Affinage

CDKN1B

Cyclin-dependent kinase inhibitor 1B · UniProt P46527

Round 2 corrected
Length
198 aa
Mass
22.1 kDa
Annotated
2026-04-28
130 papers in source corpus 34 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKN1B (p27Kip1) is a master regulator of cell cycle progression, integrating mitogenic, metabolic, and cytoskeletal signals through both CDK-dependent and CDK-independent mechanisms. As an intrinsically disordered protein, p27 inhibits cyclin E–Cdk2 and cyclin A–Cdk2 by inserting into the catalytic cleft to mimic ATP, while at low stoichiometry it acts as an assembly factor for cyclin D–Cdk4 complexes (PMID:8033212, PMID:8684460, PMID:9106657). p27 abundance is controlled post-transcriptionally by translational regulation, by SCF-Skp2-mediated nuclear degradation triggered by Cdk2 phosphorylation at T187, by cytoplasmic KPC-dependent ubiquitination after CRM1-mediated export, and by selective autophagy via SQSTM1/p62; Akt phosphorylation at T157 enforces cytoplasmic retention while LKB1-AMPK phosphorylation at T198 stabilizes p27 and promotes autophagy over apoptosis (PMID:9192873, PMID:10559916, PMID:15531880, PMID:12244302, PMID:17237771, PMID:26569626). Beyond cell cycle control, cytoplasmic p27 exerts CDK-independent functions including RhoA inhibition to promote motility, Akt stabilization for survival signaling, regulation of invadopodia turnover through PAK1–Cortactin interaction, and control of cytokinesis by inhibiting citron kinase (PMID:16489017, PMID:28287395, PMID:22293177).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Establishing that p27Kip1 is a broad-spectrum CDK inhibitor that blocks Rb phosphorylation and S-phase entry resolved the identity of the activity that arrests the cell cycle in response to contact inhibition and TGF-β signaling.

    Evidence Co-immunoprecipitation, in vitro kinase assays, overexpression cell cycle analysis in mammalian cells

    PMID:8033212

    Open questions at the time
    • Mechanism of selectivity among different cyclin-CDK pairs not defined
    • In vivo loss-of-function not yet tested
  2. 1996 High

    The crystal structure of p27-KID bound to cyclin A–Cdk2 revealed that an intrinsically disordered protein inhibits a kinase by inserting into the catalytic cleft, explaining how a single polypeptide simultaneously contacts both cyclin and CDK subunits; concurrently, the dual role of p27 as both an inhibitor of cyclin E–Cdk2 and an assembly factor for cyclin D–Cdk4 was established.

    Evidence X-ray crystallography at 2.3 Å (p27-KID/cyclin A–Cdk2); in vitro assembly kinetics and nuclear targeting assays for cyclin D–Cdk4

    PMID:8684460 PMID:9106657

    Open questions at the time
    • Full-length p27 structure unresolved due to disorder
    • Concentration-dependent switch from assembly factor to inhibitor not structurally explained
  3. 1996 High

    Demonstration that p27 protein levels fluctuate without mRNA changes established post-transcriptional control—translational regulation and protein half-life—as the dominant mode of p27 regulation, shifting the field away from transcriptional models.

    Evidence Polysome fractionation, metabolic labeling, pulse-chase in synchronized cells; antisense oligonucleotides in serum-deprived fibroblasts

    PMID:8596954 PMID:8629023

    Open questions at the time
    • Translational regulatory elements and trans-acting factors not identified
    • Relative contribution of translation vs. degradation not quantified
  4. 1997 High

    Identification of T187 as the Cdk2 phosphorylation site that triggers p27 proteasomal degradation established the feedback loop whereby the kinase target marks its own inhibitor for destruction, explaining the abrupt cyclin E–Cdk2 activation at the restriction point.

    Evidence Site-directed mutagenesis (T187A), in vitro kinase assays, pulse-chase degradation, cell cycle analysis

    PMID:9192873 PMID:9311993

    Open questions at the time
    • E3 ubiquitin ligase identity not yet known
    • Whether T187 phosphorylation is the sole degradation signal unclear
  5. 1999 High

    Identification of Skp2 as the F-box protein that recognizes phospho-T187-p27 for SCF-mediated ubiquitination, and demonstration that cyclin D sequesters p27 away from cyclin E–Cdk2, together defined the two principal mechanisms—targeted degradation and titration—by which cells relieve p27-mediated inhibition during G1.

