Affinage

CDK4

Cyclin-dependent kinase 4 · UniProt P11802

Length
303 aa
Mass
33.7 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDK4 is a serine/threonine protein kinase that couples mitogenic signals to G1-to-S cell-cycle progression and to a broad program of cellular metabolism, growth, and lysosome control. It assembles specifically with D-type cyclins into holoenzymes whose catalytic activity additionally requires CAK-mediated phosphorylation of Thr172 — assembly can occur without this modification, but Thr172-deficient mutants remain inactive (PMID:8302605, PMID:8139570, PMID:17092340). Holoenzyme maturation is supported by a ternary chaperone complex in which Cdc37 bridges CDK4 and Hsp90, coupling CDK4 conformation to the Hsp90 ATPase cycle (PMID:16949366). Beyond phosphorylating RB to drive E2F-dependent transcription, active CDK4 directly phosphorylates a diverse substrate set: CDC25A on Ser40 to promote its βTrCP-dependent turnover as a G1/S negative feedback loop (PMID:28192398), TSC2 (Ser1217/Ser1452) and FLCN to activate and spatially control mTORC1 (PMID:31395606, PMID:32294430), TFEB/TFE3 to drive their nuclear export and thereby gate lysosome biogenesis to cell-cycle position (PMID:32662822), AMPKα2 to repress fatty acid oxidation and favor glycolysis (PMID:29053957), and IRS2 (Ser388) within a CCND3-CDK4 insulin feedback loop in adipocytes (PMID:26657864). Through these substrates and an E2F1-dependent transcriptional arm, CDK4 governs adipogenesis via PPARγ, glucose-stimulated insulin secretion via Kir6.2, replicative lifespan, lysosomal degradation/autophagic flux, and cell-size checkpoint control (PMID:16213226, PMID:19597485, PMID:17420273, PMID:31395606, PMID:34022133). CDK4 activity is constrained by INK4 inhibitor binding — abrogated by the oncogenic, melanoma-causing R24C mutation (PMID:11606789) — and by a reversible oxidant-induced disulfide between CDK4 Cys135 and cyclin D that inhibits the kinase under oxidative conditions and is lost (hyperactivating CDK4) in pulmonary arterial hypertension tissue (PMID:37955182). CDK4 is amplified or transcriptionally upregulated (by c-MYC) in tumors, and HR+ breast cancers depend selectively on CDK4 over CDK6 (PMID:8221695, PMID:10688915, PMID:40068598).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1993 High

    Established that CDK4 is a genuine oncogenic target by showing its locus is amplified in tumors, raising it as a driver of dysregulated proliferation.

    Evidence FISH, copy-number Southern, Northern, and sequencing in osteosarcoma/rhabdomyosarcoma lines

    PMID:8221695

    Open questions at the time
    • Did not define the kinase's biochemical activity or substrates
    • Coding sequence unmutated, leaving functional consequence of overexpression unresolved at the time
  2. 1994 High

    Defined the partner specificity of CDK4 by showing it associates preferentially with cyclin D1, establishing the cyclin D-CDK4 holoenzyme as a distinct CDK class.

    Evidence Reciprocal co-immunoprecipitation in tumor lines and diploid fibroblasts

    PMID:8302605

    Open questions at the time
    • Did not establish activation requirements
    • Cell-type differences in cyclin D partners not mechanistically explained
  3. 1994 High

    Resolved how the holoenzyme becomes catalytically competent, separating assembly from activation by identifying CAK phosphorylation of Thr172 as the activating step.

    Evidence Baculovirus co-expression in Sf9 cells, in vitro kinase assays, Thr172 mutagenesis

    PMID:8139570

    Open questions at the time
    • Identity of the physiological CAK left open
    • Did not address upstream control of Thr172 by extracellular signals
  4. 2000 High

    Connected mitogenic transcription to CDK4 levels by showing c-MYC directly transactivates the CDK4 promoter, explaining how growth signals raise CDK4 abundance.

    Evidence SAGE, promoter analysis, ectopic-expression rescue in c-MYC-deficient cells

    PMID:10688915

    Open questions at the time
    • Only partial rescue of the growth defect by CDK4
    • Other c-MYC targets contributing to the phenotype not excluded
  5. 2006 High

    Provided the structural basis for CDK4 maturation by determining the Hsp90-Cdc37-CDK4 ternary complex architecture, linking chaperoning to the kinase's conformational cycle.

