A promoter in melanoma; UBE2N/miR-934 stability assays with luciferase and xenografts","pmids":["30635286","27323399","30858922","31373842"],"confidence":"Medium","gaps":["Direct molecular link between CDK6 and NF-kB not biochemically defined","UBE2N-cognate E3 ligase not identified"]},{"year":2021,"claim":"Explained tumor-selective CDK6 dependency and inhibitor sensitivity through conformation/chaperone state, showing thermounstable HSP90/CDC37-bound CDK6 is the targetable pool.","evidence":"CETSA thermal stability, Co-IP of CDK6 with HSP90/CDC37, CDK6 degraders, and CRISPR CDK4/CDK6 dependency analysis","pmids":["34568836"],"confidence":"High","gaps":["Structural basis of the thermounstable conformer not solved","What sets the chaperone-bound vs free equilibrium in tissues unknown"]},{"year":2022,"claim":"Linked CDK6 to metabolic/autophagy control via mTORC1-HK2 and to INK4-dependent resistance to CDK6 degraders, refining how CDK6 abundance and complex composition dictate therapeutic response.","evidence":"CDK6-KO HeLa glycolysis/autophagy readouts; PROTAC (BSJ-03-123) degradation with INK4-CDK6 complex protection assays","pmids":["35167417","35326705"],"confidence":"Medium","gaps":["Whether mTORC1-HK2 effect is via direct CDK6 catalysis or transcriptional output unclear","Single-lab metabolic readouts"]},{"year":2023,"claim":"Broadened CDK6's noncanonical signaling and tumor-immune roles, implicating it in Wnt/GSK3-beta activation, cGAS-STING-driven interferon responses, and HOXB9/PBX2-mediated transcriptional upregulation.","evidence":"CDK6-GSK3-beta Co-IP with Wnt reporters and XO44 profiling; Cdk6 deletion with Sting-KO epistasis and DNA-damage/IFN readouts; HOXB9/PBX2 ChIP and CDK6 rescue in gastric cancer","pmids":["37872167","37833461","37272544"],"confidence":"Medium","gaps":["CDK6-GSK3-beta interaction requires independent replication","Mechanism by which CDK6 loss raises DNA damage not defined"]},{"year":2024,"claim":"Pinpointed kinase-independent CDK6 functions in HSC fitness and identified new transcriptional interactors (MAZ, NFY-A), with pharmacological validation that CDK4/6 inhibition enhances HSC repopulation.","evidence":"CDK6 K43M vs Cdk6-/- mice, serial transplantation, RNA-seq, interactor identification, and palbociclib treatment of human HSCs","pmids":["38684032"],"confidence":"High","gaps":["Direct binding mode of CDK6 to MAZ/NFY-A not structurally defined","How kinase-dead CDK6 outperforms null mechanistically unresolved"]},{"year":null,"claim":"How CDK6 is targeted to specific gene promoters and what its full direct substrate repertoire is beyond pRB, PFKP/PKM2, and TSC2 remain unresolved, leaving the basis of kinase-independent transcriptional selectivity open.","evidence":"No single discovery resolves the recruitment mechanism or comprehensive substrate set across the timeline","pmids":[],"confidence":"Medium","gaps":["No structural model of promoter-bound CDK6 transcription complexes","Comprehensive CDK6 substrate map lacking","DNA-binding/adaptor partners that recruit CDK6 to chromatin incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,13,22]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,9,17,20]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,13,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15,17,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,31]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,9,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,22,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[22,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,16,31]}],"complexes":["cyclin D-CDK6 complex","HSP90/CDC37 chaperone complex"],"partners":["CCND1","CCND3","RB1","RUNX1","UBE2N","GSK3B","HSP90","CDC37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q00534","full_name":"Cyclin-dependent kinase 6","aliases":["Cell division protein kinase 6","Serine/threonine-protein kinase PLSTIRE"],"length_aa":326,"mass_kda":36.9,"function":"Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and negatively regulates cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans. May play a role in the centrosome organization during the cell cycle phases (PubMed:23918663)","subcellular_location":"Cytoplasm; Nucleus; Cell projection, ruffle; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q00534/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDK6","classification":"Not Classified","n_dependent_lines":655,"n_total_lines":1208,"dependency_fraction":0.5422185430463576},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDKN2A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CDK6","total_profiled":1310},"omim":[{"mim_id":"620524","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 16; DCAF16","url":"https://www.omim.org/entry/620524"},{"mim_id":"620335","title":"CELL DIVISION CYCLE 20B; CDC20B","url":"https://www.omim.org/entry/620335"},{"mim_id":"617775","title":"G PROTEIN-COUPLED RECEPTOR 15 LIGAND; GPR15LG","url":"https://www.omim.org/entry/617775"},{"mim_id":"616080","title":"MICROCEPHALY 12, PRIMARY, AUTOSOMAL RECESSIVE; MCPH12","url":"https://www.omim.org/entry/616080"},{"mim_id":"615920","title":"PROLINE-RICH PROTEIN 11; PRR11","url":"https://www.omim.org/entry/615920"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":38.3}],"url":"https://www.proteinatlas.org/search/CDK6"},"hgnc":{"alias_symbol":["PLSTIRE"],"prev_symbol":[]},"alphafold":{"accession":"Q00534","domains":[{"cath_id":"3.30.200.20","chopping":"10-98","consensus_level":"high","plddt":87.4283,"start":10,"end":98},{"cath_id":"1.10.510.10","chopping":"103-300","consensus_level":"high","plddt":90.8528,"start":103,"end":300}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00534","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q00534-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q00534-F1-predicted_aligned_error_v6.png","plddt_mean":85.