    Evidence In vitro ubiquitination reconstitution with SCF-Skp2; genetic rescue with kinase-dead cyclin D1 in D1-null MEFs

    PMID:10508164 PMID:10559916

    Open questions at the time
    • Skp2 KO phenotype not yet characterized in vivo
    • Additional E3 ligases for p27 not excluded
  6. 2000 High

    Skp2 knockout mice accumulated p27 and showed cell cycle defects, providing definitive in vivo genetic validation that SCF-Skp2 is the principal nuclear E3 ligase for p27 degradation.

    Evidence Skp2 knockout mice, immunoblot quantification, cell cycle analysis

    PMID:10790373

    Open questions at the time
    • Whether residual p27 degradation in Skp2-null cells uses alternative ligases not resolved
  7. 2001 Medium

    Transcriptional regulation of p27 was established: c-Myc represses the p27 promoter via Myc box II, and pRb induces post-transcriptional p27 accumulation required for senescence, placing p27 at the convergence of the Myc–Rb axis.

    Evidence Promoter-reporter assays with deletion mapping; pRb reconstitution in RB-null cells with p27 antisense ablation

    PMID:11313917 PMID:11340156

    Open questions at the time
    • Direct ChIP for c-Myc at the endogenous p27 locus not shown in the original study
    • Mechanism by which pRb induces p27 accumulation post-transcriptionally not identified
  8. 2002 High

    Akt phosphorylation of p27 at T157 within the NLS provided a direct mechanistic link between PI3K survival signaling and p27 cytoplasmic mislocalization, explaining a common observation in human cancers.

    Evidence In vitro kinase assay with recombinant Akt, T157A mutagenesis, nuclear import assay, subcellular fractionation; independently confirmed in three concurrent publications

    PMID:12244301 PMID:12244302 PMID:12244303

    Open questions at the time
    • Functional consequences of cytoplasmic p27 beyond loss of nuclear CDK inhibition not yet explored
  9. 2004 High

    Discovery of the cytoplasmic KPC E3 ligase complex that ubiquitinates p27 independently of Skp2 at the G0–G1 transition resolved how p27 is degraded in the cytoplasm before Skp2 accumulates in S phase.

    Evidence In vitro ubiquitination reconstitution, dominant-negative KPC1, siRNA, CRM1 inhibition showing nuclear export precedes degradation

    PMID:15531880

    Open questions at the time
    • KPC substrate specificity beyond p27 not determined
    • Relative quantitative contribution of KPC vs. Skp2 in different tissues unknown
  10. 2006 Medium

    Cytoplasmic p27 was shown to have CDK-independent oncogenic functions—inhibiting RhoA to promote motility and stabilizing Akt for survival—redefining p27 from a pure tumor suppressor to a context-dependent oncoprotein.

    Evidence p27-deltaNLS expression, RhoA activity assay, siRNA knockdown in glioma cells, Akt stability measurement, xenograft model

    PMID:16489017

    Open questions at the time
    • Direct binding interface between p27 and RhoA not structurally characterized
    • In vivo confirmation of cytoplasmic p27 oncogenic role in genetic models not shown
  11. 2007 High

    The LKB1-AMPK pathway was found to phosphorylate p27 at T198 to stabilize it and promote autophagy instead of apoptosis under metabolic stress, establishing p27 as an integrator of energy-sensing and cell-fate decisions beyond cell cycle control.

    Evidence In vitro kinase assay, phosphomimetic T198D and non-phosphorylatable T198A mutants, autophagy vs. apoptosis readouts after metabolic stress

    PMID:17237771

    Open questions at the time
    • Downstream autophagy effectors regulated by phospho-T198-p27 not identified
    • Whether this applies broadly or only in specific cell types not tested
  12. 2007 High

    miR-221 and miR-222 were identified as potent post-transcriptional repressors of p27, adding a microRNA layer to the already complex multi-level regulation of p27 abundance.