    Evidence Complex purification, native MS, single-particle EM versus Hsp90 crystal structure

    PMID:16949366

    Open questions at the time
    • Functional consequence of chaperone disruption on cell-cycle output not quantified
    • How chaperoning intersects with cyclin loading unresolved
  6. 2006 Medium

    Argued that Thr172 phosphorylation, not assembly, is the rate-limiting and signal-responsive node specific to CDK4 versus CDK6.

    Evidence Biochemical analysis of activation states comparing CDK4 and CDK6 (review of own data)

    PMID:17092340

    Open questions at the time
    • Review-level summary of single-lab data
    • Distinct CAK activity for CDK4 not molecularly identified
  7. 2001 High

    Demonstrated causality between CDK4 escape from INK4 inhibition and cancer by showing the INK4-insensitive R24C mutation drives melanoma in vivo.

    Evidence CDK4 R24C knock-in mice with carcinogen treatment and tumor molecular analysis

    PMID:11606789

    Open questions at the time
    • Tissue selectivity for melanoma not explained
    • Downstream substrate(s) mediating tumorigenesis not pinpointed
  8. 2005 High

    Extended CDK4 function beyond proliferation to differentiation by showing it promotes adipogenesis through PPARγ.

    Evidence CDK4 knockout and R24C knock-in MEFs in adipogenic differentiation assays

    PMID:16213226

    Open questions at the time
    • Whether PPARγ is a direct CDK4 substrate not established
    • Kinase-dependence of the effect not separated from scaffolding
  9. 2007 High

    Showed CDK4 governs replicative lifespan through its kinase activity rather than mere inhibitor sequestration, implying substrates beyond RB.

    Evidence Wild-type versus catalytically inactive CDK4 overexpression in HDFs across INK4a backgrounds

    PMID:17420273

    Open questions at the time
    • The relevant non-RB substrates not identified in this study
    • Mechanism additive with p16 loss not dissected
  10. 2009 High

    Linked CDK4 to systemic glucose physiology by defining a glucose-CDK4-pRB-E2F1 axis controlling Kir6.2 and insulin secretion in beta cells.

    Evidence ChIP, CDK4-/- and E2f1-/- mice, Kir6.2 rescue, glucose tolerance tests

    PMID:19597485

    Open questions at the time
    • Direct CDK4 phosphorylation events upstream of E2F1 in this context not detailed
    • Crosstalk with insulin-pathway activation of CDK4 partially defined
  11. 2015 High

    Identified IRS2 Ser388 as a direct CDK4 substrate, establishing a CCND3-CDK4 positive feedback loop sustaining adipocyte insulin signaling.

    Evidence Global kinome analysis, in vivo/in vitro phosphorylation, CDK4 KO and R24C mice, IRS2 mutagenesis

    PMID:26657864

    Open questions at the time
    • Generalizability of IRS2 phosphorylation beyond adipose tissue unclear
    • Quantitative contribution to whole-body insulin sensitivity not isolated
  12. 2017 High

    Defined a metabolic substrate by showing CDK4 directly phosphorylates and inhibits AMPKα2, shifting cells toward glycolysis and away from fatty acid oxidation.

    Evidence In vitro kinase assay, AMPKα2 mutagenesis, CDK4 KO mice, metabolic flux measurements

    PMID:29053957

    Open questions at the time
    • Phosphosite on AMPKα2 not specified here
    • Interplay with the canonical AMPK kinases not addressed
  13. 2017 High

    Revealed a cell-cycle feedback substrate by showing cyclin D-CDK4/6 phosphorylates CDC25A on Ser40 to drive its βTrCP-dependent degradation at G1/S.

    Evidence In vitro kinase assay, synchronization, Ser40 mutagenesis, proteasome inhibition

    PMID:28192398

    Open questions at the time
    • Single-lab finding
    • Quantitative impact on G1/S timing not modeled
  14. 2017 High

    Uncovered an immunologic consequence of CDK4/6 inhibition: derepression of endogenous retroviral elements and type III interferon via reduced E2F-target DNMT1, enhancing antitumor immunity.

    Evidence Mouse tumor models, clinical transcriptomics, mechanistic cell assays

    PMID:28813415

    Open questions at the time
    • CDK4 versus CDK6 contribution not separated
    • Direct kinase substrates upstream of DNMT1 not pinpointed
  15. 2019 High

    Tied CDK4 to lysosomal mTORC1 signaling by showing it phosphorylates FLCN and is required for lysosomal degradation and autophagic flux.

    Evidence Pharmacologic/genetic CDK4 inactivation, in vitro phosphorylation, lysosomal assays, xenografts

    PMID:31395606

    Open questions at the time
    • FLCN phosphosite(s) not enumerated here
    • Whether lysosomal defect is fully FLCN-dependent unresolved
  16. 2020 High

    Established CDK4/6 as a direct mTORC1 activator by identifying TSC2 (Ser1217/Ser1452) as a substrate, coupling cell growth to cell-cycle progression.