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDK6","jax_strain_url":"https://www.jax.org/strain/search?query=CDK6"},"sequence":{"accession":"Q00534","fasta_url":"https://rest.uniprot.org/uniprotkb/Q00534.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q00534/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00534"}},"corpus_meta":[{"pmid":"8114739","id":"PMC_8114739","title":"Identification of G1 kinase activity for cdk6, a novel cyclin D partner.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8114739","citation_count":787,"is_preprint":false},{"pmid":"26658964","id":"PMC_26658964","title":"Targeting CDK4 and CDK6: From Discovery to Therapy.","date":"2015","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/26658964","citation_count":744,"is_preprint":false},{"pmid":"35304604","id":"PMC_35304604","title":"Targeting CDK4 and CDK6 in cancer.","date":"2022","source":"Nature reviews. 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cyclins D1, D2, and D3 in human cell lysates and is activated by coexpression with D-type cyclins in Sf9 insect cells. Endogenous CDK6 phosphorylates pRB (retinoblastoma protein) in vitro, and its kinase activity is activated during mid-G1 in phytohemagglutinin-stimulated T cells.\",\n      \"method\": \"Co-immunoprecipitation from human cell lysates, Sf9 insect cell coexpression, in vitro pRB phosphorylation assay, kinase activity timing in primary T cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with defined substrate (pRB), reconstitution in insect cells, multiple orthogonal methods, foundational study replicated by many subsequent labs\",\n      \"pmids\": [\"8114739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CDK6 (PLSTIRE) and CDK4 (PSK-J3) form a distinct subset of CDKs that associate specifically with cyclin D1 in a squamous carcinoma cell line; in diploid fibroblasts, CDK2 and CDK5 can also co-precipitate with cyclin D1 alongside CDK4.\",\n      \"method\": \"Co-immunoprecipitation from tumor cell lines and human diploid fibroblasts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in multiple cell types, independently confirming the cyclin D1-CDK6 interaction established in PMID:8114739\",\n      \"pmids\": [\"8302605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CDK6 (PLSTIRE/p40cdk6) is the earliest inducible CDK in mitogen-stimulated human T lymphocytes. Cyclins D2 and D3 are the major associated cyclins, with D2 predominating in early G1. Kinase activity (measured by in vitro phosphorylation of recombinant truncated Rb) parallels protein accumulation and occurs independently of IL-2-mediated cell cycle progression.\",\n      \"method\": \"Immunoprecipitation/kinase assay with recombinant Rb substrate, co-immunoprecipitation of cyclin partners, cyclosporin A/FK506 treatment to dissect IL-2 dependence\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with defined substrate, pharmacological dissection, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"7759865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The CDK6-cyclin D3 complex uniquely evades inhibition by p27(KIP1) and p21(CIP1) compared with other cyclin D-CDK combinations, retaining kinase activity in anchorage-minus G1-arrested fibroblasts. Overexpression of both CDK6 and cyclin D3 confers resistance to serum starvation- and contact-inhibition-induced G1 arrest.\",\n      \"method\": \"Kinase activity assays in anchorage-independent conditions, overexpression in BALB/c 3T3 cells, comparison with other CDK-cyclin D combinations\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay and cell-based overexpression, single lab\",\n      \"pmids\": [\"11360184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CDK6 binds to the runt domain of Runx1 (a hematopoietic transcription factor), interfering with Runx1 DNA binding and Runx1-C/EBPα interaction, thereby blocking myeloid differentiation. This function does not require CDK6 kinase activity.\",\n      \"method\": \"Co-immunoprecipitation (CDK6-Runx1 interaction), DNA-binding assays, kinase-dead CDK6 mutant overexpression, in vitro and in vivo differentiation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, kinase-dead mutant, multiple functional readouts in vitro and in vivo in single study\",\n      \"pmids\": [\"17431401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CDK4 and CDK6 extend the replicative lifespan of human diploid fibroblasts through a mechanism requiring their kinase activity, as catalytically inactive versions fail to extend lifespan. This extension is independent of p16(INK4a) sequestration.\",\n      \"method\": \"Kinase-dead mutant expression, INK4a knockout fibroblasts, replicative lifespan assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant combined with genetic INK4a loss, single lab, two orthogonal approaches\",\n      \"pmids\": [\"17420273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDK6 kinase activity is required for early thymocyte development and HSC/progenitor function. Kinase-dead CDK6 (K43M knock-in) reduces thymocyte and LSK numbers and disrupts Notch-dependent survival/differentiation, including massive upregulation of CD25. INK4-insensitive hyperactive CDK6 (R31C) causes excess proliferation countered by increased apoptosis. CDK6 modulates Notch target gene expression downstream of Notch signaling.\",\n      \"method\": \"Knock-in mice expressing kinase-dead (K43M) or INK4-insensitive (R31C) CDK6 alleles, hematopoietic phenotyping, Notch target gene expression analysis, CD25 knockout rescue experiment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in mutant mice with specific alleles, genetic rescue (CD25 knockout), multiple phenotypic readouts\",\n      \"pmids\": [\"21508411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDK6 is part of a transcription complex that induces expression of VEGF-A (pro-angiogenic) and p16(INK4a) in lymphoid malignancy cells. This transcriptional function is independent of CDK6 kinase activity and is not shared by CDK4.