    Evidence miRNA inhibitor screen, 3′UTR luciferase reporter, miRNA overexpression/inhibition in multiple cancer cell lines

    PMID:17627278

    Open questions at the time
    • Whether miR-221/222 regulation of p27 is sufficient for oncogenesis in vivo not established
  13. 2012 High

    Discovery that p27 controls cytokinesis by binding and inhibiting citron kinase, blocking its interaction with RhoA at the contractile ring, revealed a CDK-independent role in mitotic exit and genome stability.

    Evidence Reciprocal Co-IP, co-localization at contractile ring and midbody, domain mutant rescue in MEFs

    PMID:22293177

    Open questions at the time
    • Structural basis of the p27–citron kinase interaction not resolved
    • Whether cytokinesis defects contribute to tumorigenesis in p27-null mice not tested
  14. 2015 High

    p27 was shown to be selectively degraded by autophagy via interaction with SQSTM1/p62 in T lymphocytes, revealing a proteasome-independent degradation pathway critical for T-cell proliferation after antigen stimulation.

    Evidence Co-IP of p27 with SQSTM1/p62, Atg7-deficient T cells accumulating p27, genetic rescue by p27 haploinsufficiency in Atg7-null background

    PMID:26569626

    Open questions at the time
    • Whether autophagy-mediated p27 degradation occurs in non-immune cells not determined
    • Ubiquitination signals directing p27 to autophagy vs. proteasome not distinguished
  15. 2017 High

    p27 was found to promote cell invasion by localizing to invadopodia and facilitating PAK1–Cortactin interaction for invadopodia turnover, demonstrating that p27's pro-migratory activity extends to ECM degradation and invasion.

    Evidence Reciprocal Co-IP of p27 with Cortactin, co-localization imaging, Cortactin phosphorylation mutants, invasion and PAK1 activity assays

