Affinage

CDK6

Cyclin-dependent kinase 6 · UniProt Q00534

Length
326 aa
Mass
36.9 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1994 High

    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

    PMID:7759865 PMID:8114739 PMID:8302605

    Open questions at the time
    • Did not resolve which downstream pRB targets are CDK6-specific versus CDK4-redundant
    • Did not address non-pRB substrates
  2. 2001 Medium

    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

    PMID:11360184

    Open questions at the time
    • Structural basis of p27/p21 evasion not defined
    • Single lab
  3. 2007 High

    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

    PMID:17431401

    Open questions at the time
    • Did not map CDK6 binding interface on Runx1
    • Generality across other transcription factors unknown at the time
  4. 2011 High

    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

    PMID:21508411

    Open questions at the time
    • Direct CDK6 substrate(s) in Notch axis not identified
    • Mechanism of CD25 upregulation unresolved
  5. 2013 High

    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

    PMID:23948297 PMID:24196439

    Open questions at the time
    • Composition of the CDK6 transcription complex incompletely defined
    • EYA2 finding rests on single Co-IP/degradation assay (Low confidence)
  6. 2014 High

    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

    PMID:24764564 PMID:25157181 PMID:25342715

    Open questions at the time
    • How CDK6 selects target promoters not defined
    • Relative contribution of INK4 sequestration vs transcriptional roles unresolved
  7. 2014 High

    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

    PMID:24953629

    Open questions at the time
    • Identity of the K147 E3 ligase not established here
    • Whether SUMO/Ub switch operates outside glioblastoma untested
  8. 2015 High

    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

    PMID:25704240

    Open questions at the time
    • Whether the quiescence effect is kinase-dependent not fully separated here
    • Upstream control of differential CDK6 levels unresolved
  9. 2017 High

    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

    PMID:28255017 PMID:28607489

    Open questions at the time
    • In vivo stoichiometry of metabolic enzyme phosphorylation not quantified
    • Cytoskeletal mechanism (gelsolin) is correlative interactome plus KO phenotype, single lab
  10. 2017 Medium

    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

    PMID:29202464 PMID:29233926

    Open questions at the time
    • Determinants of CDK6 nuclear localization not defined
    • Generality of GLI2/MYB regulation across tumor types untested
  11. 2018 High

    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

    PMID:23624920 PMID:29523786 PMID:29899063

    Open questions at the time
    • Direct CDK6 substrate driving the p53-antagonist transcriptional program not identified
    • How kinase activity gates promoter occupancy unresolved
  12. 2019 Medium

    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

    PMID:27323399 PMID:30635286 PMID:30858922 PMID:31373842

    Open questions at the time
    • Direct molecular link between CDK6 and NF-kB not biochemically defined
    • UBE2N-cognate E3 ligase not identified
  13. 2021 High

    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

    PMID:34568836

    Open questions at the time
    • Structural basis of the thermounstable conformer not solved
    • What sets the chaperone-bound vs free equilibrium in tissues unknown
  14. 2022 Medium

    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

    PMID:35167417 PMID:35326705

    Open questions at the time
    • Whether mTORC1-HK2 effect is via direct CDK6 catalysis or transcriptional output unclear
    • Single-lab metabolic readouts
  15. 2023 Medium

    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

    PMID:37272544 PMID:37833461 PMID:37872167

    Open questions at the time
    • CDK6-GSK3-beta interaction requires independent replication
    • Mechanism by which CDK6 loss raises DNA damage not defined
  16. 2024 High