    Evidence In vitro kinase assay, Co-IP, CDK4/6 inhibition across cell lines, TSC2 loss-of-function rescue

    PMID:32294430

    Open questions at the time
    • Relative contribution of TSC2 versus FLCN to mTORC1 control not resolved
    • In vivo physiological relevance not fully tested
  17. 2020 High

    Linked cell-cycle position to organelle biogenesis by showing CDK4/6 phosphorylates TFEB/TFE3 to drive their nuclear export and suppress lysosome biogenesis.

    Evidence Co-IP, in vitro kinase assay, genetic CDK4/6 inactivation, localization, synchronization

    PMID:32662822

    Open questions at the time
    • TFEB/TFE3 phosphosites not specified
    • Single-lab finding
  18. 2020 Medium

    Identified a DNA-repair vulnerability whereby CDK4 inhibition suppresses homologous recombination proteins, rationalizing sequential taxane-then-CDK4/6i therapy in pancreatic cancer.

    Evidence Cell assays, PDX, Kras/Cdkn2a-null GEMMs, Western blot of HR proteins

    PMID:32109375

    Open questions at the time
    • Direct CDK4 substrates among HR factors not identified
    • Transcriptional versus post-translational mechanism of HR suppression unclear
  19. 2021 Medium

    Positioned CDK4 within a cell-size checkpoint, setting the target size at which p38 MAPK is inactivated to permit cell-cycle progression.

    Evidence Cell size measurements, CDK4 inhibition, genetic manipulation, cell-cycle analysis

    PMID:34022133

    Open questions at the time
    • Molecular link between CDK4 activity and p38 not defined
    • Single-lab finding
  20. 2018 Medium

    Showed CDK4/cyclin D1 sustains p53 transcriptional output by promoting RNA Pol II recruitment to p53 target promoters, adding a non-RB role at the chromatin level.

    Evidence Co-IP, siRNA, CDK4 inhibition, ChIP, gene expression analysis

    PMID:30206211

    Open questions at the time
    • Direct substrate within the transcription machinery not identified
    • Single-lab finding
  21. 2018 Medium

    Defined a proinflammatory CDK4/6→EZH2→STAT3→IκBζ axis in keratinocytes relevant to psoriasis, broadening CDK4 function into inflammation.

    Evidence Genetic/pharmacologic CDK4/6 inhibition, pathway analysis, psoriasis mouse models

    PMID:32701505

    Open questions at the time
    • EZH2 phosphosite not specified
    • CDK4 versus CDK6 contribution not separated
  22. 2013 Medium

    Implicated CDK4 in cytokinesis fidelity by showing its knockdown abrogates centrosome amplification and binucleation, with a reciprocal protein-level link to Nek2.

    Evidence shRNA knockdown in HER2+ breast cells, centrosome/binucleation quantification, Nek2 Western blot

    PMID:23776583

    Open questions at the time
    • Nek2 connection is correlative, not a defined biochemical interaction
    • Single-lab finding
  23. 2014 Medium

    Proposed Smad3 as a functional CDK4 substrate whose negative regulation modulates apoptosis (survivin/XIAP) and colony formation in breast cancer.

    Evidence Phospho-resistant Smad3 mutant, CDK4 inhibition, apoptosis and 3D colony assays

    PMID:25006666

    Open questions at the time
    • Limited mechanistic detail on direct phosphorylation
    • Single-lab finding
  24. 2023 High

    Discovered a redox switch controlling CDK4: a reversible Cys135-cyclin D disulfide inhibits the kinase under oxidation, with loss of the disulfide hyperactivating CDK4 in pulmonary arterial hypertension.

    Evidence Mutagenesis, tandem MS, in vitro kinase assays, redox-dead knock-in mice, disease tissue

    PMID:37955182

    Open questions at the time
    • Physiological oxidant generating the disulfide not defined
    • How redox status integrates with Thr172 activation unresolved
  25. 2025 Medium

    Distinguished CDK4 from CDK6 dependencies, showing HR+ breast cancers need CDK4 while hematopoiesis relies on CDK6, motivating CDK4-selective inhibition to spare neutrophils.