\",\n      \"method\": \"Transcription complex identification, shRNA knockdown, kinase-dead CDK6 mutant, B-ALL mouse model with p185BCR-ABL+, VEGF-A and p16 promoter assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant combined with in vivo leukemia model and promoter analysis, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"23948297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDK6 binds to and promotes degradation of the EYA2 protein (a transcriptional activator/phosphatase involved in development), establishing a novel CDK6 interaction partner beyond the established pRB pathway.\",\n      \"method\": \"Co-immunoprecipitation (CDK6-EYA2), protein degradation assays\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and degradation assay, single lab, limited mechanistic follow-up described in abstract\",\n      \"pmids\": [\"24196439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDK6 functions as part of a transcriptional complex in hematopoietic and leukemic stem cells, suppressing Egr1 transcription. CDK6-deficient HSCs fail to efficiently repopulate and are more susceptible to 5-FU treatment. In BCR-ABL(p210+) leukemic stem cells, CDK6 loss impairs disease induction, and Egr1 knockdown in CDK6-deficient LSKs rescues colony formation, establishing a CDK6-Egr1 axis.\",\n      \"method\": \"Cdk6-/- mice, competitive transplantation, 5-FU challenge, BCR-ABL transformation, transcriptional profiling, Egr1 shRNA knockdown rescue experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with epistasis rescue (Egr1 knockdown), multiple in vivo assays, replicated mechanistic concept across normal and leukemic stem cells\",\n      \"pmids\": [\"25342715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDK6 SUMOylation at Lys216 by UBC9 (mediated by CDK1 phosphorylation of UBC9 during mitosis) stabilizes CDK6 protein throughout the cell cycle. CDK6 SUMOylation at Lys216 blocks ubiquitination at Lys147, preventing ubiquitin-mediated CDK6 degradation. This mechanism operates in glioblastoma.\",\n      \"method\": \"SUMO1 modification identification, site-directed mutagenesis (K216 and K147), UBC9 co-immunoprecipitation, ubiquitination assays, CDK1 phosphorylation of UBC9 demonstrated\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of modification sites, identification of writer (UBC9/CDK1), competition between SUMO and ubiquitin pathways, multiple orthogonal biochemical methods in single study\",\n      \"pmids\": [\"24953629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In MLL-rearranged AML, CDK6 is transcriptionally activated by mutant MLL and is required for maintaining the differentiation block. Depletion of CDK6 (but not CDK4) induces myeloid differentiation, and this is phenocopied by a selective CDK6 small-molecule inhibitor.\",\n      \"method\": \"shRNA knockdown (CDK6 vs CDK4 selectivity), MLL-AF9 mouse model, myeloid differentiation assays, CDK6 inhibitor treatment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic selectivity (CDK6 vs CDK4 knockdown), in vivo mouse model, pharmacological confirmation, independent validation across multiple MLL fusion contexts\",\n      \"pmids\": [\"24764564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDK6 protein levels regulate quiescence exit kinetics in human HSC subsets. Long-term HSCs (LT-HSCs) lack CDK6 protein; short-term HSCs (ST-HSCs) contain high CDK6 protein and enter the cell cycle rapidly upon stimulation. Enforced CDK6 expression in LT-HSCs shortens quiescence exit and confers competitive advantage without impairing function.\",\n      \"method\": \"Western blotting for CDK6 protein in sorted human HSC subsets, lentiviral CDK6 overexpression, competitive transplantation, time-lapse imaging of cell cycle entry\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein quantification across sorted HSC subsets, gain-of-function with functional readout (competitive repopulation), computational modeling validation\",\n      \"pmids\": [\"25704240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cyclin D3-CDK6 kinase phosphorylates and inhibits two key glycolytic enzymes, 6-phosphofructokinase (PFKP) and pyruvate kinase M2 (PKM2), redirecting glycolytic intermediates into the pentose phosphate pathway and serine synthesis pathway. Inhibition of cyclin D3-CDK6 depletes NADPH and glutathione, increases reactive oxygen species, and causes apoptosis in tumor cells.\",\n      \"method\": \"In vitro kinase assays with 6-phosphofructokinase and PKM2 as substrates, patient-derived xenografts in mice, metabolic flux analysis, CDK6 inhibitor treatment\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay demonstrating phosphorylation of metabolic enzyme substrates, validated in vivo with xenografts, multiple orthogonal metabolic readouts\",\n      \"pmids\": [\"28607489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hedgehog signaling drives CDK6 expression through GLI2 binding to the Cdk6 promoter in medulloblastoma. CDK6 is identified as a direct transcriptional target of the Hedgehog/GLI2 pathway, and CDK6 promotes uncontrolled cell proliferation in Hh-associated medulloblastoma.\",\n      \"method\": \"Gli2-EGFP reporter knock-in mouse models of Hh-associated medulloblastoma, GLI2 ChIP on Cdk6 promoter, genetic and pharmacological CDK6 inhibition, survival analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct promoter binding, in vivo genetic models, pharmacological validation in two mouse models\",\n      \"pmids\": [\"29202464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Ph+ ALL cells, CDK6 is predominantly localized in the nucleus (whereas CDK4 is almost exclusively cytoplasmic), and CDK6 expression is required for Ph+ ALL cell growth through MYB-mediated transcriptional upregulation of CDK6, cyclin D3, and BCL2.