    PMID:28287395

    Open questions at the time
    • Whether this mechanism operates in vivo during metastasis not shown
    • How p27 is recruited to invadopodia is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How p27 switches between its CDK-inhibitory, assembly-factor, and CDK-independent cytoskeletal functions in a context-dependent manner—and whether these functions are coordinated by a unified phosphorylation code or reflect independent pools—remains unresolved.
  • Full-length p27 structure in complex with different partners not determined
  • Quantitative modeling of p27 partitioning among cyclin-CDK, RhoA, citron kinase, and Cortactin pools lacking
  • In vivo contribution of each CDK-independent function to tumorigenesis not genetically dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140313 molecular sequestering activity 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 4 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1640170 Cell Cycle 7 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 2 R-HSA-5357801 Programmed Cell Death 1
Partners
CCNA2CCNE1CDK2CITCTTNSKP2SQSTM1STMN1
Complex memberships
SCF-Skp2cyclin A-Cdk2cyclin D-Cdk4cyclin E-Cdk2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 p27Kip1 was cloned as a cyclin-dependent kinase inhibitor that associates with cyclin E-Cdk2 complexes in vivo and in vitro, prevents their activation, inhibits previously activated complexes, and overexpression obstructs cell entry into S phase. p27Kip1 potently inhibits Rb phosphorylation by cyclin E-Cdk2, cyclin A-Cdk2, and cyclin D2-Cdk4. Co-immunoprecipitation, in vitro kinase assay, overexpression in cells, Rb phosphorylation assay Cell High 8033212
1996 Crystal structure of the p27Kip1 kinase inhibitory domain bound to the phosphorylated cyclin A-Cdk2 complex was determined at 2.3 Å, showing p27Kip1 binds as an extended structure interacting with both cyclin A and Cdk2, binding in a groove on cyclin A and inserting into the Cdk2 catalytic cleft to mimic ATP. X-ray crystallography at 2.3 Å resolution Nature High 8684460
1996 p27Kip1 protein accumulation during cell cycle arrest is regulated post-transcriptionally by translational control; mRNA levels remain unchanged while protein levels fluctuate, and translational efficiency as well as protein half-life contribute to periodic accumulation in G1. Cell synchronization, polysome fractionation, metabolic labeling, pulse-chase Science High 8596954
1996 p27Kip1 is an essential component of the pathway connecting mitogenic signals to the cell cycle restriction point; depletion of serum causes p27 accumulation that inactivates G1 cyclin-CDK complexes, and antisense inhibition of p27 prevents cell cycle arrest upon mitogen depletion. Antisense oligonucleotides, CDK kinase assays, cell cycle analysis in serum-deprived fibroblasts Science High 8629023
1997 Cyclin E-CDK2 phosphorylates p27Kip1 at T187 in vivo and in vitro, and this phosphorylation leads to elimination of p27 from the cell, enabling G1-to-S phase transit. Mutation of T187 to alanine creates a p27 protein whose level is not modulated by cyclin E. p27 can interact with cyclin E-CDK2 in two ways: one resulting in phosphorylation and release, the other in tight binding and inhibition, with ATP concentration governing which predominates. In vitro kinase assay, site-directed mutagenesis, cell transfection, immunoblot, cell cycle analysis Genes & development High 9192873
1997 p27Kip1 must be phosphorylated by CDK2 on the TPKK site (C-terminal CDK target) to be degraded by the proteasome. Phosphorylation-dependent degradation requires association of p27 with active cyclin E-CDK2 in a non-inhibitory conformation where p27 contacts cyclin but not CDK. Retroviral expression of p27 point mutants, proteasome inhibitor treatment, in vitro phosphorylation, pulse-chase The EMBO journal High 9311993
1997 p27Kip1 (and p21Cip1) promote the assembly of cyclin D-Cdk4 complexes in vivo and in vitro with 35–80-fold increase in association constant, primarily by decreasing Koff; at low concentrations they promote active kinase assembly, while at high concentrations they inhibit activity. p27 and p21 also target Cdk4 and cyclin D1 to the nucleus. In vitro assembly assays, immunodepletion, kinetic binding studies, nuclear fractionation Genes & development High 9106657
1999 SKP2 specifically recognizes p27Kip1 in a phosphorylation-dependent manner characteristic of an F-box-protein-substrate interaction, and is a rate-limiting component of the ubiquitin ligase machinery that ubiquitinates and degrades phosphorylated p27 both in vivo and in vitro. Co-immunoprecipitation, in vitro ubiquitination assay, SKP2 overexpression and depletion, phosphorylation-dependent binding assay Nature cell biology High 10559916