    Evidence CDK4-selective inhibitor (atirmociclib), dependency studies, in vivo efficacy/toxicity

    PMID:40068598

    Open questions at the time
    • Molecular basis of tissue-specific CDK4 versus CDK6 reliance not fully defined
    • Long-term clinical durability not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDK4's many direct substrates (TSC2, FLCN, TFEB/TFE3, AMPKα2, IRS2, EZH2, Smad3) are selected and prioritized in a given cell state, and how Thr172, chaperone loading, and the Cys135 redox switch are integrated to set kinase output, remain open.
  • No unified model coordinating substrate choice with activation inputs
  • Physiological signals controlling the redox switch unknown
  • Tissue-specific substrate hierarchies not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 4 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-1643685 Disease 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2
Partners
CCND1CCND3CDC37FLCNHSP90MDM2TP53TSC2
Complex memberships
Cyclin D-CDK4 holoenzymeHsp90-Cdc37-CDK4 chaperone complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 CDK4 (PSK-J3) and CDK6 (PLSTIRE) associate specifically with cyclin D1, forming a distinct subset of CDK complexes. In squamous carcinoma cells with amplified CCND1, cyclin D1 associates specifically with CDK4 and CDK6, while in diploid fibroblasts CDK2 and CDK5 can also co-precipitate with cyclin D1. Co-immunoprecipitation from tumor cell lines and diploid fibroblasts Oncogene High 8302605
1994 Assembly of cyclin D-CDK4 holoenzymes requires both subunit co-expression and serum stimulation in mammalian cells; phosphorylation of CDK4 on Thr172 by a CDK-activating kinase (CAK) is required for catalytic activity but assembly can proceed without this modification. CDK4 mutants that cannot be phosphorylated by CAK remain catalytically inactive. Baculovirus co-expression in Sf9 cells, in vitro kinase assays, site-directed mutagenesis of Thr172 Molecular and cellular biology High 8139570
1993 CDK4 gene is located on human chromosome 12q13 and is co-amplified with MDM2 and GLI in osteosarcoma and rhabdomyosarcoma cell lines, leading to overexpression of CDK4 mRNA and protein without mutations in the coding sequence. FISH, Southern blot copy number analysis, Northern blot, nucleotide sequencing Cancer research High 8221695
2006 CDK4 forms a stable ternary complex with the Hsp90 molecular chaperone and the cochaperone adaptor Cdc37; the stoichiometry and 3D structure of this complex were determined by single-particle electron microscopy, showing Cdc37 bridges CDK4 and Hsp90, and CDK4 conformational changes are coupled to the Hsp90 ATPase cycle. Complex purification, native mass spectrometry, single-particle electron microscopy, comparison with Hsp90 crystal structure Molecular cell High 16949366
2000 c-MYC transcriptionally activates CDK4 expression through four highly conserved c-MYC binding sites in the CDK4 promoter; c-MYC-deficient cells show delayed cell-cycle progression associated with reduced CDK4 induction, and ectopic CDK4 expression partially rescues this growth defect. Serial analysis of gene expression (SAGE), promoter analysis, ectopic expression rescue in c-MYC-deficient cells Proceedings of the National Academy of Sciences of the United States of America High 10688915
2001 The CDK4 R24C mutation, which renders CDK4 insensitive to INK4 inhibitors including p16INK4a, is sufficient to cause melanoma susceptibility in knock-in mice upon carcinogenic treatment; these tumors do not harbor p19ARF/p53 pathway mutations, establishing a specific role for the p16INK4a/CDK4/Rb pathway in melanoma. CDK4 R24C knock-in mouse model, carcinogenic treatment, tumor molecular analysis Proceedings of the National Academy of Sciences of the United States of America High 11606789
2005 CDK4 promotes adipogenesis through activation of PPARgamma; CDK4 knockout mouse embryonic fibroblasts show reduced adipogenic potential while activating CDK4 mutations increase it. CDK4 effects extend beyond differentiation control to adipocyte function through PPARgamma activation. CDK4 knockout and CDK4 R24C knock-in mouse embryonic fibroblasts, adipogenic differentiation assays Cell metabolism High 16213226