\",\n      \"method\": \"Immunofluorescence/subcellular fractionation showing differential CDK6/CDK4 localization, MYB shRNA knockdown with rescue by CDK6 re-expression, pharmacological CDK6 inhibition in vitro and in vivo\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization by immunofluorescence with functional consequence, MYB-CDK6 transcriptional axis established by epistasis, single lab\",\n      \"pmids\": [\"29233926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDK6 kinase activity negatively regulates the conversion of white fat to beige fat (browning) by suppressing RUNX1. CDK6-null or kinase-dead (K43M) mice show increased beige fat formation and energy expenditure. Re-expression of CDK6 in CDK6-null cells or RUNX1 ablation in K43M cells reverses these phenotypes. RUNX1 binds to proximal promoter regions of Ucp-1 and Pgc1α.\",\n      \"method\": \"CDK6 knockout and kinase-dead knock-in mice, adipocyte-specific CDK6 re-expression, RUNX1 knockout, ChIP of RUNX1 on Ucp-1 and Pgc1α promoters, metabolic phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with CDK6 KO, kinase-dead KI, and RUNX1 KO rescue; ChIP validation; multiple metabolic readouts; single lab with orthogonal genetic approaches\",\n      \"pmids\": [\"29523786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDK6 kinase activity promotes a transcriptional program that antagonizes p53 responses in hematopoietic cells. CDK6 binds to promoters of p53 antagonists including Prmt5, Ppm1d, and Mdm4. Cells lacking CDK6 kinase function require TP53 mutation to achieve fully transformed immortalized state.\",\n      \"method\": \"CDK6 ChIP at promoters of p53 antagonist genes, kinase-dead CDK6 mouse models, immortalization assays, TP53 mutation frequency analysis in human tumors with low CDK6\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct CDK6 promoter binding, kinase-dead genetic model, human tumor correlation, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"29899063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDK6 in JAK2V617F MPN coordinates NF-κB signaling, promotes cytokine production, and inhibits apoptosis in addition to regulating malignant stem cell quiescence. These effects are largely kinase-independent, as palbociclib (kinase inhibitor) does not mirror the effects of CDK6 absence.\",\n      \"method\": \"Cdk6-/- mice in JAK2V617F MPN model, palbociclib treatment comparison, NF-κB signaling assays, apoptosis and cytokine production measurements\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO vs pharmacological kinase inhibition comparison establishing kinase-independent function, in vivo MPN model, single lab\",\n      \"pmids\": [\"30635286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In AML with FLT3-ITD mutations, CDK6 (but not CDK4) is overexpressed through a signaling pathway involving FLT3-ITD → SRC-family kinase HCK → CDK6. FLT3-ITD fails to transform primary hematopoietic progenitors from Cdk6-/- mice, establishing CDK6 as the primary target of CDK4/6 inhibitors in this AML subtype.\",\n      \"method\": \"Cdk6-/- mouse hematopoietic progenitor transformation assays, shRNA knockdown of CDK6 vs CDK4, HCK inhibition, FLT3-ITD signaling pathway dissection\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO transformation assay as epistasis, pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"27323399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In melanoma cells, CDK6 knockdown reduces VEGF-A expression and endothelial cell stimulation; this effect is associated with reduced CDK6 localization on the VEGF-A promoter, establishing a CDK6 transcriptional role in tumor angiogenesis in solid tumors.\",\n      \"method\": \"shRNA knockdown of CDK4 vs CDK6, CDK6 ChIP on VEGF-A promoter, xenotransplantation mouse model, endothelial cell growth stimulation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP evidence for CDK6 at VEGF-A promoter, in vivo xenograft validation, CDK4 vs CDK6 comparison, single lab\",\n      \"pmids\": [\"30858922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBE2N (ubiquitin-conjugating enzyme 2N) promotes CDK6 protein degradation through ubiquitination. miR-934 targets the 3'-UTR of UBE2N mRNA, downregulating UBE2N protein, which in turn attenuates CDK6 ubiquitination and promotes CDK6 protein accumulation in bladder cancer cells.\",\n      \"method\": \"miR-934 binding to UBE2N 3'-UTR confirmed by luciferase reporter assay, UBE2N knockdown/overexpression, CDK6 protein stability assays, xenograft tumor growth in vivo\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — UBE2N identified as E2 for CDK6 ubiquitination, luciferase validation of miR-UBE2N interaction, in vivo xenograft confirmation, single lab\",\n      \"pmids\": [\"31373842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cyclin D-CDK4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. Pharmacological CDK4/6 inhibition leads to rapid, TSC2-dependent reduction of mTORC1 activity in multiple cell lines including breast cancer cells, coupling cell growth to cell cycle progression.\",\n      \"method\": \"In vitro CDK4/6 phosphorylation of TSC2 (identifying specific phosphorylation sites), pharmacological inhibition in multiple cell lines, TSC2 genetic rescue experiments, mTORC1 activity readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay identifying specific TSC2 phosphorylation sites, TSC2-dependent genetic rescue, multiple cell lines, single lab\",\n      \"pmids\": [\"32294430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDK6 contributes to cytoskeletal stability in erythrocytes through kinase-dependent and kinase-independent mechanisms. In erythroblasts, CDK6 is partly associated with the cytoskeleton. Mass spectrometry identified CDK6 interaction with proteins involved in cytoskeleton organization including gelsolin. CDK6-deficient erythroblasts show impaired F-actin formation and lower gelsolin levels.