{"gene":"CKS1B","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1995,"finding":"Crystal structure of human CksHs1 determined at 2.9 Å resolution, revealing a single polypeptide domain fold with a four-stranded beta-sheet flanked by two alpha-helices, and identifying a phosphate-binding pocket with conserved residues Lys11, Arg20, Ser51, Trp54, and Arg71 as a potential recognition site for phosphorylated CDK residues. A novel beta-hinge region (Glu61–His65) was identified that controls monomer versus domain-swapped dimer conformation.","method":"X-ray crystallography at 2.9 Å resolution","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional residue identification, foundational structural paper","pmids":["7791211"],"is_preprint":false},{"year":1996,"finding":"Crystal structure of human CDK2 in complex with CksHs1 at 2.6 Å resolution revealed that CksHs1 binds via all four beta-strands to the CDK2 C-terminal lobe, far from the N-terminal lobe, cyclin, and regulatory phosphorylation sites. Mutational analysis confirmed this interface is biologically critical. The beta-hinge opening to form the domain-swapped dimer sterically precludes CDK2 binding. The complex exposes the phosphate-binding region of Cks and the ATP-binding site of CDK2 on one face, suggesting CKS1B targets CDK2 to phosphoproteins.","method":"X-ray crystallography at 2.6 Å + site-directed mutagenesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutational analysis, replicated structural work from same group","pmids":["8601310"],"is_preprint":false},{"year":1995,"finding":"TGF-beta treatment strongly downregulates CKShs1 transcripts in mink lung cells and keratinocytes within 10 hours (prior to growth arrest), and this downregulation is abolished in cells expressing a dominant-negative TGF-beta type 2 receptor. This places CKShs1 downstream of TGF-beta receptor signaling and suggests a role in TGF-beta-mediated G1/G2 cell cycle arrest.","method":"Northern blot analysis; genetic test using stably transfected dominant-negative TGF-beta receptor cell line","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (Northern blot + genetic dominant-negative receptor model) in single lab","pmids":["8845303"],"is_preprint":false},{"year":2001,"finding":"The carboxyl-terminal region of p45(SKP2) directly associates with CksHs1, and this interaction negatively regulates the binding of CksHs1 to CDK2. Overexpression of CksHs1 inhibits CDK2 kinase activity, and additional expression of p45(SKP2) overcomes this inhibition and restores CDK2 kinase activity. The proposed mechanism is that SKP2 sequesters CksHs1, preventing it from binding and inhibiting CDK2.","method":"Co-immunoprecipitation, CDK2 kinase activity assay, overexpression experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus functional kinase activity readout, single lab","pmids":["11349131"],"is_preprint":false},{"year":2002,"finding":"CksHs1 has marginal thermodynamic stability (ΔG ~3.0 kcal/mol at 25°C) and low kinetic stability (unfolding rate ~1 s⁻¹ in water). Refolding from denatured states to monomeric form is slowed by transient oligomerization via domain swapping. Interconversion between monomer and domain-swapped dimer requires unfolding and is faster in CksHs1 than in yeast suc1, reflecting faster unfolding rates.","method":"Biochemical folding/unfolding kinetics assays, equilibrium denaturation","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution and biophysical characterization, single lab","pmids":["11802719"],"is_preprint":false},{"year":2005,"finding":"RNA interference knockdown of CKS1B mRNA in myeloma cell lines led to reduced CKS1B protein, accumulation of p27Kip1, and profound growth inhibition, establishing that CKS1B regulates SCF(Skp2)-mediated ubiquitination and proteolysis of p27Kip1 in myeloma cells.","method":"RNAi knockdown; Western blot for p27Kip1; cell proliferation assay","journal":"Hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with defined molecular readout, single lab","pmids":["16188652"],"is_preprint":false},{"year":2007,"finding":"Lentiviral shRNA knockdown of CKS1B in multiple myeloma cell lines caused stabilization of p27Kip1, cell cycle arrest, and apoptosis. Notably, CKS1B ablation induced strong apoptosis even in a cell line with biallelic deletion of p27Kip1 (CDKN1B), demonstrating that CKS1B regulates myeloma cell survival through both SKP2/p27Kip1-dependent and independent mechanisms.","method":"Lentiviral shRNA knockdown; cell cycle analysis; apoptosis assay; forced expression of non-degradable p27T187A; SKP2 knockdown","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic manipulations (CKS1B KD, SKP2 KD, p27T187A overexpression, p27-null cell line) establishing pathway-dependent and independent roles","pmids":["17303695"],"is_preprint":false},{"year":2010,"finding":"Forced expression of CKS1B in multiple myeloma cells activated STAT3 and MEK/ERK signaling pathways and increased multidrug resistance. Stimulation of these pathways partially rescued cells from CKS1B-knockdown-induced death, and BCL2 was identified as a downstream target of MEK/ERK signaling in this context.","method":"Forced overexpression; shRNA knockdown; pathway inhibitors; Western blot; cell viability assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiments with pathway inhibitors plus overexpression/knockdown, single lab","pmids":["20930946"],"is_preprint":false},{"year":2015,"finding":"CKS1B mechanistically connects to a miR-197/CKS1B/STAT3 axis regulating PD-L1 expression and chemoresistance in NSCLC. miR-197 targets CKS1B, and loss of miR-197 leads to CKS1B upregulation driving STAT3-mediated expression of oncogenic genes (Bcl-2, c-Myc, cyclin D1) and PD-L1. miR-197 mimic sensitized PD-L1-high drug-resistant cells to chemotherapy.","method":"In vitro and in vivo functional assays; miR-197 mimic transfection; mechanistic pathway analysis","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional rescue with miRNA mimic, single lab, multiple readouts","pmids":["25597412"],"is_preprint":false},{"year":2015,"finding":"CKS1B-overexpressing myeloma cells are resistant to the proteasome inhibitor bortezomib but sensitive to the NEDD8 inhibitor MLN4924. MLN4924 induced stabilization of p21 (not p27), and shRNA knockdown of p21 abolished MLN4924 sensitivity, establishing that MLN4924 overcomes CKS1B-induced drug resistance via p21 stabilization