2009 CDK4 activates the CDK4-pRB-E2F1 pathway in pancreatic beta cells to regulate insulin secretion; CDK4 is activated by glucose via the insulin pathway, leading to E2F1 activation and transcriptional upregulation of Kir6.2 (a K-ATP channel subunit), thereby controlling glucose-induced insulin secretion. CDK4 inhibition or E2F1 knockout reduces Kir6.2 expression and impairs insulin secretion. Chromatin immunoprecipitation, genetic knockouts (CDK4-/-, E2f1-/-) in mice, rescue of Kir6.2 expression, glucose tolerance tests Nature cell biology High 19597485
2015 CDK4 is an essential insulin effector in adipocytes; insulin activates the CCND3-CDK4 complex, which phosphorylates IRS2 at Ser388, creating a positive feedback loop maintaining adipocyte insulin signaling. CDK4-deficient mice show impaired lipogenesis and increased lipolysis, while CDK4 R24C hyperactive mice show the opposite. CDK4 deficiency impairs insulin signaling globally in white adipose tissue. Global kinome analysis, in vivo and in vitro phosphorylation assays, CDK4 knockout and R24C knock-in mice, IRS2 mutagenesis The Journal of clinical investigation High 26657864
2017 CDK4 promotes anaerobic glycolysis and represses fatty acid oxidation by directly phosphorylating and inhibiting AMPKα2. Expression of non-phosphorylatable AMPKα2 mutants or CDK4 inhibition increases fatty acid oxidation in mouse embryonic fibroblasts and myotubes. CDK4-deficient mice show increased oxidative metabolism and exercise capacity. In vitro kinase assay, site-directed mutagenesis of AMPKα2, CDK4 knockout mice, metabolic flux measurements Molecular cell High 29053957
2017 CyclinD1-CDK4/6 complexes directly phosphorylate CDC25A on Ser40 during G1 phase in vitro and in cells, and this phosphorylation (along with Ser88) decreases CDC25A stability in a βTrCP-dependent manner, creating a negative feedback loop controlling G1/S transition. In vitro kinase assay, cell cycle synchronization, site-directed mutagenesis of Ser40, proteasome inhibitor experiments Oncogene High 28192398
2017 CDK4/6 inhibition suppresses proliferation of regulatory T cells and activates tumor cell expression of endogenous retroviral elements, increasing intracellular double-stranded RNA and stimulating type III interferon production. Both effects are associated with reduced activity of the E2F target DNMT1 (DNA methyltransferase 1), thereby enhancing tumor antigen presentation and cytotoxic T-cell clearance. Mouse tumor models (breast carcinoma and other solid tumors), transcriptomic analysis of clinical biopsies, mechanistic cell-based assays Nature High 28813415
2019 CDK4 phosphorylates the tumor suppressor folliculin (FLCN), regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. CDK4 also directly regulates lysosomal function and is essential for lysosomal degradation; CDK4 inhibition or knockout causes accumulation of undigested material in lysosomes, impairs autophagic flux, and induces cancer cell senescence. Pharmacological CDK4 inhibition, genetic CDK4 inactivation, in vitro phosphorylation assays, lysosomal function assays, xenograft models Cancer research High 31395606
2020 CyclinD-CDK4/6 directly binds and phosphorylates TSC2 on Ser1217 and Ser1452, activating mTORC1. CDK4/6 inhibition leads to a rapid, TSC2-dependent reduction of mTORC1 activity in multiple human and mouse cell lines. This mechanism couples cell growth (via mTORC1) with cell-cycle progression (via E2F). In vitro kinase assay, co-immunoprecipitation, pharmacological CDK4/6 inhibition in multiple cell lines, TSC2 loss-of-function rescue experiments Cell reports High 32294430
2020 CDK4/6 interact with and directly phosphorylate TFEB and TFE3 transcription factors in the nucleus, promoting their nuclear export and thereby inactivating them. During the cell cycle, lysosome numbers increase in S and G2/M phases when cyclin D turnover diminishes CDK4/6 activity, linking cell-cycle position to lysosome biogenesis. Co-immunoprecipitation, in vitro kinase assay, genetic CDK4/6 inactivation, subcellular localization studies, cell cycle synchronization The Journal of cell biology High 32662822
2020 CDK4 inhibition suppresses homologous recombination proteins required for recovery from chromosomal damage induced by taxanes, enabling sequential CDK4/6 inhibitor treatment after taxanes to prevent cellular proliferation in pancreatic ductal adenocarcinoma. Cell-based assays, patient-derived xenografts, genetically engineered mouse models (Kras G12V/Cdkn2a-null), Western blot analysis of HR protein levels Cancer cell Medium 32109375
