Affinage

CKS1B

Cyclin-dependent kinases regulatory subunit 1 · UniProt P61024

Length
79 aa
Mass
9.7 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CKS1B encodes a small, evolutionarily conserved cyclin-dependent kinase (CDK)-binding subunit that functions as an obligate adaptor for the SCF(Skp2) E3 ubiquitin ligase to target phosphorylated p27(Kip1) for ubiquitin-dependent proteolysis, thereby driving G1-S cell cycle progression (PMID:11231585, PMID:11463388, PMID:16209941). Structural studies show CKS1 bridges Skp2 and p27 through three distinct binding surfaces — a Skp2-interaction interface on its α-helices, a phosphate-binding pocket that captures pThr187 of p27, and a CDK-binding site — and induces allosteric conformational changes that stabilize the SCF complex (PMID:12140288, PMID:16979657, PMID:37400515). Beyond substrate-adaptor function, CKS1 recruits the 19S proteasome to chromatin in a CDK1-dependent manner to promote nucleosome eviction and transcription of mitotic genes including CCNB1, CCNA2, and CDK1, and genome-wide it enhances CDK1-mediated multisite and non-proline-directed phosphorylation (PMID:12827207, PMID:18625720, PMID:36840943). CKS1B also has Skp2/p27-independent oncogenic functions, activating NF-κB, STAT3, and MEK/ERK signaling in cancer contexts, and its inhibition selectively depletes AML leukemic stem cells through RAC1 hyperactivation and lethal ROS accumulation (PMID:20930946, PMID:21917729, PMID:35731890).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    The structural basis of CKS1-CDK interaction was established: the crystal structure of CKS1 bound to CDK2 revealed binding via all four β-strands to the CDK C-terminal lobe and an exposed phosphate-binding region, suggesting CKS1 could target CDKs to phosphoprotein substrates.

    Evidence X-ray crystallography at 2.6 Å with mutagenesis validation of the binding interface

    PMID:8601310

    Open questions at the time
    • No substrate for the phosphate-binding pocket identified
    • Role in CDK regulation in vivo undetermined
  2. 2001 High

    The long-sought function of mammalian CKS1 was resolved: it is an essential and non-redundant accessory factor for SCF(Skp2)-mediated ubiquitination of Thr187-phosphorylated p27(Kip1), directly bridging Skp2 to its substrate.

    Evidence Fully reconstituted in vitro ubiquitin ligation with purified components; confirmed independently by Cks1-knockout mouse showing elevated p27 and proliferation defects

    PMID:11231585 PMID:11463388

    Open questions at the time
    • Structural details of the ternary Skp2-Cks1-p27 interaction unresolved
    • Whether Cks1 has ubiquitin-ligase-independent cell cycle roles unknown
  3. 2002 High

    Three functionally separable binding sites on CKS1 were mapped — Skp2-binding, anion/phosphate-binding, and CDK-binding — each independently required for p27 ubiquitination, establishing CKS1 as a multi-contact adaptor rather than a simple bridge.

    Evidence Systematic site-directed mutagenesis with in vitro ubiquitination and binding assays

    PMID:12140288

    Open questions at the time
    • Atomic-resolution structure of the full complex not yet available
    • Whether the CDK-binding site contributes allosterically or solely via proximity unknown
  4. 2003 High

    A transcription-linked function was uncovered in yeast: Cks1 recruits the proteasome to gene promoters (e.g., CDC20) in a CDK1-dependent manner to enable periodic transcriptional activation, revealing a role entirely distinct from SCF-mediated ubiquitination.

    Evidence ChIP at the CDC20 promoter; genetic analysis of cks1 mutants in S. cerevisiae

    PMID:12827207

    Open questions at the time
    • Whether this proteasome-recruitment function is conserved in mammals undetermined
    • Mechanism by which proteasome presence activates transcription unclear
  5. 2003 High

    The Skp2 residues critical for CKS1 binding were identified: Asp-331 in the Skp2 C-terminal tail is essential for the Skp2-Cks1 interaction and p27 ubiquitination, establishing the interface as a targetable surface.

    Evidence Site-directed mutagenesis of Skp2 with co-IP and in vitro ubiquitination assays

    PMID:12813041 PMID:15452136

    Open questions at the time
    • No high-resolution structure of the Skp2-Cks1 binary complex yet
    • Whether disruption of this interface affects other Skp2 substrates unknown
  6. 2004 High

    CKS1 protein turnover was linked to the cell cycle: APC/C(Cdh1) degrades both Skp2 and Cks1 in G1, creating a bistable switch — when Cdh1 is silenced, Cks1/Skp2 accumulate prematurely and cause premature S-phase entry through p27 destruction.

    Evidence Cdh1 RNAi in G1-phase cells with epistasis by Skp2 double knockdown; cell cycle analysis

    PMID:14622140 PMID:15014502

    Open questions at the time
    • Identity of the degron on CKS1 recognized by APC/C(Cdh1) not mapped
    • Whether CKS1 degradation in M phase uses a different E3 unknown
  7. 2005 High

    The crystal structure of the Skp1-Skp2-Cks1-p27 phosphopeptide complex provided atomic detail: CKS1 contacts Skp2 LRR and C-terminal tail, its phosphate pocket captures pThr187, and p27 Glu185 inserts into the Skp2-Cks1 interface, fully explaining the adaptor mechanism.