1999 Cyclins D1 and D2 sequester p27Kip1 and p21Cip1 via formation of cyclin-CDK complexes, and this sequestration is required for Myc-induced cyclin E-CDK2 activation and proliferation; cyclin D1 mutants forming kinase-defective but CKI-binding complexes restore Myc sensitivity in cyclin D1-null cells. Biochemical co-immunoprecipitation, genetic rescue with cyclin D1 kinase-dead mutant in primary embryo fibroblasts, cyclin D1/D2 knockout mice The EMBO journal High 10508164
2000 Targeted disruption of Skp2 in mice results in marked accumulation of p27Kip1, demonstrating that the SCF(Skp2) ubiquitin ligase complex mediates p27 degradation in vivo. Skp2 knockout mice, immunoblot, cell cycle analysis, ubiquitylation assay The EMBO journal High 10790373
2002 Akt/PKB phosphorylates p27Kip1 at threonine 157 (within its nuclear localization signal), impairing nuclear import of p27 and causing cytoplasmic retention, thereby preventing p27-mediated G1 arrest. T157A mutant p27 localizes exclusively to the nucleus and resists Akt-mediated nuclear exclusion. In vitro kinase assay with recombinant Akt, site-directed mutagenesis (T157A), subcellular fractionation, nuclear import assay, co-transfection with active Akt Nature medicine High 12244301 12244302 12244303
2004 KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 (RING-finger) and KPC2 (ubiquitin-like and ubiquitin-associated domains), is a cytoplasmic E3 ubiquitin ligase that interacts with and ubiquitinates p27Kip1 independent of Skp2, controlling p27 degradation at the G0-G1 transition after nuclear export by CRM1. Co-immunoprecipitation, in vitro ubiquitination assay, dominant-negative KPC1, siRNA knockdown, subcellular fractionation, CRM1 inhibition Nature cell biology High 15531880
2006 Thermodynamic characterization by ITC and circular dichroism showed that p27-KID acts as a thermodynamic tether in the ternary p27-KID/Cdk2/cyclin A complex, substantially increasing thermal stability and favorability of association (ΔGA more negative). Phosphorylation of Cdk2 at Thr160 further stabilizes the ternary complex. Isothermal titration calorimetry (ITC), circular dichroism thermal denaturation Biochimica et biophysica acta High 16458085
2007 The LKB1-AMPK energy-sensing pathway phosphorylates p27Kip1 at Thr198, increasing p27 stability and directly linking nutrient/bioenergetic sensing to cell cycle progression. Phospho-T198 p27 is sufficient to induce autophagy, and p27 knockdown under metabolic stress that activates LKB1-AMPK results in apoptosis instead of autophagy. In vitro kinase assay, phosphomimetic/non-phosphorylatable mutants (T198D/T198A), siRNA knockdown, autophagy and apoptosis assays Nature cell biology High 17237771
2007 miR-221 and miR-222 are potent post-transcriptional repressors of p27Kip1; miRNA inhibitors that block miR-221/222 activity in cancer cell lines elevate p27Kip1 levels and suppress proliferation. High miR-221/222 expression in glioblastomas correlates with low p27Kip1 protein levels. miRNA inhibitor functional screen, luciferase 3'UTR reporter assay, miRNA overexpression and inhibition, immunoblot The EMBO journal High 17627278
2008 Protein kinase CK2-alpha' phosphorylates p27Kip1, promoting its proteasomal degradation in cardiomyocytes in response to angiotensin II; conversely, unphosphorylated p27 potently inhibits CK2-alpha', forming a regulatory feedback loop in differentiated cardiomyocytes that is analogous to but distinct from the p27-Cdk2 feedback loop. In vitro kinase assay, co-immunoprecipitation, proteasome inhibitor treatment, dominant-negative CK2, cardiac hypertrophy model Nature medicine High 18311148
2011 p57 and p27 cooperate to maintain hematopoietic stem cell quiescence through interaction with Hsc70; combined deficiency of p57 and p27 allows nuclear import of an Hsc70/cyclin D1 complex, concomitant Rb phosphorylation, and loss of HSC quiescence. Regulation of cytoplasmic localization of the Hsc70/cyclin D1 complex by p57 and p27 is identified as a key mechanism. Double knockout mice, co-immunoprecipitation, subcellular fractionation, transplantation assay, flow cytometry Cell stem cell High 21885020
2012 p27Kip1 controls cytokinesis via regulation of citron kinase (citron-K) activity; p27 interacts with citron-K in vitro and in vivo, colocalizes at the contractile ring and mid-body during telophase, and prevents citron-K interaction with its activator RhoA. p27CK- mutants unable to bind cyclin-CDK cause cytokinesis/abscission defects and multinucleation, while mutations preventing citron-K binding rescue the phenotype. Co-immunoprecipitation, immunofluorescence co-localization, p27 point mutant analysis, domain rescue experiments, mouse embryonic fibroblasts The Journal of clinical investigation High 22293177
2015 Autophagy selectively degrades CDKN1B/p27Kip1 in T lymphocytes; p27 forms polymers and physically associates with the autophagy receptor SQSTM1/p62. In Atg7-deficient T cells, p27 accumulates and cannot be degraded after TCR stimulation, and genetic deletion of one p27 allele restores proliferative capacity of autophagy-deficient T cells. Co-immunoprecipitation (p27-SQSTM1/p62), adoptive transfer infection model, genetic rescue (p27 heterozygous deletion in Atg7-null T cells), flow cytometry S-phase entry Autophagy High 26569626