2021 CDK4 activity sets the target cell size required for p38 MAPK inactivation and cell-cycle progression in a size checkpoint mechanism; CDK4 and p38 cooperate analogously to a thermostat, where p38 senses size irregularities and CDK4 sets the target size. Cell size measurements, CDK4 inhibition, genetic manipulation, cell cycle analysis Developmental cell Medium 34022133
2007 CDK4 can extend the replicative lifespan of human diploid fibroblasts through kinase-dependent, p16INK4a-independent mechanisms; catalytically inactive CDK4 cannot extend lifespan, indicating effects depend on phosphorylation of substrates other than sequestration of CDK inhibitors. p16INK4a deficiency and CDK4 overexpression have additive effects on replicative lifespan. Overexpression of wild-type and catalytically inactive CDK4 in HDFs with INK4a mutations or repression, replicative lifespan assays Molecular and cellular biology High 17420273
2006 CDK4 T-loop phosphorylation at Thr172 is a specific, determining target for cell cycle control by extracellular factors; this phosphorylation is regulated in CDK4 but not CDK6, indicating CDK4-activating kinase activity may be distinctly controlled for CDK4. Biochemical analysis of CDK4 activation states, comparison with CDK6 Cell division Medium 17092340
2018 CDK4 and CyclinD1 physically associate with p53-MDM2 complexes; CDK4 inhibition attenuates p53-responsive gene induction by reducing RNA Polymerase II recruitment to p53 target gene promoters (without reducing p53 binding or histone acetylation), revealing a role for CDK4/CyclinD1 in sustaining p53 transcriptional activity. Co-immunoprecipitation, siRNA knockdown, CDK4 inhibition, chromatin immunoprecipitation, gene expression analysis Cell death & disease Medium 30206211
2018 CDK4/6 phosphorylates EZH2 in keratinocytes, triggering methylation-induced activation of STAT3, which then induces IκBζ, a key proinflammatory transcription factor required for cytokine synthesis in psoriasis. Pharmacological or genetic inhibition of CDK4/6 abrogates this proinflammatory signaling. Genetic and pharmacological CDK4/6 inhibition in keratinocytes and mouse models, pathway analysis, topical drug application in psoriasis mouse models The Journal of clinical investigation Medium 32701505
2013 CDK4 knockdown abrogates centrosome amplification and binucleation in HER2+ breast cancer cells; CDK4 and Nek2 are molecularly connected (protein levels of Nek2 diminish upon CDK4 knockdown and vice versa), and CDK4 controls cytokinesis fidelity upstream of Nek2. shRNA knockdown of CDK4 in HER2+ breast cancer cell lines, centrosome and binucleation quantification, Western blot for Nek2 PloS one Medium 23776583
2023 Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide bond between CDK4 C135 and cyclin D C7/8 that inhibits kinase activity, decreases RB phosphorylation, and induces cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, and this disulfide is reduced (CDK4 hyperactive) in pulmonary arterial hypertension patient tissue. Site-directed mutagenesis, tandem mass spectrometry, in vitro kinase assays, redox-dead knock-in mouse model, disease tissue analysis Circulation research High 37955182
2014 CDK4 inhibition combined with doxorubicin decreases colony formation and increases apoptosis in breast cancer cells; CDK4-mediated phosphorylation negatively regulates Smad3, and a Smad3 construct resistant to CDK4 phosphorylation (5M) phenocopies CDK4 inhibition by decreasing colony formation and altering apoptotic protein expression including survivin and XIAP. Smad3 phosphorylation-resistant mutant expression, CDK4 inhibitor treatment, apoptosis assays, 3D Matrigel colony assay Cancer biology & therapy Medium 25006666
2025 HR+ breast cancer cells are highly dependent on CDK4 but not CDK6 for proliferation; human bone marrow-derived cells rely primarily on CDK6 (not CDK4) for hematopoiesis, explaining the hematologic toxicity of dual CDK4/6 inhibitors. A CDK4-selective inhibitor (atirmociclib) reduces neutrophil suppression while maintaining antitumor activity. CDK4-selective inhibitor development, pharmacological comparison, cell line dependency studies, in vivo efficacy and toxicity studies Cancer cell Medium 40068598