    Evidence X-ray crystallography with biochemical validation

    PMID:16209941

    Open questions at the time
    • Full-length p27 dynamics in the complex unresolved
    • Structural basis for CKS1 specificity over CKS2 unclear
  8. 2005 High

    The chromatin-associated proteasome-recruitment function was generalized: in yeast, CKS1/CDK1 recruits proteasomes to coding regions genome-wide for transcription independently of CDK kinase activity, establishing CKS1 as a non-enzymatic chromatin remodeling factor.

    Evidence ChIP with kinase-dead Cdc28 mutants; gene expression profiling in cks1 mutants

    PMID:15629725

    Open questions at the time
    • Whether this is kinase-activity-independent in mammals not tested
    • Which specific proteasome subunits mediate the transcriptional effect unclear
  9. 2006 High

    CKS1 was shown to act allosterically: hydrogen-deuterium exchange revealed that CKS1 binding to Skp2 induces long-range conformational changes at distant LRR regions and stabilizes the Skp2-Skp1 interaction, extending its role beyond simple bridging.

    Evidence HXMS on Skp2 ± CKS1

    PMID:16979657

    Open questions at the time
    • Whether allosteric effects influence recognition of non-p27 substrates unknown
    • No structure of the Skp2 conformational change captured
  10. 2007 High

    CKS1B was demonstrated to have Skp2/p27-independent pro-survival functions in cancer: shRNA depletion of CKS1B induced apoptosis in a myeloma line with biallelic p27 deletion, and Myc was identified as a direct transcriptional activator of CKS1 that drives lymphomagenesis through p27 suppression.

    Evidence Genetic epistasis with p27-null myeloma cells; Eμ-Myc;Cks1−/− mouse lymphoma model with delayed tumor onset

    PMID:17303695 PMID:17464290

    Open questions at the time
    • Molecular identity of p27-independent survival targets unknown
    • Whether Myc regulation of CKS1 is direct at the promoter not fully resolved
  11. 2008 High

    Combined loss of CKS1 and CKS2 in mammals proved essential for viability: double knockout causes embryonic lethality at the morula stage, and combined depletion in cultured cells causes G2 arrest due to loss of CCNB1, CCNA2, and CDK1 transcription — rescued by cyclin B1 re-expression.

    Evidence Cks1/Cks2 double-KO mice; RNAi in MEFs and HeLa; molecular rescue

    PMID:18625720

    Open questions at the time
    • Individual contributions of CKS1 vs. CKS2 to mitotic gene transcription not separated
    • Whether transcriptional role operates through proteasome recruitment in mammals not tested
  12. 2010 High

    The mechanism of proteasome-mediated chromatin remodeling was deepened: CKS1, CDK1, and the 19S proteasome reduce nucleosome density by binding the histone H4 N-terminal tail, and this nucleosome eviction does not require 20S protease activity.

    Evidence ChIP; H4 tail binding assays; protease-dead proteasome mutants in yeast

    PMID:20855529

    Open questions at the time
    • Mammalian validation of H4-tail binding by CKS1 lacking
    • Whether nucleosome eviction is the primary mechanism for CKS1-dependent transcription undetermined
  13. 2010 Medium

    SKP2/p27-independent oncogenic signaling downstream of CKS1B was mapped: CKS1B overexpression activates STAT3 and MEK/ERK pathways in myeloma, with BCL2 as a downstream effector.

    Evidence Forced CKS1B expression with phospho-signaling blots; pharmacological inhibitor rescue in myeloma cells

    PMID:20930946

    Open questions at the time
    • Direct molecular mechanism connecting CKS1B to STAT3/ERK activation unidentified
    • Single-lab finding without independent replication
  14. 2012 High

    Genetic epistasis in double-knockout MEFs definitively separated CKS1 functions: CKS1 has a p27-independent role at G1-S (reduced CDK2 kinase activity persists in Cks1−/−;p27−/− cells), whereas mitotic entry defects and premature senescence are p27-dependent; CKS2 counteracts CKS1 to stabilize p27 in vivo.

    Evidence Cks1/p27 double-KO MEFs with CDK2 kinase assays; Cks2−/− mice with replication and DNA damage analysis

    PMID:22508990 PMID:22898779

    Open questions at the time
    • Identity of the p27-independent G1-S substrate(s) of CKS1 unknown
    • How CKS2 mechanistically opposes CKS1 at the molecular level unclear
  15. 2023 High

    CKS1 was revealed as a proteome-wide enhancer of CDK1 substrate phosphorylation: together with Cyclin A, CKS1 enables non-proline-directed and multisite CDK1 phosphorylation across the cell cycle phosphoproteome, preferring sites with a +3 lysine.

    Evidence Quantitative phosphoproteomics with and without CKS1; fixed-cell kinase assay

    PMID:36840943

    Open questions at the time
    • Whether CDK2-CKS1 has analogous substrate-expansion activity untested
    • Structural basis for +3 lysine preference not resolved
  16. 2023 High

    Cryo-EM of the full hexameric CDK2-CycA-CKS1-p27-Skp1-Skp2 complex confirmed a CKS1-centered hinge motion between open and closed conformations, rationalizing how conformational dynamics facilitate p27 recognition.