rather than p27.","method":"shRNA knockdown of p21; proliferation, viability, clonogenic, and senescence assays; immunoblot analysis","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA rescue experiment establishes p21-dependent mechanism, single lab with multiple orthogonal cellular readouts","pmids":["26156395"],"is_preprint":false},{"year":2016,"finding":"Genetic epistasis in yeast showed that CKS1 overexpression synthetic dosage lethality (SDL) with mitotic entry checkpoint genes requires Swe1 inhibitory activity on CDK Cdc28, and SDL with mitotic exit network genes is suppressed by modulating CDK inhibitor Sic1. Mutation of polo-like kinase Cdc5 (human PLK1 ortholog) is lethal with overexpressed CKS1. In human cancer cells, CKS1B overexpression increased sensitivity to PLK1 knockdown and pharmacological PLK1 inhibition, conserving the yeast SDL interaction.","method":"High-throughput yeast SDL screen; epistasis with Swe1 and Sic1 mutants; shRNA knockdown of PLK1 in human tumor cell lines; PLK1 inhibitor treatment of CKS1B-overexpressing cells; WEE1+PLK1 double inhibition epistasis","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in yeast validated by multiple orthogonal approaches including shRNA and pharmacological inhibition in human cancer cells across multiple cell lines","pmids":["27558135"],"is_preprint":false},{"year":2017,"finding":"Ectopic CKS1B overexpression in lung cancer cells induced chemoresistance to cisplatin and doxorubicin through Hsp90 and MEK1/2 pathways, independent of the canonical Skp2-p27 pathway. Inhibition of either Hsp90 or MEK1/2 alone resensitized CKS1B-overexpressing cells to chemotherapy, and 3-COA was identified as a novel Hsp90 inhibitor that mimics this resensitization.","method":"shRNA knockdown; selective pathway inhibitors (Hsp90, MEK1/2); in vitro and in vivo tumor models; overexpression of CKS1B","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA plus pharmacological inhibitors establishing Hsp90/MEK1/2 as non-canonical pathway components, single lab, in vitro and in vivo","pmids":["28288818"],"is_preprint":false},{"year":2024,"finding":"GLI2 directly binds the CKS1B promoter to regulate CKS1B transcription in cardiomyocytes (CMs). CKS1B overexpression in late-stage hiPSC-CMs promoted proliferation with loss of maturation, identifying CKS1B as a downstream effector of the HH-GLI2 signaling cascade that controls the proliferation-to-maturation transition in CMs.","method":"GLI2 promoter binding assay (ChIP-type); hiPSC-CM overexpression of CKS1B; maturation indices; calcium handling measurements; transcriptomic analysis","journal":"Stem cells translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding plus functional overexpression in defined cell model, single lab","pmids":["38761090"],"is_preprint":false},{"year":2021,"finding":"CKS1B knockdown in hepatocellular carcinoma (HCC) cell lines inhibited proliferation, induced apoptosis, suppressed migration and invasion, and decreased p-STAT3 levels and STAT3 target genes (TIMP-1, Bcl-2, VEGF). Overexpression of CKS1B had opposite effects, establishing CKS1B promotion of HCC progression via JAK/STAT3 pathway activation.","method":"shRNA knockdown; overexpression plasmid; MTT, colony formation, flow cytometry, wound healing, transwell assays; Western blot for p-STAT3 and targets","journal":"Animal cells and systems","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with multiple orthogonal cellular readouts, single lab","pmids":["34408811"],"is_preprint":false},{"year":2025,"finding":"CKS1B forms a complex with S-phase kinase-associated protein (SKP1/SKP2) to promote ubiquitination and degradation of IRF3 (interferon regulatory factor 3), thereby suppressing type I interferon signaling and antigen presentation in tumor cells. This drives persistent CD8+ T cell stimulation and exhaustion. Pharmacological blockade of the CKS1B-IRF3 interaction with compound 14i restored CD8+ T cell function and synergized with immune checkpoint blockade.","method":"Single-cell and spatial proteomics; co-immunoprecipitation (CKS1B-SKP complex with IRF3); ubiquitination assay; pharmacological blockade with 14i; in vivo tumor models; immune checkpoint blockade combination","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex identification by Co-IP with functional ubiquitination readout and pharmacological validation, single study, multiple methods","pmids":["42090485"],"is_preprint":false},{"year":2025,"finding":"FOXM1 transcriptionally regulates CKS1B expression in pancreatic ductal adenocarcinoma (PDAC), establishing a novel FOXM1-CKS1B signaling axis. CKS1B knockdown sensitized PDAC cells to gemcitabine and oxaliplatin and reduced cancer stemness properties.","method":"Molecular biology methods (chromatin binding/promoter assays implied); in vitro and in vivo PDAC models; CKS1B knockdown with chemosensitivity assays; stemness assays","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional regulation claim supported by molecular biology methods not fully detailed in abstract, single lab","pmids":["39897042"],"is_preprint":false},{"year":2020,"finding":"CKS1B knockdown in papillary thyroid carcinoma (PTC) cells inhibited cell viability and invasion, suppressed STAT3/PD-L1 signaling, and reduced Akt phosphorylation. STAT3 or PD-L1 inhibition reversed the pro-tumorigenic effects of CKS1B overexpression.","method":"siRNA knockdown; overexpression plasmid; MTT and transwell assays; Western blot for p-STAT3, p-Akt, PD-L1; pharmacological inhibitors (WP1066, Pembrolizumab)","journal":"Journal of clinical laboratory analysis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic depth, pharmacological rescue but no direct binding or reconstitution","pmids":["32960462"],"is_preprint":false},{"year":2025,"finding":"CKS1B knockdown in NSCLC cells inhibited proliferation, migration, and invasion; reduced MEK and ERK phosphorylation (MAPK/ERK signaling); and upregulated E-cadherin while downregulating N-cadherin, suppressing EMT.","method":"siRNA knockdown; Western blot for p-MEK, p-ERK, E-cadherin, N-cadherin; proliferation and invasion assays","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, no direct mechanistic connection established","pmids":["41171587"],"is_preprint":false},{"year":2025,"finding":"CKS1B knockdown in NSCLC cells and xenografts enhanced radiosensitivity by stimulating apoptosis, inhibiting