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 CDK4/6 inhibition triggers anti-tumour immunity. Nature 1193 28813415
2016 Treating cancer with selective CDK4/6 inhibitors. Nature reviews. Clinical oncology 904 27030077
2015 Targeting CDK4 and CDK6: From Discovery to Therapy. Cancer discovery 744 26658964
2000 Identification of CDK4 as a target of c-MYC. Proceedings of the National Academy of Sciences of the United States of America 408 10688915
2022 Targeting CDK4 and CDK6 in cancer. Nature reviews. Cancer 404 35304604
2018 CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest. Trends in cell biology 378 30061045
2022 CDK4 and CDK6 kinases: From basic science to cancer therapy. Science (New York, N.Y.) 362 35025636
1993 Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer research 362 8221695
2016 Targeting CDK4/6 in patients with cancer. Cancer treatment reviews 360 27017286
2020 Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition. Cancer cell 320 32289274
1994 CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1. Oncogene 291 8302605
1994 Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase. Molecular and cellular biology 275 8139570
2006 Structure of an Hsp90-Cdc37-Cdk4 complex. Molecular cell 248 16949366
2014 Molecular pathways: CDK4 inhibitors for cancer therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 201 24795392
2020 Cyclin D-CDK4/6 functions in cancer. Advances in cancer research 170 32723562
2020 Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors. International journal of molecular sciences 146 32899866
2005 Cdk4 promotes adipogenesis through PPARgamma activation. Cell metabolism 135 16213226
2019 Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer. Cells 129 30959874
2001 Invasive melanoma in Cdk4-targeted mice. Proceedings of the National Academy of Sciences of the United States of America 128 11606789
2020 Senescence as a therapeutically relevant response to CDK4/6 inhibitors. Oncogene 125 32541838
2020 The application and prospect of CDK4/6 inhibitors in malignant solid tumors. Journal of hematology & oncology 122 32357912
2021 Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer. Frontiers in oncology 121 34327137
2020 CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma. Cancer cell 119 32109375
2020 Cdk4 and Cdk6 Couple the Cell-Cycle Machinery to Cell Growth via mTORC1. Cell reports 111 32294430
2009 The CDK4-pRB-E2F1 pathway controls insulin secretion. Nature cell biology 111 19597485
2015 The Role of CDK4/6 Inhibition in Breast Cancer. The oncologist 106 25876993
2007 Mice thrive without Cdk4 and Cdk2. Molecular oncology 97 19383288
2018 MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 92 29739788
2017 Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas. Journal of hematology & oncology 89 28629371
2022 Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors. Science China. Life sciences 88 35982377
2020 CDK4/6 regulate lysosome biogenesis through TFEB/TFE3. The Journal of cell biology 88 32662822
2020 A unique CDK4/6 inhibitor: Current and future therapeutic strategies of abemaciclib. Pharmacological research 87 32068118
1995 MDM2 and CDK4 gene amplification in Ewing's sarcoma. The Journal of pathology 87 7738717
2011 Elevated expression of CDK4 in lung cancer. Journal of translational medicine 84 21477379
2015 CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 80 25810375
1997 p16/CDKN2 and CDK4 gene mutations in sporadic melanoma development and progression. International journal of cancer 79 9036865
2016 Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 78 27986745
2018 A Combination CDK4/6 and IGF1R Inhibitor Strategy for Ewing Sarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 77 30397176
2018 Combined CDK4/6 and Pan-mTOR Inhibition Is Synergistic Against Intrahepatic Cholangiocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 75 30084835
2006 Regulation of CDK4. Cell division 63 17092340
2022 Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer. NPJ precision oncology 62 36153348
2020 Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer. Frontiers in pharmacology 61 33364954
2015 CDK4 is an essential insulin effector in adipocytes. The Journal of clinical investigation 61 26657864
2018 JMJD6 promotes hepatocellular carcinoma carcinogenesis by targeting CDK4. International journal of cancer 60 30125344
2020 CDK4/6 inhibitors: a novel strategy for tumor radiosensitization. Journal of experimental & clinical cancer research : CR 59 32933570
2017 CDK4 Phosphorylates AMPKα2 to Inhibit Its Activity and Repress Fatty Acid Oxidation. Molecular cell 59 29053957
2017 Mechanisms of therapeutic CDK4/6 inhibition in breast cancer. Seminars in oncology 58 29935900
2007 CDK4 and CDK6 delay senescence by kinase-dependent and p16INK4a-independent mechanisms. Molecular and cellular biology 55 17420273
2018 Expression and therapeutic implications of cyclin-dependent kinase 4 (CDK4) in osteosarcoma. Biochimica et biophysica acta. Molecular basis of disease 54 29452249
2019 Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma. Bioorganic & medicinal chemistry letters 52 31307887
2000 Expression of p19INK4d, CDK4, CDK6 in glioblastoma multiforme. British journal of neurosurgery 52 10884881