    Evidence Cryo-EM at 3.4 Å with 3D variability analysis

    PMID:37400515

    Open questions at the time
    • Functional consequence of open vs. closed states not tested biochemically
    • Whether ubiquitin transfer occurs preferentially in one conformation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the CKS1-dependent, p27-independent G1-S substrates; the molecular mechanism by which CKS1 activates STAT3, MEK/ERK, and NF-κB signaling; and whether the yeast proteasome-recruitment/nucleosome-eviction mechanism operates through the same H4-tail interaction in mammalian cells.
  • p27-independent G1-S target(s) not identified
  • Direct mechanism linking CKS1B to STAT3/MEK/NF-κB activation not established
  • Mammalian validation of CKS1-dependent nucleosome eviction via H4 tail not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 2 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3 GO:0005829 cytosol 2
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 1
Partners
CCNA2CCNB1CDK1CDK2CDKN1BFRS2SKP1SKP2
Complex memberships
CDK1-Cyclin B-Cks1CDK2-Cyclin A-Cks1SCF(Skp2)-Cks1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 CKS1 (Cks1) is an essential accessory factor for the SCF(Skp2) ubiquitin ligase complex: human Cks1 binds directly to Skp2, greatly increases binding of Thr187-phosphorylated p27 to Skp2, and reconstitutes ubiquitin ligation of p27 in a completely purified in vitro system. No other Cks family member substitutes. Reconstituted ubiquitin ligation in a fully purified system; binding assays; specificity tested with other Cks family members Nature cell biology High 11231585 11463388
2005 Crystal structure of the Skp1-Skp2-Cks1 complex bound to a p27(Kip1) phosphopeptide shows Cks1 binds the leucine-rich repeat domain and C-terminal tail of Skp2; the phosphorylated Thr187 of p27 is recognized by the Cks1 phosphate-binding site; an invariant Glu185 of p27 inserts into the Skp2-Cks1 interface; Cdk2-cyclin A contributes to p27 recruitment to the SCF(Skp2)-Cks1 complex. X-ray crystal structure (Skp1-Skp2-Cks1-p27 phosphopeptide complex) combined with biochemical binding assays Molecular cell High 16209941
2023 Cryo-EM structure of the hexameric CDK2-cyclin A-CKS1-p27-SKP1-SKP2 complex at 3.4 Å resolution confirms p27 structural dynamics (disordered to nascent secondary structure on binding) and reveals a hinge motion centred on CKS1 that gives rise to open and closed conformations proposed to facilitate p27 recognition by SCF(SKP2). Cryo-EM single-particle analysis with 3D variability analysis and local refinement Scientific reports High 37400515
1996 Crystal structure of human CDK2 in complex with CksHs1 (CKS1B ortholog) at 2.6 Å shows CksHs1 binds via all four β-strands to the CDK2 C-terminal lobe; mutational analysis confirms this interface is biologically critical; the conserved phosphate-binding region on Cks is exposed, suggesting Cks may target CDK2 to phosphoproteins. X-ray crystallography at 2.6 Å plus mutational analysis of binding interface Cell High 8601310
2002 Three distinct binding sites of Cks1 are required for p27 ubiquitin ligation: (1) Skp2-binding site on the α2/α1-helix region, (2) anion-binding site, and (3) CDK-binding site. The Skp2-binding and anion-binding sites mediate initial binding of Skp2-Cks1 to C-terminal phospho-p27; the CDK-binding site further strengthens interaction via Cdk2/cyclin E bound to phospho-p27. In vitro ubiquitin ligation assays with Cks1 mutants; binding assays with Skp2, Cdk2/cyclin E, and phospho-p27 peptides The Journal of biological chemistry High 12140288
2004 Both Skp2 and its cofactor Cks1 are unstable in G1 phase and are targeted for degradation by the APC/C(Cdh1) ubiquitin ligase. Silencing Cdh1 by RNAi stabilizes Skp2 and Cks1, causing increased p21/p27 proteolysis and premature S-phase entry; concomitant Skp2 knockdown reverses this, establishing Skp2 as an essential target of APC/C(Cdh1). RNAi silencing of Cdh1 in G1 cells; cell cycle analysis; epistasis by double knockdown Nature High 15014502
2003 Cks1 protein is degraded via the ubiquitin-proteasome pathway in a cell-cycle-dependent manner, with degradation particularly pronounced in M phase; Cks1 is modified with polyubiquitin chains both in vivo and in vitro, and proteasome inhibitors block its degradation. Proteasome inhibitor treatment; in vivo and in vitro ubiquitination assays; cell-cycle fractionation Genes to cells Medium 14622140
2003 In S. cerevisiae, Cks1 promotes mitosis by facilitating transcriptional activation of CDC20 (APC/C activator): Cks1 is required for periodic dissociation of Cdc28 kinase from the CDC20 promoter and for periodic recruitment of the proteasome to the CDC20 promoter, thereby enabling CDC20 transcription. ChIP assays at CDC20 promoter; genetic analysis of Cks1-deficient yeast; proteasome recruitment assays Nature High 12827207
2005 In S. cerevisiae, Cks1/Cdc28 (CDK1) complex is recruited to multiple coding regions and is required for efficient transcription of a subset of genes; this transcriptional role is mediated by recruiting proteasomes to coding regions and is independent of Cdc28 kinase activity. Without Cks1, neither Cdc28 nor the proteasome are recruited to chromatin. ChIP; kinase-dead Cdc28 mutants; gene expression analysis in cks1 mutants Molecular cell High 15629725