cell cycle progression, and impairing DNA damage repair. CKS1B-induced radioresistance was mediated through the PI3K/AKT signaling pathway.","method":"shRNA knockdown; xenograft model with ionizing radiation; apoptosis, cell cycle, DNA damage repair assays; Western blot for PI3K/AKT pathway components","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement inferred from knockdown without direct binding or reconstitution of PI3K/AKT connection","pmids":["40262716"],"is_preprint":false}],"current_model":"CKS1B (CksHs1) is a small, conserved CDK regulatory subunit that binds via its beta-strand face to the C-terminal lobe of CDK2, positions the complex toward phosphoprotein substrates, and—in complex with SKP1/SKP2—promotes ubiquitin-mediated degradation of CDK inhibitors p27Kip1 and, as recently shown, IRF3; beyond this canonical SCF(SKP2) adaptor role, CKS1B activates STAT3 and MEK/ERK/BCL2 signaling to drive cell proliferation, drug resistance, and immune evasion, is transcriptionally regulated by GLI2 and FOXM1, and its overexpression creates a synthetic dosage-lethal dependency on PLK1 activity."},"narrative":{"mechanistic_narrative":"CKS1B is a small CDK regulatory subunit that couples cyclin-dependent kinase complexes to phosphoprotein substrates and to SCF-mediated proteolysis, functioning as a hub for cell-cycle control and proliferative signaling [PMID:8601310, PMID:17303695]. Structurally it is a single compact domain with a four-stranded beta-sheet flanked by two helices, presenting an anion/phosphate-binding pocket (Lys11, Arg20, Ser51, Trp54, Arg71) and a beta-hinge region whose opening generates a domain-swapped dimer; in the monomeric state it docks via all four beta-strands onto the CDK2 C-terminal lobe—away from the cyclin and regulatory phosphorylation sites—simultaneously exposing the CDK2 ATP site and its own phosphate pocket, positioning the kinase toward phosphorylated substrates [PMID:7791211, PMID:8601310]. CKS1B is a required cofactor for SCF(SKP2)-driven ubiquitination and degradation of the CDK inhibitor p27Kip1: its depletion stabilizes p27Kip1 and arrests proliferation, while its interaction with SKP2 also reciprocally modulates CKS1B availability to CDK2 [PMID:11349131, PMID:16188652]. Beyond the canonical SKP2/p27 axis, CKS1B sustains tumor-cell survival, proliferation, and drug resistance through STAT3 and MEK/ERK signaling with BCL2 as a downstream effector, and SCF-coupled degradation of IRF3 suppresses type I interferon signaling and antigen presentation, promoting CD8+ T-cell exhaustion [PMID:17303695, PMID:20930946, PMID:42090485]. CKS1B expression is controlled transcriptionally by GLI2 within HH signaling and by FOXM1, and its overexpression establishes a synthetic-dosage-lethal dependence on PLK1 conserved from yeast to human cancer cells [PMID:27558135, PMID:38761090].","teleology":[{"year":1995,"claim":"Established the atomic architecture of human CKS1B, defining a phosphate-binding pocket and a conformational beta-hinge switch that would underlie its substrate-targeting and oligomerization behavior.","evidence":"X-ray crystallography of CksHs1 at 2.9 Å with conserved-residue identification","pmids":["7791211"],"confidence":"High","gaps":["Did not show binding to any physiological phosphoprotein","Functional role of the phosphate pocket inferred, not demonstrated"]},{"year":1996,"claim":"Resolved how CKS1B engages CDK2, showing a beta-strand interface on the CDK2 C-terminal lobe that leaves the kinase active site free, supporting a model in which CKS1B targets CDK2 to phosphoproteins.","evidence":"X-ray crystallography of the CDK2–CksHs1 complex at 2.6 Å with site-directed mutagenesis of the interface","pmids":["8601310"],"confidence":"High","gaps":["Specific phosphoprotein substrates engaged via the exposed pocket not identified","No cyclin present in the structure"]},{"year":1995,"claim":"Placed CKS1B downstream of TGF-beta receptor signaling, linking its transcriptional regulation to growth arrest.","evidence":"Northern blot after TGF-beta treatment plus a dominant-negative TGF-beta type 2 receptor cell line","pmids":["8845303"],"confidence":"Medium","gaps":["Mechanism connecting CKS1B downregulation to arrest not defined","No direct transcriptional regulator identified"]},{"year":2001,"claim":"Showed that SKP2 directly binds CKS1B and competes with its CDK2 interaction, revealing a regulatory partition of CKS1B between CDK2 inhibition and SCF engagement.","evidence":"Co-immunoprecipitation, CDK2 kinase assays, and overexpression in cells","pmids":["11349131"],"confidence":"Medium","gaps":["Single-lab biochemistry without structural mapping of the SKP2-CKS1B interface","Physiological balance between the two states not quantified"]},{"year":2002,"claim":"Characterized the marginal thermodynamic and kinetic stability of CKS1B and linked refolding to transient domain-swapped oligomerization.","evidence":"Equilibrium denaturation and folding/unfolding kinetics in vitro","pmids":["11802719"],"confidence":"Medium","gaps":["Biological relevance of the dimer in cells unresolved","No connection to in-cell CDK2 or SKP2 binding"]},{"year":2007,"claim":"Demonstrated that CKS1B drives myeloma survival through both SKP2/p27Kip1-dependent and -independent routes, expanding its role beyond the canonical degradation pathway.","evidence":"Lentiviral shRNA, SKP2 knockdown, non-degradable p27T187A expression, and a p27-null cell line with apoptosis/cell-cycle readouts","pmids":["17303695","16188652"],"confidence":"High","gaps":["Identity of the p27-independent survival mechanism not defined here","Restricted to myeloma models"]},{"year":2010,"claim":"Connected CKS1B to STAT3 and MEK/ERK/BCL2 signaling as a driver of proliferation and multidrug resistance, providing a candidate non-canonical effector arm.","evidence":"Overexpression, shRNA, pathway inhibitors, and viability rescue in myeloma cells","pmids":["20930946"],"confidence":"Medium","gaps":["Direct molecular link between CKS1B and pathway activation not established","Single lineage context"]},{"year":2016,"claim":"Identified a conserved synthetic-dosage-lethal dependency: CKS1B overexpression sensitizes cells to loss of PLK1 activity, defining a targetable vulnerability.","evidence":"Yeast SDL screen with Swe1/Sic1 epistasis plus PLK1 shRNA and pharmacological inhibition in human cancer cell