    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

    PMID:38684032

    Open questions at the time
    • Direct binding mode of CDK6 to MAZ/NFY-A not structurally defined
    • How kinase-dead CDK6 outperforms null mechanistically unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0140110 transcription regulator activity 4 GO:0016740 transferase activity 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-1640170 Cell Cycle 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2
Partners
CCND1CCND3CDC37GSK3BHSP90RB1RUNX1UBE2N
Complex memberships
HSP90/CDC37 chaperone complexcyclin D-CDK6 complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 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. Co-immunoprecipitation from human cell lysates, Sf9 insect cell coexpression, in vitro pRB phosphorylation assay, kinase activity timing in primary T cells Molecular and cellular biology High 8114739
1994 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. Co-immunoprecipitation from tumor cell lines and human diploid fibroblasts Oncogene High 8302605
1995 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. Immunoprecipitation/kinase assay with recombinant Rb substrate, co-immunoprecipitation of cyclin partners, cyclosporin A/FK506 treatment to dissect IL-2 dependence Journal of immunology High 7759865
2001 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. Kinase activity assays in anchorage-independent conditions, overexpression in BALB/c 3T3 cells, comparison with other CDK-cyclin D combinations Oncogene Medium 11360184
2007 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. Co-immunoprecipitation (CDK6-Runx1 interaction), DNA-binding assays, kinase-dead CDK6 mutant overexpression, in vitro and in vivo differentiation assays The EMBO journal High 17431401
2007 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. Kinase-dead mutant expression, INK4a knockout fibroblasts, replicative lifespan assays Molecular and cellular biology Medium 17420273
2011 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. Knock-in mice expressing kinase-dead (K43M) or INK4-insensitive (R31C) CDK6 alleles, hematopoietic phenotyping, Notch target gene expression analysis, CD25 knockout rescue experiment Blood High 21508411
2013 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. Transcription complex identification, shRNA knockdown, kinase-dead CDK6 mutant, B-ALL mouse model with p185BCR-ABL+, VEGF-A and p16 promoter assays Cancer cell High 23948297
2013 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. Co-immunoprecipitation (CDK6-EYA2), protein degradation assays Cell cycle Low 24196439
2014 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. Cdk6-/- mice, competitive transplantation, 5-FU challenge, BCR-ABL transformation, transcriptional profiling, Egr1 shRNA knockdown rescue experiments Blood High 25342715
2014 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. SUMO1 modification identification, site-directed mutagenesis (K216 and K147), UBC9 co-immunoprecipitation, ubiquitination assays, CDK1 phosphorylation of UBC9 demonstrated Nature communications High 24953629
2014 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. shRNA knockdown (CDK6 vs CDK4 selectivity), MLL-AF9 mouse model, myeloid differentiation assays, CDK6 inhibitor treatment Blood High 24764564
2015 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. Western blotting for CDK6 protein in sorted human HSC subsets, lentiviral CDK6 overexpression, competitive transplantation, time-lapse imaging of cell cycle entry Cell stem cell High 25704240
2017 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. In vitro kinase assays with 6-phosphofructokinase and PKM2 as substrates, patient-derived xenografts in mice, metabolic flux analysis, CDK6 inhibitor treatment Nature High 28607489
2017 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. Gli2-EGFP reporter knock-in mouse models of Hh-associated medulloblastoma, GLI2 ChIP on Cdk6 promoter, genetic and pharmacological CDK6 inhibition, survival analysis The Journal of clinical investigation High 29202464
2017 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. 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 Cancer research Medium 29233926
2018 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. 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 Nature communications High 29523786
2018 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. 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 Cancer discovery High 29899063