2010 In S. cerevisiae, Cks1, Cdk1, and the 19S proteasome collaborate to reduce nucleosome density on chromatin during gene induction; Cks1, Cdk1, and the 19S proteasome subunit are each recruited to chromatin by binding the histone H4 amino-terminal tail; this nucleosome eviction activity of the proteasome does not require the 20S protease activity. ChIP; histone H4 tail binding assays; genetic rescue experiments; proteasome activity mutants Molecular and cellular biology High 20855529
2008 Simultaneous disruption of CKS1 and CKS2 causes embryonic lethality in mice at the morula stage; RNAi silencing of both CKS genes in MEFs or HeLa cells causes G2 arrest followed by rereplication and polyploidy; this arrest is attributable to impaired transcription of CCNB1, CCNA2, and CDK1 genes; restoration of cyclin B1 expression rescues the cell cycle arrest. CKS1/CKS2 double-knockout mice; RNAi in MEFs and HeLa; RT-PCR for cyclin/CDK mRNAs; rescue by cyclin B1 re-expression; Cks2 ChIP to promoters Molecular and cellular biology High 18625720
2003 A negatively charged residue Asp-331 in the C-terminal region of Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27; mutation to Ala disrupts this interaction and abolishes SCF(Skp2)-mediated p27 ubiquitination without affecting Skp2 self-ubiquitination; conservative Asp-to-Glu substitution preserves function. Site-directed mutagenesis of Skp2; co-immunoprecipitation; in vitro ubiquitination assay The Journal of biological chemistry High 12813041
2004 Eight amino acid residues in two discrete regions of Skp2 constitute the functional binding surface for Cks1; four of these are located in the structurally flexible C-terminal tail of Skp2; mutation of any single residue abolishes Cks1 association and p27 ubiquitination. Alanine scanning mutagenesis of Skp2; co-immunoprecipitation; in vitro p27 ubiquitination assay The Journal of biological chemistry High 15452136
2006 Hydrogen/deuterium exchange mass spectrometry shows that Cks1 binding to Skp2 causes conformational changes in both proteins at regions distant from the direct binding sites: Cks1 binds to C-terminal LRRs of Skp2, inducing conformational changes at the distant N-terminal LRRs (near the F-box); Cks1 binding also significantly stabilizes the Skp2-Skp1 interaction. Hydrogen/deuterium exchange monitored by mass spectrometry (HXMS) Journal of molecular biology High 16979657
2004 Cks1 associates with unphosphorylated FRS2 (FGFR substrate 2) in quiescent cells; FGF-dependent FGFR tyrosine kinase activation induces FRS2 phosphorylation, causing release of Cks1 from FRS2, which then promotes p27(Kip1) degradation and G1/S transition. Co-immunoprecipitation of Cks1 and FRS2; phosphorylation-dependent release assay; p27 degradation analysis in 3T3 cells The Journal of biological chemistry Medium 15513912
2005 FoxM1 transcription factor is essential for transcription of CKS1 (and Skp2); loss of FoxM1 reduces Cks1 and Skp2 expression, causing accumulation of p21 and p27 nuclear levels; this was demonstrated by quantitative ChIP and expression assays showing FoxM1 directly occupies and activates the CKS1 promoter. Quantitative ChIP; siRNA depletion of FoxM1; gene expression assays in Foxm1-/- MEFs and U2OS cells Molecular and cellular biology High 16314512
2007 Cks1 transcription is directly induced by the Myc oncogene; elevated Cks1 suppresses p27(Kip1) to drive lymphomagenesis; loss of Cks1 in Eμ-Myc B cells elevates p27, reduces proliferation, and markedly delays lymphoma development. Cks1-/- mice crossed into Eμ-Myc model; tumor onset analysis; p27 and proliferation measurements; chromatin association of Myc at Cks1 promoter The EMBO journal High 17464290
2007 CKS1B promotes myeloma cell growth and survival through both SKP2/p27(Kip1)-dependent and -independent mechanisms; shRNA ablation of CKS1B induces apoptosis even in a myeloma cell line with biallelic deletion of p27, indicating a p27-independent pro-survival function. Lentiviral shRNA knockdown of CKS1B; cell cycle arrest and apoptosis assays; comparison with SKP2 knockdown and non-degradable p27(T187A) overexpression Blood High 17303695
2010 CKS1B overexpression activates STAT3 and MEK/ERK signaling pathways in multiple myeloma cells, with BCL2 as a downstream target of MEK/ERK; these are SKP2/p27-independent pathways; pharmacological inhibition of STAT3 and MEK/ERK partially abrogates CKS1B knockdown-induced cell death. Forced CKS1B expression; western blotting for p-STAT3 and p-ERK; pathway inhibitor rescue assays; shRNA knockdown Oncotarget Medium 20930946
2011 Cks1 promotes NF-κB-dependent IL-8 expression in hepatocellular carcinoma via a Skp2/p27-independent mechanism: Cks1 targets IκBα through regulation of IκB kinase complex components, leading to NF-κB activation and IL-8 upregulation; IL-8 knockdown alone is sufficient to blunt HCC growth. RNAi knockdown of Cks1; rescue with IL-8 or p27 manipulation; IκBα and NF-κB pathway analysis; comparison with Skp2 knockdown Cancer research Medium 21917729
2007 Cks1 depletion in breast cancer cells decreases CDK1 expression at the mRNA level and causes G2-M accumulation due to blocked mitotic entry; restoration of CDK1 reduces the G2-M accumulation, establishing a functional link between Cks1 and CDK1 transcription. RNAi depletion of Cks1; RT-PCR for CDK1 mRNA; CDK1 rescue experiments; cell cycle analysis by flow cytometry Cancer research Medium 18056467