lines","pmids":["27558135"],"confidence":"High","gaps":["Molecular basis of the CKS1B-PLK1 lethal interaction not resolved","Yeast-to-human mechanistic conservation inferred from phenotype"]},{"year":2024,"claim":"Placed CKS1B transcriptionally downstream of HH-GLI2 signaling controlling a proliferation-to-maturation switch, extending its role beyond cancer.","evidence":"GLI2 promoter-binding assay and CKS1B overexpression in hiPSC-cardiomyocytes with maturation and calcium readouts","pmids":["38761090"],"confidence":"Medium","gaps":["Downstream effectors in cardiomyocytes not mapped","Single developmental model"]},{"year":2025,"claim":"Revealed an immune-evasion function in which the CKS1B-SKP1/SKP2 complex ubiquitinates and degrades IRF3 to suppress type I interferon signaling and drive CD8+ T-cell exhaustion, with pharmacological disruption restoring immunity.","evidence":"Spatial/single-cell proteomics, Co-IP of the CKS1B-SKP complex with IRF3, ubiquitination assay, compound 14i blockade, and checkpoint-blockade combination in vivo","pmids":["42090485"],"confidence":"Medium","gaps":["Whether IRF3 is a direct SCF(SKP2) substrate via CKS1B docking not structurally shown","Single study"]},{"year":null,"claim":"How CKS1B partitions between its CDK2-targeting, SCF-adaptor, and signaling functions to selectively destabilize specific substrates (p27Kip1, IRF3) in different tissue contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CKS1B within an SCF(SKP2)-substrate complex","Determinants of substrate selectivity unknown","Direct versus indirect basis of STAT3/MEK-ERK/PI3K-AKT engagement not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,6,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,6,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14]}],"complexes":["SCF(SKP2)"],"partners":["CDK2","SKP2","SKP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61024","full_name":"Cyclin-dependent kinases regulatory subunit 1","aliases":[],"length_aa":79,"mass_kda":9.7,"function":"Binds to the catalytic subunit of the cyclin dependent kinases and is essential for their biological function","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P61024/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CKS1B","classification":"Common Essential","n_dependent_lines":903,"n_total_lines":1090,"dependency_fraction":0.828440366972477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CKS1B","total_profiled":1310},"omim":[{"mim_id":"611007","title":"MEX3 RNA-BINDING FAMILY MEMBER A; MEX3A","url":"https://www.omim.org/entry/611007"},{"mim_id":"116900","title":"CDC28 PROTEIN KINASE 1B; CKS1B","url":"https://www.omim.org/entry/116900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CKS1B"},"hgnc":{"alias_symbol":["ckshs1","CKS1"],"prev_symbol":[]},"alphafold":{"accession":"P61024","domains":[{"cath_id":"3.30.170.10","chopping":"6-71","consensus_level":"high","plddt":96.0882,"start":6,"end":71}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61024","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61024-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61024-F1-predicted_aligned_error_v6.png","plddt_mean":92.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CKS1B","jax_strain_url":"https://www.jax.org/strain/search?query=CKS1B"},"sequence":{"accession":"P61024","fasta_url":"https://rest.uniprot.org/uniprotkb/P61024.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61024/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61024"}},"corpus_meta":[{"pmid":"25597412","id":"PMC_25597412","title":"The clinical relevance of the 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1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma.","date":"2005","source":"Hematology (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/16188652","citation_count":125,"is_preprint":false},{"pmid":"20930946","id":"PMC_20930946","title":"Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance.","date":"2010","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/20930946","citation_count":101,"is_preprint":false},{"pmid":"7791211","id":"PMC_7791211","title":"Crystal structure of the human cell cycle protein CksHs1: single domain fold with similarity to kinase N-lobe domain.","date":"1995","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7791211","citation_count":67,"is_preprint":false},{"pmid":"29283424","id":"PMC_29283424","title":"Integrated MicroRNA-mRNA Analysis Reveals miR-204 Inhibits Cell Proliferation in 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cannabidiol in experimental stroke models.","date":"2023","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38104887","citation_count":13,"is_preprint":false},{"pmid":"32908255","id":"PMC_32908255","title":"The survival impact of CKS1B gains or amplification is dependent on the background karyotype and TP53 deletion status in patients with myeloma.","date":"2020","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/32908255","citation_count":13,"is_preprint":false},{"pmid":"35174774","id":"PMC_35174774","title":"Regulation of microRNA miR-197-3p/CDC28 protein kinase regulatory subunit 1B (CKS1B) axis by Circular RNA hsa_circ_0000285 promotes glioma progression.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35174774","citation_count":12,"is_preprint":false},{"pmid":"28439706","id":"PMC_28439706","title":"CKS1BP7, a Pseudogene of CKS1B, is Co-Amplified with IGF1R in Breast Cancers.","date":"2017","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/28439706","citation_count":12,"is_preprint":false},{"pmid":"34408811","id":"PMC_34408811","title":"CKS1B promotes the progression of hepatocellular carcinoma by activating JAK/STAT3 signal pathway.","date":"2021","source":"Animal cells and systems","url":"https://pubmed.ncbi.nlm.nih.gov/34408811","citation_count":11,"is_preprint":false},{"pmid":"20737481","id":"PMC_20737481","title":"CKS1B amplification is a frequent event in cutaneous squamous cell carcinoma with aggressive clinical behaviour.","date":"2010","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20737481","citation_count":11,"is_preprint":false},{"pmid":"11349131","id":"PMC_11349131","title":"Association of the cell cycle regulatory proteins p45(SKP2) and CksHs1. Functional effect on CDK2 complex formation and kinase activity.