2019 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. Cdk6-/- mice in JAK2V617F MPN model, palbociclib treatment comparison, NF-κB signaling assays, apoptosis and cytokine production measurements Blood Medium 30635286
2019 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. Cdk6-/- mouse hematopoietic progenitor transformation assays, shRNA knockdown of CDK6 vs CDK4, HCK inhibition, FLT3-ITD signaling pathway dissection Oncotarget Medium 27323399
2019 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. shRNA knockdown of CDK4 vs CDK6, CDK6 ChIP on VEGF-A promoter, xenotransplantation mouse model, endothelial cell growth stimulation assay Oncotarget Medium 30858922
2019 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. miR-934 binding to UBE2N 3'-UTR confirmed by luciferase reporter assay, UBE2N knockdown/overexpression, CDK6 protein stability assays, xenograft tumor growth in vivo FASEB journal Medium 31373842
2020 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. In vitro CDK4/6 phosphorylation of TSC2 (identifying specific phosphorylation sites), pharmacological inhibition in multiple cell lines, TSC2 genetic rescue experiments, mTORC1 activity readouts Cell reports High 32294430
2017 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. Mass spectrometry of CDK6 interaction partners, Cdk6-/- mouse erythrocytes, F-actin staining, cytoskeletal fractionation, mechanical stress assays Haematologica Medium 28255017
2021 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. Thermal stability assays (CETSA), Co-IP of CDK6 with HSP90/CDC37, CDK6 degrader treatment, CRISPR CDK4/CDK6 differential dependency analysis Nature cancer High 34568836
2012 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. RNA pull-down (gadd7-TDP-43 interaction), Co-IP (TDP-43-CDK6 mRNA RIP), UV irradiation, CDK6 mRNA stability assays, G1/S checkpoint analysis The EMBO journal High 23103768
2014 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. Cdk6 R31C knock-in mice, double Cdk4 R24C/Cdk6 R31C knock-in, BCR-ABL transformation assays, INK4 binding co-immunoprecipitation, hematopoietic transplantation Blood Medium 25157181
2022 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. CRISPR/CDK6 knockout in cervical cancer cell lines, mTORC1 activity assays, HK2 expression analysis, glycolysis measurement (glucose consumption, lactate/ATP production), autophagy markers Cell cycle Medium 35167417
2024 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. CDK6 K43M and CDK6-/- knock-in/knockout mouse models, serial transplantation, RNA-seq, CDK6 interactor identification (MAZ, NFY-A), palbociclib treatment of human HSCs Blood High 38684032
2023 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. 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) Nature communications Medium 37872167
2022 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. 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 Cancers Medium 35326705
2013 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. Chondrocyte-specific Cdk6 and Ccnd1 transgenic mice, kinase-dead CDK6 rescue, p53 knockout rescue, BrdU incorporation, TUNEL assay, E2F target gene expression analysis Oncogene High 23624920
2005 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. p38 MAPK, ERK, PI3K inhibitors in differentiating ATDC5 prechondrocytes, CDK6 mRNA/protein analysis, CDK6 overexpression in differentiation assays, proteasome inhibitor controls Journal of cellular physiology Medium 15795936
2018 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. Co-immunoprecipitation of CDK6/CCND1 complex in presence/absence of p27, immunofluorescence co-localization, flow cytometry cell cycle analysis, MTT proliferation assay Cell cycle Medium 30317923
2023 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). ChIP (HOXB9/PBX2 at CDK6 promoter), Co-IP (HOXB9-PBX2 heterodimer), CDK6 knockdown phenocopy of HOXB9 knockdown, CDK6 rescue of HOXB9 depletion The Journal of pathology Medium 37272544
2023 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. Cdk4 and Cdk6 genetic deletion in tumor cells, DNA damage quantification, cGAS-STING pathway activation assays, Sting knockout epistasis, in vivo tumor growth Communications biology Medium 37833461
2022 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. 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 Biology direct Medium 38978074