2000 CKS1-/- mice are abnormally small and cells from them proliferate poorly, particularly under limiting mitogen conditions, with elevated p27(Kip1) levels; Cks1 is essential for recognition of p27 for ubiquitination in vivo and in vitro, and for targeting the SCF(Skp2) E3 to CDK-bound p27. CKS1 knockout mice; in vitro p27 ubiquitination reconstitution with purified recombinant proteins; cell proliferation assays Molecular cell High 11463388
2007 CKS1 expression is transcriptionally regulated during the cell cycle via a CDE/CHR tandem element in its promoter; p53 (but not p63 or p73) represses CKS1 transcription in a dose-dependent manner through this promoter without a canonical p53 binding site; NF-Y is the main transcriptional activator but does not mediate p53 repression. Reporter gene assays with CDE/CHR mutants; inducible p53 expression systems; promoter mutagenesis; RT-PCR and western blot Cell cycle Medium 17377499
2006 In S. cerevisiae, Cks1 overexpression is synthetically dosage lethal with mutations affecting mitotic entry (requiring Swe1 inhibitory kinase activity on Cdc28) and mitotic exit (suppressed by Sic1 CDK inhibitor modulation); the human ortholog of this interaction is conserved: CKS1B overexpression sensitizes human breast cancer cells to PLK1 inhibition. Yeast high-throughput synthetic dosage lethality screen; shRNA and pharmacological PLK1 inhibition in CKS1B-overexpressing human cancer cell lines Genetics Medium 27558135
2012 CKS2 counteracts CKS1 to stabilize p27; in Cks2-/- cells, unopposed CKS1 activity leads to loss of p27, unrestricted cyclin A/CDK2 activity, shortened cell cycle, increased replication fork velocity, and DNA damage; in vivo, loss of Cks2 limits cortical progenitor differentiation into neurons. Cks2-/- knockout mice; BrdU/EdU replication assays; DNA damage markers; neuronal differentiation analysis Developmental cell High 22898779
2021 A ternary CDK1:Cyclin-B:CKS1 complex (CCC) was reconstituted from purified recombinant proteins; the inclusion of CKS1 boosts kinase processivity of CDK1:Cyclin-B in vitro. Recombinant protein reconstitution; in vitro kinase processivity assays; comparison of CC vs. CCC complexes Protein science Medium 34791727
2023 CKS1, together with Cyclin A, promotes non-proline-directed CDK1 phosphorylation genome-wide; CKS1 has a proteome-wide role as an enhancer of multisite CDK1 phosphorylation, preferably on sites with a +3 lysine residue; 70% of cell-cycle-regulated non-proline-directed phosphorylations are CDK1 sites whose kinase was previously unidentified. Fixed-cell kinase assay; phosphoproteomics; CDK1 activity titration with and without CKS1 Cell reports High 36840943
2014 Inhibition of Hsp90 (using 17-AAG) destabilizes Cks1 in cancer cells by promoting its ubiquitination and proteasomal degradation; Cks1 depends on Hsp90-Cdc37 chaperone machinery for conformational stability; Hsp90 inhibition also reduces Skp2 and CDK1 levels. 17-AAG treatment; cycloheximide chase; HA-ubiquitin transfection and Cks1 immunoprecipitation; western blotting Cancer chemotherapy and pharmacology Medium 25544127
2017 Cks1 and Cks2 proteins interact with both MllN and MllC subunits of Mll1 and together regulate Mll1 protein levels throughout the cell cycle; small molecule modulation of Cks-dependent protein degradation (MLN4924, C1) preferentially reduces proliferation of MLL-rearranged AML cell lines. Co-immunoprecipitation of Cks1/Cks2 with Mll1 subunits; western blot for Mll1 levels in Cks1/2-depleted cells; pharmacological inhibitor treatment Biochimica et biophysica acta. Molecular cell research Medium 28939057
2022 CKS1-dependent protein degradation is a key vulnerability in AML leukemic stem cells: a small-molecule CKS1 inhibitor depletes patient-derived AML blasts and leukemic stem cells in vivo while protecting normal hematopoietic stem cells; proteomic analysis reveals CKS1 inhibition in AML causes hyperactivation of RAC1 and accumulation of lethal reactive oxygen species, whereas healthy hematopoietic cells enter quiescence. Patient-derived xenograft mouse model; small-molecule CKS1 inhibitor; quantitative proteomics; ROS measurement; HSC quiescence assays Science translational medicine High 35731890
2000 Cks1 mediates vascular smooth muscle cell polyploidization: Cks1 overexpression promotes cyclin B degradation, disrupts the mitotic spindle checkpoint, and induces cell cycle re-entry and polyploidization; retroviral transduction of Cks1 alone is sufficient to recapitulate this phenotype in normotensive VSMC. Retroviral Cks1 overexpression in VSMC; cyclin B protein quantification; colcemid mitotic spindle checkpoint assay; ploidy analysis The Journal of biological chemistry Medium 11005810
2017 In S. cerevisiae, TORC1 inactivation causes Sic1-pThr173 to serve as a docking site for Cks1, sequestering Clb5-CDK-Cks1 complexes and preventing them from flagging Sic1 for ubiquitin-dependent proteolysis; this converts Sic1 from a degradation target to an inhibitor of cyclin-CDK-Cks1. Yeast genetic and biochemical experiments; phospho-Thr173 binding assays; epistasis with greatwall kinase and TORC1 pathway components Cell discovery Medium 28496991
2012 Cks1 has a p27(Kip1)-independent function in the G1-S transition: Cks1-/-; p27-/- double-knockout MEFs retain defects in G1-S transition, decreased CDK2-associated kinase activity, and proliferation defects; mitotic entry defects and premature senescence in Cks1-/- cells are p27-dependent. Cks1/p27 double-knockout MEFs; CDK2 kinase assay; cell cycle analysis; senescence assays Molecular and cellular biology High 22508990