\",\n      \"method\": \"Mass spectrometry of CDK6 interaction partners, Cdk6-/- mouse erythrocytes, F-actin staining, cytoskeletal fractionation, mechanical stress assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry interactome with functional validation (F-actin, gelsolin), genetic KO phenotype, single lab\",\n      \"pmids\": [\"28255017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tumors expressing both CDK4 and CDK6 have increased reliance on CDK6 for cell cycle progression. CDK4/6 inhibitors and degraders potently bind and inhibit CDK6 selectively in tumors where CDK6 is highly thermounstable and strongly associated with the HSP90/CDC37 chaperone complex. In contrast, thermostable CDK6 (not associated with HSP90/CDC37) is resistant to CDK4/6i binding.\",\n      \"method\": \"Thermal stability assays (CETSA), Co-IP of CDK6 with HSP90/CDC37, CDK6 degrader treatment, CRISPR CDK4/CDK6 differential dependency analysis\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — thermal stability assay distinguishing CDK6 conformational states, Co-IP identifying HSP90/CDC37 complex, multiple cell lines, CDK6-selective degraders validating mechanism\",\n      \"pmids\": [\"34568836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The lncRNA gadd7, induced by UV irradiation, directly binds TDP-43 and interferes with the TDP-43-CDK6 mRNA interaction, resulting in CDK6 mRNA degradation and G1/S checkpoint enforcement. This establishes TDP-43 as an RNA-binding protein that stabilizes Cdk6 mRNA.\",\n      \"method\": \"RNA pull-down (gadd7-TDP-43 interaction), Co-IP (TDP-43-CDK6 mRNA RIP), UV irradiation, CDK6 mRNA stability assays, G1/S checkpoint analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown, RIP demonstrating displacement of TDP-43 from CDK6 mRNA, mRNA stability assays, functional checkpoint readout in single study\",\n      \"pmids\": [\"23103768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In BCR-ABL(p210+) leukemogenesis, CDK6-deficient Cdk4 becomes more susceptible to p16(INK4a) binding (sequestration), whereas cells with both CDK4 R24C and CDK6 R31C (INK4-insensitive) alleles show accelerated disease. This demonstrates that CDK6 normally sequesters INK4 proteins away from CDK4.\",\n      \"method\": \"Cdk6 R31C knock-in mice, double Cdk4 R24C/Cdk6 R31C knock-in, BCR-ABL transformation assays, INK4 binding co-immunoprecipitation, hematopoietic transplantation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with two INK4-insensitive alleles, Co-IP of p16INK4a with CDK4, single lab\",\n      \"pmids\": [\"25157181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDK6 increases glycolysis and suppresses autophagy in cervical cancer cells through an mTORC1-HK2 (hexokinase 2) pathway. CDK6 knockout in HeLa cells inhibits mTORC1 and HK2 expression, reduces glycolysis, and induces autophagy and apoptosis.\",\n      \"method\": \"CRISPR/CDK6 knockout in cervical cancer cell lines, mTORC1 activity assays, HK2 expression analysis, glycolysis measurement (glucose consumption, lactate/ATP production), autophagy markers\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple metabolic readouts, consistent with complementary mechanism established in PMID:28607489, single lab\",\n      \"pmids\": [\"35167417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Kinase-inactivated CDK6 (CDK6 K43M knock-in) in mouse HSCs enhances long-term repopulation and homing compared with CDK6-null HSCs. Transcriptome analysis identifies MAZ (myc-associated zinc finger protein) and NFY-A (nuclear transcription factor Y subunit alpha) as critical CDK6 interactors regulating HSC quiescence and self-renewal. Pharmacological CDK4/6 kinase inhibition in murine and human HSCs increases repopulation capability, validating kinase-independent CDK6 function in HSC fitness.\",\n      \"method\": \"CDK6 K43M and CDK6-/- knock-in/knockout mouse models, serial transplantation, RNA-seq, CDK6 interactor identification (MAZ, NFY-A), palbociclib treatment of human HSCs\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinase-dead vs null genetic comparison distinguishing kinase-independent function, transcriptome plus interactor identification, pharmacological validation in human HSCs, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"38684032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK6 binds to and regulates the activity of GSK3β in a noncanonical (kinase-independent) pathway, leading to activation of Wnt/β-catenin signaling in lenvatinib-resistant hepatocellular carcinoma. CDK6 upregulation in this context is mediated by ERK/YAP1 signaling.\",\n      \"method\": \"Co-IP (CDK6-GSK3β interaction), CDK6 knockdown/inhibition with GSK3β activity readout, Wnt/β-catenin reporter assays, ERK/YAP1 pathway inhibition, chemical biology kinase profiling (XO44 probe)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of CDK6-GSK3β, pathway epistasis, single lab; noncanonical pathway requires further independent replication\",\n      \"pmids\": [\"37872167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p16INK4A and p18INK4C protect CDK6 from PROTAC-mediated degradation: CDK6 complexes containing these INK4 proteins are resistant to BSJ-03-123-mediated degradation, and INK4 protein levels define the proliferative response to CDK6 degradation in AML subtypes.\",\n      \"method\": \"CDK6-specific PROTAC (BSJ-03-123) treatment in AML cell lines with different INK4 levels, Co-IP demonstrating INK4-CDK6 complex protection from degradation, INK4 protein quantification\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical demonstration that INK4-CDK6 complexes resist PROTAC degradation, functional proliferation readout, single lab\",\n      \"pmids\": [\"35326705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of CDK6 together with cyclin D1 (but not CDK6 alone) in chondrocytes inhibits chondrocyte maturation and causes p53-dependent apoptosis through dysregulation of E2F target genes, requiring CDK6 kinase activity. Kinase-negative CDK6 with cyclin D1 abolishes these effects.