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Molecular and cellular biology 787 8114739
2015 Targeting CDK4 and CDK6: From Discovery to Therapy. Cancer discovery 744 26658964
2022 Targeting CDK4 and CDK6 in cancer. Nature reviews. Cancer 404 35304604
2022 CDK4 and CDK6 kinases: From basic science to cancer therapy. Science (New York, N.Y.) 362 35025636
2013 Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 316 24045179
1994 CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1. Oncogene 291 8302605
2017 The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature 289 28607489
2015 CDK6 levels regulate quiescence exit in human hematopoietic stem cells. Cell stem cell 255 25704240
2013 A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer cell 244 23948297
2014 CDK6 as a key regulator of hematopoietic and leukemic stem cell activation. Blood 208 25342715
2016 Long noncoding RNA NEAT1 promotes laryngeal squamous cell cancer through regulating miR-107/CDK6 pathway. Journal of experimental & clinical cancer research : CR 180 26822763
2012 Long non-coding RNA gadd7 interacts with TDP-43 and regulates Cdk6 mRNA decay. The EMBO journal 174 23103768
2020 The role of CDK6 in cancer. International journal of cancer 147 32406095
2015 CDK6-a review of the past and a glimpse into the future: from cell-cycle control to transcriptional regulation. Oncogene 147 26500059
2014 Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 146 24764564
2010 miR-129 regulates cell proliferation by downregulating Cdk6 expression. Cell cycle (Georgetown, Tex.) 140 20404570
2015 miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6. Molecular cancer 116 25889927
2015 Targeting CDK6 in cancer: State of the art and new insights. Cell cycle (Georgetown, Tex.) 114 26315616
2020 Cdk4 and Cdk6 Couple the Cell-Cycle Machinery to Cell Growth via mTORC1. Cell reports 111 32294430
2019 Selective degradation of CDK6 by a palbociclib based PROTAC. Bioorganic & medicinal chemistry letters 104 30935795
2014 SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression. Nature communications 104 24953629
2005 Cell cycle progression without cyclin D-CDK4 and cyclin D-CDK6 complexes. Cell cycle (Georgetown, Tex.) 104 15738651
2007 Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. The EMBO journal 95 17431401
2006 From cell cycle to differentiation: an expanding role for cdk6. Cell cycle (Georgetown, Tex.) 79 16410727
2020 Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs. Blood 75 32040545
2006 Beyond the cell cycle: a new role for Cdk6 in differentiation. Journal of cellular biochemistry 69 16294322
2018 CDK6 Antagonizes p53-Induced Responses during Tumorigenesis. Cancer discovery 68 29899063
2011 CDK6 kinase activity is required for thymocyte development. Blood 66 21508411
2018 CDK6 inhibits white to beige fat transition by suppressing RUNX1. Nature communications 65 29523786
2022 Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma. Nature communications 63 35197447
2021 Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders. Nature cancer 59 34568836
2007 CDK4 and CDK6 delay senescence by kinase-dependent and p16INK4a-independent mechanisms. Molecular and cellular biology 55 17420273
2015 miR-340 inhibits glioblastoma cell proliferation by suppressing CDK6, cyclin-D1 and cyclin-D2. Biochemical and biophysical research communications 54 25817794
1995 Regulation of synthesis and activity of the PLSTIRE protein (cyclin-dependent kinase 6 (cdk6)), a major cyclin D-associated cdk4 homologue in normal human T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 53 7759865
2000 Expression of p19INK4d, CDK4, CDK6 in glioblastoma multiforme. British journal of neurosurgery 52 10884881
2015 GAS5 Inhibits Gastric Cancer Cell Proliferation Partly by Modulating CDK6. Oncology research and treatment 51 26278580
2017 Hedgehog signaling drives medulloblastoma growth via CDK6. The Journal of clinical investigation 50 29202464
2024 Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 49 38943828
2022 Isoginkgetin, a potential CDK6 inhibitor, suppresses SLC2A1/GLUT1 enhancer activity to induce AMPK-ULK1-mediated cytotoxic autophagy in hepatocellular carcinoma. Autophagy 49 36048765