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Molecular and cellular biology 557 16314512
2001 The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27. Nature cell biology 429 11231585
2004 Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature 422 15014502
2001 A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1. Molecular cell 326 11463388
2005 Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Molecular cell 254 16209941
2015 The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer. Molecular therapy : the journal of the American Society of Gene Therapy 221 25597412
1996 Crystal structure and mutational analysis of the human CDK2 kinase complex with cell cycle-regulatory protein CksHs1. Cell 215 8601310
1989 The Saccharomyces cerevisiae CKS1 gene, a homolog of the Schizosaccharomyces pombe suc1+ gene, encodes a subunit of the Cdc28 protein kinase complex. Molecular and cellular biology 192 2664468
2007 CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood 139 17303695
2005 Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. Hematology (Amsterdam, Netherlands) 124 16188652
2008 Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells. Molecular and cellular biology 105 18625720
2003 Cks1-dependent proteasome recruitment and activation of CDC20 transcription in budding yeast. Nature 105 12827207
2010 Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance. Oncotarget 101 20930946
1993 The Cdk-associated protein Cks1 functions both in G1 and G2 in Saccharomyces cerevisiae. Genes & development 92 8491379
2007 Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis. The EMBO journal 85 17464290
2005 The expression of the ubiquitin ligase subunit Cks1 in human breast cancer. Breast cancer research : BCR 84 16168119
2008 Aberrant expression of Cks1 and Cks2 contributes to prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death. International journal of cancer 82 18498131
2002 Three different binding sites of Cks1 are required for p27-ubiquitin ligation. The Journal of biological chemistry 72 12140288
1995 Crystal structure of the human cell cycle protein CksHs1: single domain fold with similarity to kinase N-lobe domain. Journal of molecular biology 67 7791211
2003 High expression of Cks1 in human non-small cell lung carcinomas. Biochemical and biophysical research communications 66 12670508
2004 Role of Cks1 overexpression in oral squamous cell carcinomas: cooperation with Skp2 in promoting p27 degradation. The American journal of pathology 64 15579456
2008 Fluoxetine mediates G0/G1 arrest by inducing functional inhibition of cyclin dependent kinase subunit (CKS)1. Biochemical pharmacology 60 18371935
2006 Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells. Oncogene 60 16924241
2000 Cks1 is required for G(1) cyclin-cyclin-dependent kinase activity in budding yeast. Molecular and cellular biology 59 10913169
2013 Inhibitors of SCF-Skp2/Cks1 E3 ligase block estrogen-induced growth stimulation and degradation of nuclear p27kip1: therapeutic potential for endometrial cancer. Endocrinology 54 24035998
2013 High-throughput screening AlphaScreen assay for identification of small-molecule inhibitors of ubiquitin E3 ligase SCFSkp2-Cks1. Journal of biomolecular screening 53 23589337
2017 Long noncoding RNA MALAT1 affects the efficacy of radiotherapy for esophageal squamous cell carcinoma by regulating Cks1 expression. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 50 27935117
2007 Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells. Cancer research 49 18056467
2005 A kinase-independent function of Cks1 and Cdk1 in regulation of transcription. Molecular cell 49 15629725
2017 Integrated MicroRNA-mRNA Analysis Reveals miR-204 Inhibits Cell Proliferation in Gastric Cancer by Targeting CKS1B, CXCL1 and GPRC5A. International journal of molecular sciences 42 29283424
2015 NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 40 26156395
2000 Crystal structure and mutational analysis of the Saccharomyces cerevisiae cell cycle regulatory protein Cks1: implications for domain swapping, anion binding and protein interactions. Structure (London, England : 1993) 38 10997903
2020 Targeted Inhibition of the E3 Ligase SCFSkp2/Cks1 Has Antitumor Activity in RB1-Deficient Human and Mouse Small-Cell Lung Cancer. Cancer research 34 32265224
2020 Circular RNA NOX4 promotes the development of colorectal cancer via the microRNA‑485‑5p/CKS1B axis. Oncology reports 34 32901890
2012 The CDK subunit CKS2 counteracts CKS1 to control cyclin A/CDK2 activity in maintaining replicative fidelity and neurodevelopment. Developmental cell 34 22898779
2009 Role of Cks1 amplification and overexpression in breast cancer. Biochemical and biophysical research communications 32 19161979