2018 To Cycle or Fight-CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity. Clinical cancer research : an official journal of the American Association for Cancer Research 51 30224338
2025 CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety. Cancer cell 50 40068598
2020 Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows. Molecular cancer therapeutics 49 32546660
1999 Mutation testing in melanoma families: INK4A, CDK4 and INK4D. British journal of cancer 49 10390011
2021 CDK4/6 inhibitors: a brief overview and prospective research directions. RSC advances 48 35479560
2020 The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis. The Journal of clinical investigation 44 32701505
1994 Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes. Cytogenetics and cell genetics 43 8275715
2020 Current Therapeutic Progress of CDK4/6 Inhibitors in Breast Cancer. Cancer management and research 41 32523378
2017 CDK4/6 inhibitors in HER2-positive breast cancer. Critical reviews in oncology/hematology 41 28325261
2019 The interplay of CDK4 and CDK6 in melanoma. Oncotarget 40 30858922
2023 Phase II trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/ CDKN2A. Signal transduction and targeted therapy 39 37875500
2013 Cdk4 and nek2 signal binucleation and centrosome amplification in a her2+ breast cancer model. PloS one 39 23776583
2019 SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors. Science advances 38 31555743
2025 Targeting CDK4/6 in breast cancer. Experimental & molecular medicine 37 39930131
2024 Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer. Cancer research 37 38277141
2021 Inducible deletion of CDK4 and CDK6 - deciphering CDK4/6 inhibitor effects in the hematopoietic system. Haematologica 37 32855282
2021 Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK. Developmental cell 37 34022133
2019 CDK4 Regulates Lysosomal Function and mTORC1 Activation to Promote Cancer Cell Survival. Cancer research 37 31395606
2017 CyclinD-CDK4/6 complexes phosphorylate CDC25A and regulate its stability. Oncogene 37 28192398
2015 CDK4/6 inhibitors in breast cancer. Anti-cancer drugs 36 26053278
2022 Targeting CDK4/6 for Anticancer Therapy. Biomedicines 34 35327487
2016 Roles of Cell Cyle Regulators Cyclin D1, CDK4, and p53 in Knee Osteoarthritis. Genetic testing and molecular biomarkers 34 27391794
2000 Inverse expression of Cdk4 and p16 in epithelial ovarian tumors. Gynecologic oncology 34 11063650
2022 Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything? NPJ precision oncology 33 35444175
2020 CDK4/6 and MAPK-Crosstalk as Opportunity for Cancer Treatment. Pharmaceuticals (Basel, Switzerland) 33 33255177
2018 Clinical development of CDK4/6 inhibitor for breast cancer. Breast cancer (Tokyo, Japan) 31 29392622
2018 CDK4 inhibition diminishes p53 activation by MDM2 antagonists. Cell death & disease 31 30206211
2024 MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation. Nature communications 30 38424044
2022 Targeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib. The oncologist 30 35917168
2021 Development of CDK4/6 Inhibitors: A Five Years Update. Molecules (Basel, Switzerland) 30 33803309
2023 Development of PROTAC degrader probe of CDK4/6 based on DCAF16. Bioorganic chemistry 28 37276679
2015 CDK4/6 Inhibitor PD0332991 in Glioblastoma Treatment: Does It Have a Future? Frontiers in oncology 28 26649278
2014 MDM2 and CDK4 expression in periosteal osteosarcoma. Human pathology 28 25680902
2023 SETDB1 Modulates Degradation of Phosphorylated RB and Anticancer Efficacy of CDK4/6 Inhibitors. Cancer research 27 36637424
2023 Immunomodulatory effects of CDK4/6 inhibitors. Biochimica et biophysica acta. Reviews on cancer 27 37182667
1999 Localization and expression of cdc2 and cdk4 in Alzheimer brain tissue. Dementia and geriatric cognitive disorders 27 10325446
2022 Combined inhibition of ACLY and CDK4/6 reduces cancer cell growth and invasion. Oncology reports 26 36562384
2021 The role of CDK4/6 inhibitors in early breast cancer. Breast (Edinburgh, Scotland) 26 34087775
2018 Targeting CDK4/6 pathways and beyond in breast cancer. Breast (Edinburgh, Scotland) 26 30359883
2017 CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC. Molecular cancer research : MCR 26 28209757
2023 Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation. Circulation research 25 37955182
2020 The Utility of MDM2 and CDK4 Immunohistochemistry and MDM2 FISH in Craniofacial Osteosarcoma. Head and neck pathology 25 32026294
2020 Getting under the skin: The role of CDK4/6 in melanomas. European journal of medicinal chemistry 25 32712436
2020 How selective are clinical CDK4/6 inhibitors? Medicinal research reviews 25 33300617
2025 Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer. Nature cancer 24 39885369
2020 Metabolic Adaptations to MEK and CDK4/6 Cotargeting in Uveal Melanoma. Molecular cancer therapeutics 24 32430489
2014 CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and survivin. Cancer biology & therapy 23 25006666
2017 CDK4 expression in chordoma: A potential therapeutic target. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 22 29194728
2023 Recent Progress in CDK4/6 Inhibitors and PROTACs. Molecules (Basel, Switzerland) 21 38138549

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