\",\n      \"method\": \"Chondrocyte-specific Cdk6 and Ccnd1 transgenic mice, kinase-dead CDK6 rescue, p53 knockout rescue, BrdU incorporation, TUNEL assay, E2F target gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic mouse models combined with kinase-dead rescue and p53 KO rescue, multiple phenotypic readouts, epistasis established\",\n      \"pmids\": [\"23624920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p38 MAPK signaling pathway mediates downregulation of CDK6 mRNA/protein during chondrocyte differentiation. Inhibition of p38 MAPK (but not ERK or PI3K) blocks CDK6 reduction during ATDC5 differentiation. Enforced CDK6 expression blocks chondrocyte differentiation without affecting proliferation, through a mechanism largely independent of cell cycle regulation.\",\n      \"method\": \"p38 MAPK, ERK, PI3K inhibitors in differentiating ATDC5 prechondrocytes, CDK6 mRNA/protein analysis, CDK6 overexpression in differentiation assays, proteasome inhibitor controls\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection identifying p38 MAPK as upstream regulator, CDK6 overexpression with differentiation readout, single lab\",\n      \"pmids\": [\"15795936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"p27(Kip1) inhibits formation of the CDK6/cyclin D1 (CCND1) complex without directly affecting CDK6 or CCND1 expression levels, thereby blocking cell cycle progression. CCND1 does not regulate the cell cycle independently but functions together with CDK6.\",\n      \"method\": \"Co-immunoprecipitation of CDK6/CCND1 complex in presence/absence of p27, immunofluorescence co-localization, flow cytometry cell cycle analysis, MTT proliferation assay\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP showing p27 disrupts CDK6/CCND1 complex formation, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"30317923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The HOXB9/PBX2 transcription factor heterodimer transcriptionally upregulates CDK6 in gastric cancer, downstream of E2F1-induced HOXB9 expression. CDK6 knockdown phenocopies HOXB9 depletion (G1 arrest, cytoskeletal effects).\",\n      \"method\": \"ChIP (HOXB9/PBX2 at CDK6 promoter), Co-IP (HOXB9-PBX2 heterodimer), CDK6 knockdown phenocopy of HOXB9 knockdown, CDK6 rescue of HOXB9 depletion\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP establishing transcription factor complex at CDK6 promoter, CDK6 rescue epistasis, single lab\",\n      \"pmids\": [\"37272544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK6 deficiency or inhibition increases endogenous DNA damage levels, which triggers the cGAS-STING signaling pathway to activate type I interferon responses in tumor cells. Sting knockout reverses the anti-tumor effect of Cdk4 or Cdk6 deficiency.\",\n      \"method\": \"Cdk4 and Cdk6 genetic deletion in tumor cells, DNA damage quantification, cGAS-STING pathway activation assays, Sting knockout epistasis, in vivo tumor growth\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Sting KO rescue of CDK6 KO phenotype), DNA damage and IFN pathway readouts, single lab\",\n      \"pmids\": [\"37833461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDC1-mediated m6A methylation of CDK6 mRNA regulates CDK6 expression in retinal vascular endothelial cells through mRNA decay in the nucleus. YTHDC1 also inhibits CDK6 nuclear export. In vivo, CDK6 overexpression reverses the protective effects of YTHDC1 knockdown on STZ-induced retinal tissue damage.\",\n      \"method\": \"m6A-IP-qPCR (m6A modification on CDK6 mRNA), YTHDC1 overexpression/knockdown, CDK6 mRNA nuclear/cytoplasmic fractionation, in vivo STZ diabetic retinopathy model with rescue by CDK6 overexpression\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-IP identifying CDK6 mRNA as m6A target, nuclear export assay, in vivo rescue, single lab\",\n      \"pmids\": [\"38978074\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDK6 is a cyclin D1/D2/D3-activated kinase that phosphorylates pRB to drive G1-to-S phase progression, but also functions kinase-independently as a transcriptional regulator (promoting VEGF-A, suppressing Egr1 and p53 target genes by binding gene promoters), phosphorylates metabolic enzymes (6-phosphofructokinase, PKM2, TSC2) to couple cell metabolism and growth to the cell cycle, is stabilized by SUMO1 modification at Lys216 (which blocks ubiquitination at Lys147), and plays specialized roles in hematopoietic and leukemic stem cell activation, differentiation control (via Runx1 and RUNX1 binding), and cytoskeletal organization in erythrocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDK6 is a cyclin D-dependent kinase that couples mitogenic signaling to cell cycle entry, phosphorylating the retinoblastoma protein during mid-G1 in association with cyclins D1, D2, and D3 [#0, #1, #2]. Its kinase activity extends well beyond pRB: cyclin D3-CDK6 phosphorylates the glycolytic enzymes 6-phosphofructokinase (PFKP) and PKM2 to redirect carbon flux into the pentose phosphate and serine synthesis pathways, sustaining NADPH/glutathione and limiting reactive oxygen species [#13], and CDK4/6 phosphorylates TSC2 to activate mTORC1, thereby linking cell growth to division [#22]. In parallel, CDK6 acts kinase-independently as a chromatin-associated transcriptional regulator, occupying gene promoters to induce VEGF-A [#7, #20], suppress Egr1 in hematopoietic and leukemic stem cells [#9], and repress p53-antagonist genes including Prmt5, Ppm1d, and Mdm4 [#17]. CDK6 has prominent specialized roles in the hematopoietic system, where its protein level governs HSC quiescence-exit kinetics and self-renewal [#12, #28], it sustains the differentiation block in MLL-rearranged and other leukemias [#11], and it binds the runt domain of Runx1 to block myeloid differentiation independent of catalysis [#4]. CDK6 abundance and inhibitor sensitivity are set post-translationally: SUMOylation at Lys216 by UBC9 blocks ubiquitination at Lys147 to stabilize the protein [#10], UBE2N-mediated ubiquitination drives its degradation [#21], and association with the HSP90/CDC37 chaperone defines a thermounstable conformer selectively targeted by CDK4/6 inhibitors and degraders [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established CDK6's foundational identity as a D-type cyclin-activated kinase that phosphorylates pRB and is activated during G1, defining its place in cell cycle entry.