2009 Loss of cks1 homeostasis deregulates cell division cycle. Journal of cellular and molecular medicine 32 19228269
2006 Oncostatin M induces growth arrest by inhibition of Skp2, Cks1, and cyclin A expression and induced p21 expression. Cancer research 31 16818624
2019 MicroRNA-1258 Inhibits the Proliferation and Migration of Human Colorectal Cancer Cells through Suppressing CKS1B Expression. Genes 30 31717435
2016 A Synthetic Dosage Lethal Genetic Interaction Between CKS1B and PLK1 Is Conserved in Yeast and Human Cancer Cells. Genetics 30 27558135
2011 Cell-cycle regulator Cks1 promotes hepatocellular carcinoma by supporting NF-κB-dependent expression of interleukin-8. Cancer research 30 21917729
2016 Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 29 27638366
2019 Downregulation of CKS1B restrains the proliferation, migration, invasion and angiogenesis of retinoblastoma cells through the MEK/ERK signaling pathway. International journal of molecular medicine 28 31115482
2019 MicroRNA-940 inhibits glioma cells proliferation and cell cycle progression by targeting CKS1. American journal of translational research 28 31497204
2006 CD28 costimulation mediates transcription of SKP2 and CKS1, the substrate recognition components of SCFSkp2 ubiquitin ligase that leads p27kip1 to degradation. Cell cycle (Georgetown, Tex.) 28 16969077
2020 CKS1B as Drug Resistance-Inducing Gene-A Potential Target to Improve Cancer Therapy. Frontiers in oncology 27 33102238
2007 Expression of cyclin-dependent kinase subunit 1 (Cks1) is regulated during the cell cycle by a CDE/CHR tandem element and is downregulated by p53 but not by p63 or p73. Cell cycle (Georgetown, Tex.) 27 17377499
2006 Significant increase of CKS1B amplification from monoclonal gammopathy of undetermined significance to multiple myeloma and plasma cell leukaemia as demonstrated by interphase fluorescence in situ hybridisation. British journal of haematology 27 16889615
2004 Direct cell cycle regulation by the fibroblast growth factor receptor (FGFR) kinase through phosphorylation-dependent release of Cks1 from FGFR substrate 2. The Journal of biological chemistry 27 15513912
2001 Identification of novel cyclin-dependent kinases interacting with the CKS1 protein of Arabidopsis. Journal of experimental botany 27 11432958
2010 CKS1B nuclear expression is inversely correlated with p27Kip1 expression and is predictive of an adverse survival in patients with multiple myeloma. Haematologica 26 20421271
2005 RNA silencing of Cks1 induced G2/M arrest and apoptosis in human lung cancer cells. IUBMB life 26 16118116
2017 TORC1 coordinates the conversion of Sic1 from a target to an inhibitor of cyclin-CDK-Cks1. Cell discovery 25 28496991
2017 MicroRNA-936 induces cell cycle arrest and inhibits glioma cell proliferation by targeting CKS1. American journal of cancer research 25 29218238
2003 A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1. The Journal of biological chemistry 25 12813041
2000 Cks1 mediates vascular smooth muscle cell polyploidization. The Journal of biological chemistry 25 11005810
2017 EBV latent membrane protein 2A orchestrates p27kip1 degradation via Cks1 to accelerate MYC-driven lymphoma in mice. Blood 24 29074502
2016 p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer. Oncogene 24 27181203
2015 Developing structure-activity relationships from an HTS hit for inhibition of the Cks1-Skp2 protein-protein interaction. Bioorganic & medicinal chemistry letters 24 26463131
2013 Cks1: Structure, Emerging Roles and Implications in Multiple Cancers. Journal of cancer therapy 23 24563807
2006 Activation of ubiquitin ligase SCF(Skp2) by Cks1: insights from hydrogen exchange mass spectrometry. Journal of molecular biology 23 16979657
2002 Folding and association of the human cell cycle regulatory proteins ckshs1 and ckshs2. Biochemistry 23 11802719
2017 3-O-(Z)-coumaroyloleanolic acid overcomes Cks1b-induced chemoresistance in lung cancer by inhibiting Hsp90 and MEK pathways. Biochemical pharmacology 22 28288818
2012 Vorinostat enhances protein stability of p27 and p21 through negative regulation of Skp2 and Cks1 in human breast cancer cells. Oncology reports 22 22484732
2010 Cks1, Cdk1, and the 19S proteasome collaborate to regulate gene induction-dependent nucleosome eviction in yeast. Molecular and cellular biology 22 20855529
2022 CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia. Science translational medicine 21 35731890
2021 Reconstitution and use of highly active human CDK1:Cyclin-B:CKS1 complexes. Protein science : a publication of the Protein Society 21 34791727
2010 The degradation of cell cycle regulators by SKP2/CKS1 ubiquitin ligase is genetically controlled in rodent liver cancer and contributes to determine the susceptibility to the disease. International journal of cancer 21 19533683