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11349131","citation_count":10,"is_preprint":false},{"pmid":"20688354","id":"PMC_20688354","title":"Differential expression of CKS-1B in typical and blastoid variants of mantle cell lymphoma.","date":"2010","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20688354","citation_count":10,"is_preprint":false},{"pmid":"24973170","id":"PMC_24973170","title":"Quantitative analysis of CKS1B mRNA expression and copy number gain in patients with plasma cell disorders.","date":"2014","source":"Blood cells, molecules & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24973170","citation_count":9,"is_preprint":false},{"pmid":"34504588","id":"PMC_34504588","title":"Knockdown of LINC00657 inhibits the viability, migration and invasion of pancreatic cancer cells by regulating the miR-520h/CKS1B axis.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34504588","citation_count":9,"is_preprint":false},{"pmid":"7716171","id":"PMC_7716171","title":"Crystallization and preliminary crystallographic study of human CksHs1: a cell cycle regulatory protein.","date":"1995","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/7716171","citation_count":8,"is_preprint":false},{"pmid":"38761090","id":"PMC_38761090","title":"The HH-GLI2-CKS1B network regulates the proliferation-to-maturation transition of cardiomyocytes.","date":"2024","source":"Stem cells translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38761090","citation_count":6,"is_preprint":false},{"pmid":"39897042","id":"PMC_39897042","title":"FOXM1-Driven CKS1B Upregulation Promotes Pancreatic Cancer Progression and Therapeutic Resistance.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39897042","citation_count":3,"is_preprint":false},{"pmid":"40262716","id":"PMC_40262716","title":"CKS1B regulates the radiosensitivity of lung cancer via activating the PI3K/AKT signaling pathway.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40262716","citation_count":2,"is_preprint":false},{"pmid":"38757359","id":"PMC_38757359","title":"[Retracted] Downregulation of CKS1B restrains the proliferation, migration, invasion and angiogenesis of retinoblastoma cells through the MEK/ERK signaling pathway.","date":"2024","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38757359","citation_count":2,"is_preprint":false},{"pmid":"36819558","id":"PMC_36819558","title":"A novel human multiple myeloma cell line with a 1q21 gain genetic abnormality and CKS1B overexpression.","date":"2023","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36819558","citation_count":1,"is_preprint":false},{"pmid":"41171587","id":"PMC_41171587","title":"Multidimensional analysis of hsa-miR-140-3p and CKS1B correlation via the MAPK/ERK pathway in lung adenocarcinoma progression.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41171587","citation_count":0,"is_preprint":false},{"pmid":"39054968","id":"PMC_39054968","title":"[Retracted] Circular RNA NOX4 promotes the development of colorectal cancer via the microRNA‑485‑5p/CKS1B axis.","date":"2024","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/39054968","citation_count":0,"is_preprint":false},{"pmid":"42090485","id":"PMC_42090485","title":"CKS1B is a tumor-intrinsic factor driving CD8+ T cell exhaustion via maintaining persistent tumor-antigen stimulation.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/42090485","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22638,"output_tokens":4991,"usd":0.071389,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13244,"output_tokens":3442,"usd":0.076135,"stage2_stop_reason":"end_turn"},"total_usd":0.147524,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Crystal structure of human CksHs1 determined at 2.9 Å resolution, revealing a single polypeptide domain fold with a four-stranded beta-sheet flanked by two alpha-helices, and identifying a phosphate-binding pocket with conserved residues Lys11, Arg20, Ser51, Trp54, and Arg71 as a potential recognition site for phosphorylated CDK residues. A novel beta-hinge region (Glu61–His65) was identified that controls monomer versus domain-swapped dimer conformation.\",\n      \"method\": \"X-ray crystallography at 2.9 Å resolution\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional residue identification, foundational structural paper\",\n      \"pmids\": [\"7791211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Crystal structure of human CDK2 in complex with CksHs1 at 2.6 Å resolution revealed that CksHs1 binds via all four beta-strands to the CDK2 C-terminal lobe, far from the N-terminal lobe, cyclin, and regulatory phosphorylation sites. Mutational analysis confirmed this interface is biologically critical. The beta-hinge opening to form the domain-swapped dimer sterically precludes CDK2 binding. The complex exposes the phosphate-binding region of Cks and the ATP-binding site of CDK2 on one face, suggesting CKS1B targets CDK2 to phosphoproteins.\",\n      \"method\": \"X-ray crystallography at 2.6 Å + site-directed mutagenesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutational analysis, replicated structural work from same group\",\n      \"pmids\": [\"8601310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TGF-beta treatment strongly downregulates CKShs1 transcripts in mink lung cells and keratinocytes within 10 hours (prior to growth arrest), and this downregulation is abolished in cells expressing a dominant-negative TGF-beta type 2 receptor. This places CKShs1 downstream of TGF-beta receptor signaling and suggests a role in TGF-beta-mediated G1/G2 cell cycle arrest.\",\n      \"method\": \"Northern blot analysis; genetic test using stably transfected dominant-negative TGF-beta receptor cell line\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (Northern blot + genetic dominant-negative receptor model) in single lab\",\n      \"pmids\": [\"8845303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The carboxyl-terminal region of p45(SKP2) directly associates with CksHs1, and this interaction negatively regulates the binding of CksHs1 to CDK2. Overexpression of CksHs1 inhibits CDK2 kinase activity, and additional expression of p45(SKP2) overcomes this inhibition and restores CDK2 kinase activity. The proposed mechanism is that SKP2 sequesters CksHs1, preventing it from binding and inhibiting CDK2.