\",\n      \"evidence\": \"Co-IP from human lysates, reconstitution in Sf9 cells, in vitro pRB kinase assays, and activity timing in mitogen-stimulated T cells\",\n      \"pmids\": [\"8114739\", \"8302605\", \"7759865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which downstream pRB targets are CDK6-specific versus CDK4-redundant\", \"Did not address non-pRB substrates\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Revealed that CDK6-cyclin D3 is uniquely refractory to CIP/KIP inhibitors and can override growth-arrest signals, distinguishing CDK6 complexes from other cyclin D-CDKs.\",\n      \"evidence\": \"Kinase assays under anchorage-independent conditions and overexpression in 3T3 fibroblasts\",\n      \"pmids\": [\"11360184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of p27/p21 evasion not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated a kinase-independent transcriptional/differentiation function, showing CDK6 binds Runx1's runt domain to block myeloid differentiation, decoupling part of CDK6 biology from catalysis.\",\n      \"evidence\": \"Reciprocal Co-IP, DNA-binding assays, and kinase-dead mutant in differentiation assays in vitro and in vivo\",\n      \"pmids\": [\"17431401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map CDK6 binding interface on Runx1\", \"Generality across other transcription factors unknown at the time\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Used knock-in alleles to dissect kinase-dependent from inhibitor-resistant CDK6 functions in hematopoiesis, showing kinase activity is required for thymocyte and HSC/progenitor function downstream of Notch.\",\n      \"evidence\": \"K43M kinase-dead and R31C INK4-insensitive knock-in mice with Notch target analysis and CD25-knockout rescue\",\n      \"pmids\": [\"21508411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CDK6 substrate(s) in Notch axis not identified\", \"Mechanism of CD25 upregulation unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined CDK6 as a chromatin-bound transcriptional regulator (VEGF-A, p16) and uncovered a degradation partner (EYA2), expanding CDK6 beyond the pRB pathway.\",\n      \"evidence\": \"Transcription complex identification, kinase-dead mutants, promoter assays, B-ALL model; separate Co-IP/degradation assay for EYA2\",\n      \"pmids\": [\"23948297\", \"24196439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composition of the CDK6 transcription complex incompletely defined\", \"EYA2 finding rests on single Co-IP/degradation assay (Low confidence)\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established CDK6 as a master regulator of stem-cell activation across normal and leukemic hematopoiesis, operating through transcriptional axes (Egr1) and as a sequestrator of INK4 proteins away from CDK4.\",\n      \"evidence\": \"Cdk6-/- mice, competitive transplantation, BCR-ABL models with Egr1-knockdown epistasis, MLL-AF9 models, and R31C/R24C INK4-insensitive knock-ins\",\n      \"pmids\": [\"25342715\", \"24764564\", \"25157181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDK6 selects target promoters not defined\", \"Relative contribution of INK4 sequestration vs transcriptional roles unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how CDK6 protein levels are set post-translationally, showing SUMOylation at K216 blocks K147 ubiquitination to stabilize CDK6 in a cell-cycle-regulated manner.\",\n      \"evidence\": \"SUMO1 site mutagenesis (K216/K147), UBC9 Co-IP, ubiquitination assays, and CDK1-dependent UBC9 phosphorylation in glioblastoma\",\n      \"pmids\": [\"24953629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the K147 E3 ligase not established here\", \"Whether SUMO/Ub switch operates outside glioblastoma untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed CDK6 protein abundance is the rate-limiting determinant of quiescence-exit kinetics in human HSC subsets, providing a molecular basis for HSC heterogeneity.\",\n      \"evidence\": \"Western blotting of sorted HSC subsets, lentiviral overexpression, competitive transplantation, and time-lapse imaging\",\n      \"pmids\": [\"25704240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the quiescence effect is kinase-dependent not fully separated here\", \"Upstream control of differential CDK6 levels unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected CDK6 kinase activity directly to metabolism, identifying glycolytic enzymes PFKP and PKM2 as substrates and explaining redox vulnerability upon CDK6 inhibition; also linked CDK6 to erythrocyte cytoskeletal integrity.\",\n      \"evidence\": \"In vitro kinase assays with PFKP/PKM2, PDX metabolic flux analysis; separate mass-spec interactome (gelsolin) and Cdk6-/- erythroblast F-actin phenotyping\",\n      \"pmids\": [\"28607489\", \"28255017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo stoichiometry of metabolic enzyme phosphorylation not quantified\", \"Cytoskeletal mechanism (gelsolin) is correlative interactome plus KO phenotype, single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified upstream transcriptional drivers and differential subcellular localization of CDK6 in cancers, placing it downstream of Hedgehog/GLI2 and MYB and showing nuclear CDK6 (vs cytoplasmic CDK4) in Ph+ ALL.