2007 Substrate recognition and ubiquitination of SCFSkp2/Cks1 ubiquitin-protein isopeptide ligase. The Journal of biological chemistry 21 17409098
2015 Depletion of Cks1 and Cks2 expression compromises cell proliferation and enhance chemotherapy-induced apoptosis in HepG2 cells. Oncology reports 20 26531156
2005 Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins. Oncogene 19 15735731
2023 Cyclin A and Cks1 promote kinase consensus switching to non-proline-directed CDK1 phosphorylation. Cell reports 18 36840943
2003 Cks1 is degraded via the ubiquitin-proteasome pathway in a cell cycle-dependent manner. Genes to cells : devoted to molecular & cellular mechanisms 18 14622140
2011 Up-regulation of Cks1 and Skp2 with TNFα/NF-κB signaling in chronic progressive nephropathy. Genes to cells : devoted to molecular & cellular mechanisms 17 22017545
1995 Transforming growth factor beta down-regulation of CKShs1 transcripts in growth-inhibited epithelial cells. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 17 8845303
2012 Overexpression of Cks1 increases the radiotherapy resistance of esophageal squamous cell carcinoma. Journal of radiation research 16 22302047
2011 CDC28 protein kinase regulatory subunit 1B (CKS1B) expression and genetic status analysis in oral squamous cell carcinoma. Histology and histopathology 16 21117028
1996 Chromosomal mapping of the human genes CKS1 to 8q21 and CKS2 to 9q22. Cytogenetics and cell genetics 16 8697818
2014 Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors. Oncogene 15 25417705
2013 Akt and Cks1 are related with lymph node metastasis in gastric adenocarcinoma. Hepato-gastroenterology 15 23321124
2004 Molecular and biochemical characterization of the Skp2-Cks1 binding interface. The Journal of biological chemistry 15 15452136
2020 CKS1B promotes cell proliferation and invasion by activating STAT3/PD-L1 and phosphorylation of Akt signaling in papillary thyroid carcinoma. Journal of clinical laboratory analysis 14 32960462
2012 Cks1 is required for tumor cell proliferation but not sufficient to induce hematopoietic malignancies. PloS one 14 22624029
2006 Folding and fibril formation of the cell cycle protein Cks1. The Journal of biological chemistry 14 16675442
2020 The survival impact of CKS1B gains or amplification is dependent on the background karyotype and TP53 deletion status in patients with myeloma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 13 32908255
2017 The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability. Biochimica et biophysica acta. Molecular cell research 13 28939057
2016 TGF-β activates APC through Cdh1 binding for Cks1 and Skp2 proteasomal destruction stabilizing p27kip1 for normal endometrial growth. Cell cycle (Georgetown, Tex.) 13 26963853
2023 Cryo-EM structure of SKP1-SKP2-CKS1 in complex with CDK2-cyclin A-p27KIP1. Scientific reports 12 37400515
2023 Involvement of CKS1B in the anti-inflammatory effects of cannabidiol in experimental stroke models. Experimental neurology 12 38104887
2022 Regulation of microRNA miR-197-3p/CDC28 protein kinase regulatory subunit 1B (CKS1B) axis by Circular RNA hsa_circ_0000285 promotes glioma progression. Bioengineered 12 35174774
2019 PADI3 plays an antitumor role via the Hsp90/CKS1 pathway in colon cancer. Cancer cell international 12 31708688
2017 CKS1BP7, a Pseudogene of CKS1B, is Co-Amplified with IGF1R in Breast Cancers. Pathology oncology research : POR 12 28439706
2017 The cyclin dependent kinase subunit Cks1 is required for infection-associated development of the rice blast fungus Magnaporthe oryzae. Environmental microbiology 12 28504460
2009 High Cks1 expression in transgenic and carcinogen-initiated mammary tumors is not always accompanied by reduction in p27Kip1. International journal of oncology 12 19360356
2005 High-throughput screening for inhibitors of the Cks1-Skp2 interaction. Methods in enzymology 12 16338391
2021 CKS1B promotes the progression of hepatocellular carcinoma by activating JAK/STAT3 signal pathway. Animal cells and systems 11 34408811
2014 Cks1 proteasomal degradation is induced by inhibiting Hsp90-mediated chaperoning in cancer cells. Cancer chemotherapy and pharmacology 11 25544127
2012 Cks1 promotion of S phase entry and proliferation is independent of p27Kip1 suppression. Molecular and cellular biology 11 22508990
2010 CKS1B amplification is a frequent event in cutaneous squamous cell carcinoma with aggressive clinical behaviour. Genes, chromosomes & cancer 11 20737481
2018 Cks1 regulates human hepatocellular carcinoma cell progression through osteopontin expression. Biochemical and biophysical research communications 10 30497779