\",\n      \"method\": \"Co-immunoprecipitation, CDK2 kinase activity assay, overexpression experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus functional kinase activity readout, single lab\",\n      \"pmids\": [\"11349131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CksHs1 has marginal thermodynamic stability (ΔG ~3.0 kcal/mol at 25°C) and low kinetic stability (unfolding rate ~1 s⁻¹ in water). Refolding from denatured states to monomeric form is slowed by transient oligomerization via domain swapping. Interconversion between monomer and domain-swapped dimer requires unfolding and is faster in CksHs1 than in yeast suc1, reflecting faster unfolding rates.\",\n      \"method\": \"Biochemical folding/unfolding kinetics assays, equilibrium denaturation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution and biophysical characterization, single lab\",\n      \"pmids\": [\"11802719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RNA interference knockdown of CKS1B mRNA in myeloma cell lines led to reduced CKS1B protein, accumulation of p27Kip1, and profound growth inhibition, establishing that CKS1B regulates SCF(Skp2)-mediated ubiquitination and proteolysis of p27Kip1 in myeloma cells.\",\n      \"method\": \"RNAi knockdown; Western blot for p27Kip1; cell proliferation assay\",\n      \"journal\": \"Hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with defined molecular readout, single lab\",\n      \"pmids\": [\"16188652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Lentiviral shRNA knockdown of CKS1B in multiple myeloma cell lines caused stabilization of p27Kip1, cell cycle arrest, and apoptosis. Notably, CKS1B ablation induced strong apoptosis even in a cell line with biallelic deletion of p27Kip1 (CDKN1B), demonstrating that CKS1B regulates myeloma cell survival through both SKP2/p27Kip1-dependent and independent mechanisms.\",\n      \"method\": \"Lentiviral shRNA knockdown; cell cycle analysis; apoptosis assay; forced expression of non-degradable p27T187A; SKP2 knockdown\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic manipulations (CKS1B KD, SKP2 KD, p27T187A overexpression, p27-null cell line) establishing pathway-dependent and independent roles\",\n      \"pmids\": [\"17303695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Forced expression of CKS1B in multiple myeloma cells activated STAT3 and MEK/ERK signaling pathways and increased multidrug resistance. Stimulation of these pathways partially rescued cells from CKS1B-knockdown-induced death, and BCL2 was identified as a downstream target of MEK/ERK signaling in this context.\",\n      \"method\": \"Forced overexpression; shRNA knockdown; pathway inhibitors; Western blot; cell viability assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiments with pathway inhibitors plus overexpression/knockdown, single lab\",\n      \"pmids\": [\"20930946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CKS1B mechanistically connects to a miR-197/CKS1B/STAT3 axis regulating PD-L1 expression and chemoresistance in NSCLC. miR-197 targets CKS1B, and loss of miR-197 leads to CKS1B upregulation driving STAT3-mediated expression of oncogenic genes (Bcl-2, c-Myc, cyclin D1) and PD-L1. miR-197 mimic sensitized PD-L1-high drug-resistant cells to chemotherapy.\",\n      \"method\": \"In vitro and in vivo functional assays; miR-197 mimic transfection; mechanistic pathway analysis\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional rescue with miRNA mimic, single lab, multiple readouts\",\n      \"pmids\": [\"25597412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CKS1B-overexpressing myeloma cells are resistant to the proteasome inhibitor bortezomib but sensitive to the NEDD8 inhibitor MLN4924. MLN4924 induced stabilization of p21 (not p27), and shRNA knockdown of p21 abolished MLN4924 sensitivity, establishing that MLN4924 overcomes CKS1B-induced drug resistance via p21 stabilization rather than p27.\",\n      \"method\": \"shRNA knockdown of p21; proliferation, viability, clonogenic, and senescence assays; immunoblot analysis\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA rescue experiment establishes p21-dependent mechanism, single lab with multiple orthogonal cellular readouts\",\n      \"pmids\": [\"26156395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic epistasis in yeast showed that CKS1 overexpression synthetic dosage lethality (SDL) with mitotic entry checkpoint genes requires Swe1 inhibitory activity on CDK Cdc28, and SDL with mitotic exit network genes is suppressed by modulating CDK inhibitor Sic1. Mutation of polo-like kinase Cdc5 (human PLK1 ortholog) is lethal with overexpressed CKS1. In human cancer cells, CKS1B overexpression increased sensitivity to PLK1 knockdown and pharmacological PLK1 inhibition, conserving the yeast SDL interaction.\",\n      \"method\": \"High-throughput yeast SDL screen; epistasis with Swe1 and Sic1 mutants; shRNA knockdown of PLK1 in human tumor cell lines; PLK1 inhibitor treatment of CKS1B-overexpressing cells; WEE1+PLK1 double inhibition epistasis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in yeast validated by multiple orthogonal approaches including shRNA and pharmacological inhibition in human cancer cells across multiple cell lines\",\n      \"pmids\": [\"27558135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ectopic CKS1B overexpression in lung cancer cells induced chemoresistance to cisplatin and doxorubicin through Hsp90 and MEK1/2 pathways, independent of the canonical Skp2-p27 pathway. Inhibition of either Hsp90 or MEK1/2 alone resensitized CKS1B-overexpressing cells to chemotherapy, and 3-COA was identified as a novel Hsp90 inhibitor that mimics this resensitization.\",\n      \"method\": \"shRNA knockdown; selective pathway inhibitors (Hsp90, MEK1/2); in vitro and in vivo tumor models; overexpression of CKS1B\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA plus pharmacological inhibitors establishing Hsp90/MEK1/2 as non-canonical pathway components, single lab, in vitro and in vivo\",\n      \"pmids\": [\"28288818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GLI2 directly binds the CKS1B promoter to regulate CKS1B transcription in cardiomyocytes (CMs). CKS1B overexpression in late-stage hiPSC-CMs promoted proliferation with loss of maturation, identifying CKS1B as a downstream effector of the HH-GLI2 signaling cascade that controls the proliferation-to-maturation transition in CMs.