\",\n      \"evidence\": \"GLI2 ChIP and Gli2 reporter medulloblastoma models; subcellular fractionation/IF and MYB-knockdown rescue in Ph+ ALL\",\n      \"pmids\": [\"29202464\", \"29233926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of CDK6 nuclear localization not defined\", \"Generality of GLI2/MYB regulation across tumor types untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended kinase-dependent and kinase-independent CDK6 functions to p53 antagonism, white-to-beige fat conversion (via RUNX1), and p53-dependent apoptosis in chondrocytes.\",\n      \"evidence\": \"CDK6 ChIP at p53-antagonist promoters with kinase-dead models; CDK6 KO/K43M and RUNX1-KO fat browning with ChIP; chondrocyte transgenics with kinase-dead and p53-KO rescue\",\n      \"pmids\": [\"29899063\", \"29523786\", \"23624920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CDK6 substrate driving the p53-antagonist transcriptional program not identified\", \"How kinase activity gates promoter occupancy unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reinforced largely kinase-independent oncogenic roles of CDK6 in myeloid neoplasms (NF-kB/cytokine/apoptosis in JAK2V617F MPN; FLT3-ITD→HCK→CDK6 in AML) and a transcriptional angiogenic role in melanoma, while identifying UBE2N as the E2 driving CDK6 degradation.\",\n      \"evidence\": \"Cdk6-/- MPN and AML transformation models with palbociclib comparison and HCK dissection; CDK6 ChIP at VEGF-A promoter in melanoma; UBE2N/miR-934 stability assays with luciferase and xenografts\",\n      \"pmids\": [\"30635286\", \"27323399\", \"30858922\", \"31373842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between CDK6 and NF-kB not biochemically defined\", \"UBE2N-cognate E3 ligase not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Explained tumor-selective CDK6 dependency and inhibitor sensitivity through conformation/chaperone state, showing thermounstable HSP90/CDC37-bound CDK6 is the targetable pool.\",\n      \"evidence\": \"CETSA thermal stability, Co-IP of CDK6 with HSP90/CDC37, CDK6 degraders, and CRISPR CDK4/CDK6 dependency analysis\",\n      \"pmids\": [\"34568836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the thermounstable conformer not solved\", \"What sets the chaperone-bound vs free equilibrium in tissues unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked CDK6 to metabolic/autophagy control via mTORC1-HK2 and to INK4-dependent resistance to CDK6 degraders, refining how CDK6 abundance and complex composition dictate therapeutic response.\",\n      \"evidence\": \"CDK6-KO HeLa glycolysis/autophagy readouts; PROTAC (BSJ-03-123) degradation with INK4-CDK6 complex protection assays\",\n      \"pmids\": [\"35167417\", \"35326705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mTORC1-HK2 effect is via direct CDK6 catalysis or transcriptional output unclear\", \"Single-lab metabolic readouts\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened CDK6's noncanonical signaling and tumor-immune roles, implicating it in Wnt/GSK3-beta activation, cGAS-STING-driven interferon responses, and HOXB9/PBX2-mediated transcriptional upregulation.\",\n      \"evidence\": \"CDK6-GSK3-beta Co-IP with Wnt reporters and XO44 profiling; Cdk6 deletion with Sting-KO epistasis and DNA-damage/IFN readouts; HOXB9/PBX2 ChIP and CDK6 rescue in gastric cancer\",\n      \"pmids\": [\"37872167\", \"37833461\", \"37272544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDK6-GSK3-beta interaction requires independent replication\", \"Mechanism by which CDK6 loss raises DNA damage not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pinpointed kinase-independent CDK6 functions in HSC fitness and identified new transcriptional interactors (MAZ, NFY-A), with pharmacological validation that CDK4/6 inhibition enhances HSC repopulation.\",\n      \"evidence\": \"CDK6 K43M vs Cdk6-/- mice, serial transplantation, RNA-seq, interactor identification, and palbociclib treatment of human HSCs\",\n      \"pmids\": [\"38684032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding mode of CDK6 to MAZ/NFY-A not structurally defined\", \"How kinase-dead CDK6 outperforms null mechanistically unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDK6 is targeted to specific gene promoters and what its full direct substrate repertoire is beyond pRB, PFKP/PKM2, and TSC2 remain unresolved, leaving the basis of kinase-independent transcriptional selectivity open.\",\n      \"evidence\": \"No single discovery resolves the recruitment mechanism or comprehensive substrate set across the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of promoter-bound CDK6 transcription complexes\", \"Comprehensive CDK6 substrate map lacking\", \"DNA-binding/adaptor partners that recruit CDK6 to chromatin incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 13, 22]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 9, 17, 20]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 13, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15, 17, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 31]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 9, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 22, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [22, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 16, 31]}\n    ],\n    \"complexes\": [\n      \"cyclin D-CDK6 complex\",\n      \"HSP90/CDC37 chaperone complex\"\n    ],\n    \"partners\": [\n      \"CCND1\",\n      \"CCND3\",\n      \"RB1\",\n      \"RUNX1\",\n      \"UBE2N\",\n      \"GSK3B\",\n      \"HSP90\",\n      \"CDC37\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}