2010 Alteration in the expression of cdk4 and cdk6 proteins in oral cancer and premalignant lesions. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 49 20618617
2021 Exosomal miR-21-5p contributes to ovarian cancer progression by regulating CDK6. Human cell 48 33813728
2023 Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma. Nature communications 47 37872167
2019 Inhibition of CDK4/CDK6 Enhances Radiosensitivity of HPV Negative Head and Neck Squamous Cell Carcinomas. International journal of radiation oncology, biology, physics 47 31271827
2015 ZFP36L1 promotes monocyte/macrophage differentiation by repressing CDK6. Scientific reports 46 26542173
2017 CBX3 promotes colon cancer cell proliferation by CDK6 kinase-independent function during cell cycle. Oncotarget 45 28193906
2014 microRNA-504 inhibits cancer cell proliferation via targeting CDK6 in hypopharyngeal squamous cell carcinoma. International journal of oncology 45 24647829
2020 CDK6 Inhibition: A Novel Approach in AML Management. International journal of molecular sciences 42 32260549
2001 Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence. Oncogene 42 11360184
2019 The interplay of CDK4 and CDK6 in melanoma. Oncotarget 40 30858922
2018 miR-107 inhibits CDK6 expression, differentiation, and lipid storage in human adipocytes. Molecular and cellular endocrinology 39 30261211
2022 Functional Genomic Analysis of CDK4 and CDK6 Gene Dependency across Human Cancer Cell Lines. Cancer research 38 35395071
2018 p27 inhibits CDK6/CCND1 complex formation resulting in cell cycle arrest and inhibition of cell proliferation. Cell cycle (Georgetown, Tex.) 36 30317923
2019 CDK6 coordinates JAK2 mutant MPN via NF-κB and apoptotic networks. Blood 34 30635286
2021 CDK4, CDK6/cyclin-D1 Complex Inhibition and Radiotherapy for Cancer Control: A Role for Autophagy. International journal of molecular sciences 31 34445095
2023 DNA damage induced by CDK4 and CDK6 blockade triggers anti-tumor immune responses through cGAS-STING pathway. Communications biology 30 37833461
2020 D-galactose induces senescence of glioblastoma cells through YAP-CDK6 pathway. Aging 30 32991321
2019 MicroRNA-129 Inhibits Glioma Cell Growth by Targeting CDK4, CDK6, and MDM2. Molecular therapy. Nucleic acids 29 31954330
2020 Baicalin suppresses the cell cycle progression and proliferation of prostate cancer cells through the CDK6/FOXM1 axis. Molecular and cellular biochemistry 28 32385718
2014 Cdk4 and Cdk6 cooperate in counteracting the INK4 family of inhibitors during murine leukemogenesis. Blood 28 25157181
2019 Inhibition of UBE2N-dependent CDK6 protein degradation by miR-934 promotes human bladder cancer cell growth. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 31373842
2016 An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia. Oncotarget 26 27323399
2017 Cdk6 contributes to cytoskeletal stability in erythroid cells. Haematologica 25 28255017
2017 Targeting CDK6 and BCL2 Exploits the "MYB Addiction" of Ph+ Acute Lymphoblastic Leukemia. Cancer research 25 29233926
2015 Expression of cdk6 in head and neck squamous cell carcinoma. Clinical oral investigations 25 25929813
2013 Overexpression of Cdk6 and Ccnd1 in chondrocytes inhibited chondrocyte maturation and caused p53-dependent apoptosis without enhancing proliferation. Oncogene 25 23624920
2025 Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer. Nature cancer 24 39885369
2022 MiR-21 participates in LPS-induced myocardial injury by targeting Bcl-2 and CDK6. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 22 35064305
2019 AC002454.1 and CDK6 synergistically promote endometrial cell migration and invasion in endometriosis. Reproduction (Cambridge, England) 22 30884467
2019 miR-636 represses cell survival by targeting CDK6/Bcl-2 in cervical cancer. The Kaohsiung journal of medical sciences 22 31889428
2018 An TRIM59-CDK6 axis regulates growth and metastasis of lung cancer. Journal of cellular and molecular medicine 22 30515965
2022 CDK6 increases glycolysis and suppresses autophagy by mTORC1-HK2 pathway activation in cervical cancer cells. Cell cycle (Georgetown, Tex.) 20 35167417