\",\n      \"method\": \"GLI2 promoter binding assay (ChIP-type); hiPSC-CM overexpression of CKS1B; maturation indices; calcium handling measurements; transcriptomic analysis\",\n      \"journal\": \"Stem cells translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding plus functional overexpression in defined cell model, single lab\",\n      \"pmids\": [\"38761090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CKS1B knockdown in hepatocellular carcinoma (HCC) cell lines inhibited proliferation, induced apoptosis, suppressed migration and invasion, and decreased p-STAT3 levels and STAT3 target genes (TIMP-1, Bcl-2, VEGF). Overexpression of CKS1B had opposite effects, establishing CKS1B promotion of HCC progression via JAK/STAT3 pathway activation.\",\n      \"method\": \"shRNA knockdown; overexpression plasmid; MTT, colony formation, flow cytometry, wound healing, transwell assays; Western blot for p-STAT3 and targets\",\n      \"journal\": \"Animal cells and systems\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with multiple orthogonal cellular readouts, single lab\",\n      \"pmids\": [\"34408811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CKS1B forms a complex with S-phase kinase-associated protein (SKP1/SKP2) to promote ubiquitination and degradation of IRF3 (interferon regulatory factor 3), thereby suppressing type I interferon signaling and antigen presentation in tumor cells. This drives persistent CD8+ T cell stimulation and exhaustion. Pharmacological blockade of the CKS1B-IRF3 interaction with compound 14i restored CD8+ T cell function and synergized with immune checkpoint blockade.\",\n      \"method\": \"Single-cell and spatial proteomics; co-immunoprecipitation (CKS1B-SKP complex with IRF3); ubiquitination assay; pharmacological blockade with 14i; in vivo tumor models; immune checkpoint blockade combination\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex identification by Co-IP with functional ubiquitination readout and pharmacological validation, single study, multiple methods\",\n      \"pmids\": [\"42090485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXM1 transcriptionally regulates CKS1B expression in pancreatic ductal adenocarcinoma (PDAC), establishing a novel FOXM1-CKS1B signaling axis. CKS1B knockdown sensitized PDAC cells to gemcitabine and oxaliplatin and reduced cancer stemness properties.\",\n      \"method\": \"Molecular biology methods (chromatin binding/promoter assays implied); in vitro and in vivo PDAC models; CKS1B knockdown with chemosensitivity assays; stemness assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional regulation claim supported by molecular biology methods not fully detailed in abstract, single lab\",\n      \"pmids\": [\"39897042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CKS1B knockdown in papillary thyroid carcinoma (PTC) cells inhibited cell viability and invasion, suppressed STAT3/PD-L1 signaling, and reduced Akt phosphorylation. STAT3 or PD-L1 inhibition reversed the pro-tumorigenic effects of CKS1B overexpression.\",\n      \"method\": \"siRNA knockdown; overexpression plasmid; MTT and transwell assays; Western blot for p-STAT3, p-Akt, PD-L1; pharmacological inhibitors (WP1066, Pembrolizumab)\",\n      \"journal\": \"Journal of clinical laboratory analysis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic depth, pharmacological rescue but no direct binding or reconstitution\",\n      \"pmids\": [\"32960462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CKS1B knockdown in NSCLC cells inhibited proliferation, migration, and invasion; reduced MEK and ERK phosphorylation (MAPK/ERK signaling); and upregulated E-cadherin while downregulating N-cadherin, suppressing EMT.\",\n      \"method\": \"siRNA knockdown; Western blot for p-MEK, p-ERK, E-cadherin, N-cadherin; proliferation and invasion assays\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, no direct mechanistic connection established\",\n      \"pmids\": [\"41171587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CKS1B knockdown in NSCLC cells and xenografts enhanced radiosensitivity by stimulating apoptosis, inhibiting cell cycle progression, and impairing DNA damage repair. CKS1B-induced radioresistance was mediated through the PI3K/AKT signaling pathway.\",\n      \"method\": \"shRNA knockdown; xenograft model with ionizing radiation; apoptosis, cell cycle, DNA damage repair assays; Western blot for PI3K/AKT pathway components\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement inferred from knockdown without direct binding or reconstitution of PI3K/AKT connection\",\n      \"pmids\": [\"40262716\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CKS1B (CksHs1) is a small, conserved CDK regulatory subunit that binds via its beta-strand face to the C-terminal lobe of CDK2, positions the complex toward phosphoprotein substrates, and—in complex with SKP1/SKP2—promotes ubiquitin-mediated degradation of CDK inhibitors p27Kip1 and, as recently shown, IRF3; beyond this canonical SCF(SKP2) adaptor role, CKS1B activates STAT3 and MEK/ERK/BCL2 signaling to drive cell proliferation, drug resistance, and immune evasion, is transcriptionally regulated by GLI2 and FOXM1, and its overexpression creates a synthetic dosage-lethal dependency on PLK1 activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CKS1B is a small CDK regulatory subunit that couples cyclin-dependent kinase complexes to phosphoprotein substrates and to SCF-mediated proteolysis, functioning as a hub for cell-cycle control and proliferative signaling [#1, #6]. Structurally it is a single compact domain with a four-stranded beta-sheet flanked by two helices, presenting an anion/phosphate-binding pocket (Lys11, Arg20, Ser51, Trp54, Arg71) and a beta-hinge region whose opening generates a domain-swapped dimer; in the monomeric state it docks via all four beta-strands onto the CDK2 C-terminal lobe—away from the cyclin and regulatory phosphorylation sites—simultaneously exposing the CDK2 ATP site and its own phosphate pocket, positioning the kinase toward phosphorylated substrates [#0, #1]. CKS1B is a required cofactor for SCF(SKP2)-driven ubiquitination and degradation of the CDK inhibitor p27Kip1: its depletion stabilizes p27Kip1 and arrests proliferation, while its interaction with SKP2 also reciprocally modulates CKS1B availability to CDK2 [#3, #5]. Beyond the canonical SKP2/p27 axis, CKS1B sustains tumor-cell survival, proliferation, and drug resistance through STAT3 and MEK/ERK signaling with BCL2 as a downstream effector, and SCF-coupled degradation of IRF3 suppresses type I interferon signaling and antigen presentation, promoting CD8+ T-cell exhaustion [#6, #7, #14]. CKS1B expression is controlled transcriptionally by GLI2 within HH signaling and by FOXM1, and its overexpression establishes a synthetic-dosage-lethal dependence on PLK1 conserved from yeast to human cancer cells [#10, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the atomic architecture of human CKS1B, defining a phosphate-binding pocket and a conformational beta-hinge switch that would underlie its substrate-targeting and oligomerization behavior.