2019 Long non-coding RNA LINC00473 promotes glioma cells proliferation and invasion by impairing miR-637/CDK6 axis. Artificial cells, nanomedicine, and biotechnology 20 31561732
2017 Research on miRNA-195 and target gene CDK6 in oral verrucous carcinoma. Cancer gene therapy 20 28621315
2017 miR‑494 inhibits cell proliferation and metastasis via targeting of CDK6 in osteosarcoma. Molecular medicine reports 20 28990071
2014 Reduced mir-29b-3p expression up-regulate CDK6 and contributes to IgA nephropathy. International journal of clinical and experimental medicine 20 25664031
2021 EphA2 promotes tumorigenicity of cervical cancer by up-regulating CDK6. Journal of cellular and molecular medicine 19 33586348
2021 CDK6 Is a Therapeutic Target in Myelofibrosis. Cancer research 19 34145036
2015 Targeting cyclin D3/CDK6 activity for treatment of Parkinson's disease. Journal of neurochemistry 19 25689470
2023 Hyperoside prevents high-fat diet-induced obesity by increasing white fat browning and lipophagy via CDK6-TFEB pathway. Journal of ethnopharmacology 18 36781055
2005 Inhibition of Cdk6 expression through p38 MAP kinase is involved in differentiation of mouse prechondrocyte ATDC5. Journal of cellular physiology 18 15795936
2023 Discovery of dual PARP and CDK6 inhibitors for triple-negative breast cancer with wild-type BRCA. Bioorganic chemistry 17 37379778
2022 Cyclin-dependent kinase 6 (CDK6) as a potent regulator of the ovarian primordial-to-primary follicle transition. Frontiers in cell and developmental biology 17 36619863
2021 LncRNA LOC100129620 promotes osteosarcoma progression through regulating CDK6 expression, tumor angiogenesis, and macrophage polarization. Aging 17 34015762
2020 DDX11-AS1exacerbates bladder cancer progression by enhancing CDK6 expression via suppressing miR-499b-5p. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 17 32422563
2020 miR‑449a‑5p suppresses CDK6 expression to inhibit cardiomyocyte proliferation. Molecular medicine reports 17 33179102
2021 MiRNA-494-3p Regulates Bupivacaine-Induced Neurotoxicity by the CDK6-PI3K/AKT Signaling. Neurotoxicity research 16 34652691
2021 Gamma-mangostin isolated from garcinia mangostana suppresses colon carcinogenesis and stemness by downregulating the GSK3β/β-catenin/CDK6 cancer stem pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 16 34802869
2022 Activation of miR-500a-3p/CDK6 axis suppresses aerobic glycolysis and colorectal cancer progression. Journal of translational medicine 15 35241106
2022 CDK6 is upregulated and may be a potential therapeutic target in enzalutamide-resistant castration-resistant prostate cancer. European journal of medical research 15 35780240
2024 YTHDC1 aggravates high glucose-induced retinal vascular endothelial cell injury via m6A modification of CDK6. Biology direct 14 38978074
2023 The E2F1-HOXB9/PBX2-CDK6 axis drives gastric tumorigenesis and serves as a therapeutic target in gastric cancer. The Journal of pathology 14 37272544
2017 CDK4, CDK6, cyclin D1, p16(INK4a) and EGFR expression in glioblastoma with a primitive neuronal component. Journal of neuro-oncology 14 29150788
2023 C4orf19 inhibits colorectal cancer cell proliferation by competitively binding to Keap1 with TRIM25 via the USP17/Elk-1/CDK6 axis. Oncogene 13 36882524
2021 T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo. Frontiers in immunology 13 34248938
2020 MiR-186 represses progression of renal cell cancer by directly targeting CDK6. Human cell 13 32266659
2020 Fluorescent Peptide Biosensor for Probing CDK6 Kinase Activity in Lung Cancer Cell Extracts. Chembiochem : a European journal of chemical biology 13 33112024
2024 Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells. Blood 12 38684032
2024 Histone deacetylases facilitate Th17-cell differentiation and pathogenicity in autoimmune uveitis via CDK6/ID2 axis. Journal of advanced research 12 39107200
2022 CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML. Cancers 12 35326705
2013 CDK6 binds and promotes the degradation of the EYA2 protein. Cell cycle (Georgetown, Tex.) 12 24196439

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