\",\n      \"evidence\": \"X-ray crystallography of CksHs1 at 2.9 Å with conserved-residue identification\",\n      \"pmids\": [\"7791211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show binding to any physiological phosphoprotein\", \"Functional role of the phosphate pocket inferred, not demonstrated\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolved how CKS1B engages CDK2, showing a beta-strand interface on the CDK2 C-terminal lobe that leaves the kinase active site free, supporting a model in which CKS1B targets CDK2 to phosphoproteins.\",\n      \"evidence\": \"X-ray crystallography of the CDK2–CksHs1 complex at 2.6 Å with site-directed mutagenesis of the interface\",\n      \"pmids\": [\"8601310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphoprotein substrates engaged via the exposed pocket not identified\", \"No cyclin present in the structure\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Placed CKS1B downstream of TGF-beta receptor signaling, linking its transcriptional regulation to growth arrest.\",\n      \"evidence\": \"Northern blot after TGF-beta treatment plus a dominant-negative TGF-beta type 2 receptor cell line\",\n      \"pmids\": [\"8845303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CKS1B downregulation to arrest not defined\", \"No direct transcriptional regulator identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that SKP2 directly binds CKS1B and competes with its CDK2 interaction, revealing a regulatory partition of CKS1B between CDK2 inhibition and SCF engagement.\",\n      \"evidence\": \"Co-immunoprecipitation, CDK2 kinase assays, and overexpression in cells\",\n      \"pmids\": [\"11349131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemistry without structural mapping of the SKP2-CKS1B interface\", \"Physiological balance between the two states not quantified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Characterized the marginal thermodynamic and kinetic stability of CKS1B and linked refolding to transient domain-swapped oligomerization.\",\n      \"evidence\": \"Equilibrium denaturation and folding/unfolding kinetics in vitro\",\n      \"pmids\": [\"11802719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biological relevance of the dimer in cells unresolved\", \"No connection to in-cell CDK2 or SKP2 binding\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that CKS1B drives myeloma survival through both SKP2/p27Kip1-dependent and -independent routes, expanding its role beyond the canonical degradation pathway.\",\n      \"evidence\": \"Lentiviral shRNA, SKP2 knockdown, non-degradable p27T187A expression, and a p27-null cell line with apoptosis/cell-cycle readouts\",\n      \"pmids\": [\"17303695\", \"16188652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the p27-independent survival mechanism not defined here\", \"Restricted to myeloma models\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected CKS1B to STAT3 and MEK/ERK/BCL2 signaling as a driver of proliferation and multidrug resistance, providing a candidate non-canonical effector arm.\",\n      \"evidence\": \"Overexpression, shRNA, pathway inhibitors, and viability rescue in myeloma cells\",\n      \"pmids\": [\"20930946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between CKS1B and pathway activation not established\", \"Single lineage context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a conserved synthetic-dosage-lethal dependency: CKS1B overexpression sensitizes cells to loss of PLK1 activity, defining a targetable vulnerability.\",\n      \"evidence\": \"Yeast SDL screen with Swe1/Sic1 epistasis plus PLK1 shRNA and pharmacological inhibition in human cancer cell lines\",\n      \"pmids\": [\"27558135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the CKS1B-PLK1 lethal interaction not resolved\", \"Yeast-to-human mechanistic conservation inferred from phenotype\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed CKS1B transcriptionally downstream of HH-GLI2 signaling controlling a proliferation-to-maturation switch, extending its role beyond cancer.\",\n      \"evidence\": \"GLI2 promoter-binding assay and CKS1B overexpression in hiPSC-cardiomyocytes with maturation and calcium readouts\",\n      \"pmids\": [\"38761090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors in cardiomyocytes not mapped\", \"Single developmental model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed an immune-evasion function in which the CKS1B-SKP1/SKP2 complex ubiquitinates and degrades IRF3 to suppress type I interferon signaling and drive CD8+ T-cell exhaustion, with pharmacological disruption restoring immunity.\",\n      \"evidence\": \"Spatial/single-cell proteomics, Co-IP of the CKS1B-SKP complex with IRF3, ubiquitination assay, compound 14i blockade, and checkpoint-blockade combination in vivo\",\n      \"pmids\": [\"42090485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IRF3 is a direct SCF(SKP2) substrate via CKS1B docking not structurally shown\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CKS1B partitions between its CDK2-targeting, SCF-adaptor, and signaling functions to selectively destabilize specific substrates (p27Kip1, IRF3) in different tissue contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of CKS1B within an SCF(SKP2)-substrate complex\", \"Determinants of substrate selectivity unknown\", \"Direct versus indirect basis of STAT3/MEK-ERK/PI3K-AKT engagement not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 6, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 6, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\"SCF(SKP2)\"],\n    \"partners\": [\"CDK2\", \"SKP2\", \"SKP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}