2015 NMR-based screening identified small molecules that bind specifically to sites created by transient clusters of aromatic residues within disordered p27Kip1. One compound counteracted the Cdk2/cyclin A inhibitory function of p27 in vitro, providing proof-of-principle that small molecules can sequester p27 in a conformation incapable of folding and binding Cdk2/cyclin A. NMR-based screening, structure-activity relationship analysis, in vitro Cdk2/cyclin A inhibition assay Scientific reports Medium 26507530
2001 c-Myc represses transcription of the p27Kip1 gene; BCR engagement drops c-Myc and activates p27 transcription, and ectopic c-Myc suppresses p27 promoter activity. Repression maps to bp -20 to +20 and requires the Myc box II domain; Max facilitates c-Myc binding and repression. Promoter-reporter assay, co-immunoprecipitation of c-Myc/Max on p27 promoter, deletion and mutation analysis, northern blot, mRNA quantification Oncogene Medium 11313917
2001 pRb induces a posttranscriptional accumulation of p27Kip1 specifically bound to cyclin E, decreasing cyclin E-associated kinase activity; this accumulation is required for pRb-mediated senescence. Ablation of p27Kip1 expression abrogates pRb's ability to maintain cell cycle arrest and induce senescence. pRb reconstitution in RB-/- cells, immunoprecipitation-kinase assay, antisense ablation of p27, senescence assays Molecular and cellular biology Medium 11340156
2002 PGP9.5 (UCH-L1) interacts with JAB1 and p27Kip1, forming a heteromeric nuclear complex. Under serum restimulation, nuclear translocation of PGP9.5 and JAB1 coincides with reduced nuclear p27, suggesting PGP9.5 contributes to p27 degradation via its interaction with JAB1. Yeast two-hybrid, co-immunoprecipitation in vitro and in vivo, immunofluorescence co-localization Oncogene Medium 12082530
2006 Cyclin D1 promotes cellular migration requiring p27Kip1; cyclin D1 mutations (K112 and residues 46-90) that abolish physical interaction with p27 abolish migration induction. Cyclin D1-/- cells are p27-deficient and migration-defective; reintroduction of p27 rescues migration; p27 siRNA reverses cyclin D1-mediated migration rescue. Cyclin D1 inhibits Skp2 and promotes p27 phosphorylation at Ser10. Co-immunoprecipitation, cyclin D1 point mutants, p27 siRNA, cyclin D1-/- MEF rescue experiments, migration assays Cancer research Medium 17047061
2006 Cytoplasmic p27Kip1 down-regulates RhoA and increases cell motility, survival, and Akt levels without affecting cell cycle distribution. Knockdown of cytoplasmic p27 in U87 glioma cells (which express predominantly cytoplasmic p27) inhibits motility and survival, and reduces Akt levels and Akt turnover, demonstrating a CDK-independent oncogenic function of cytoplasmic p27. Nuclear localization signal deletion mutant (p27deltaNLS), siRNA knockdown, RhoA activity assay, motility assay, Akt stability measurement, xenograft model Cancer research Medium 16489017
2011 Threonine 198 (T198) modification regulates both p27Kip1 protein stability and cell motility by distinct mechanisms: stability is controlled by steric hindrance of the last amino acid independent of Skp2 binding, through conformational changes in the disordered C-terminus; T198 phosphorylation specifically promotes p27-stathmin interaction to regulate cell motility. T198 mutagenesis, proteasome assays, Co-immunoprecipitation of p27-stathmin, cell motility assays PloS one Medium 21423803
2017 p27Kip1 promotes cell invasion by binding to Cortactin and regulating its interaction with PAK1; p27 localizes to invadopodia, limits their number and activity, and facilitates invadopodia turnover by promoting PAK1-Cortactin interaction, whereby PAK1 phosphorylates Cortactin. Loss of p27 increases invadopodia stability due to impaired PAK1-Cortactin interaction. Co-immunoprecipitation, co-localization imaging, Cortactin phosphorylation-site mutants, invasion assays, PAK1 activity assays eLife High 28287395
2014 Genetic ablation of stathmin in p27Kip1-null mice reverses the hyperproliferative phenotypes (increased body/organ weight, retinal basal layer outgrowth, pituitary adenomas), with reduced CDK4/6 kinase activity as the molecular basis, demonstrating that stathmin cooperates with p27 to control early G1-to-S transition. Double knockout mice, CDK kinase activity assays, gene expression profiling, histological phenotyping Cell cycle Medium 25486569
2010 Siah1/SIP E3 ligase complex promotes proteasome-dependent degradation of cytoplasmic p27Kip1 under glucose starvation, regulating cell motility; SIP-/- embryonic fibroblasts have elevated cytosolic p27 and increased motility compared to wild-type. Co-immunoprecipitation, ubiquitination assay, SIP-/- fibroblasts, glucose starvation model, motility assay Cell cycle Medium 21734459
2015 COP1 E3 ubiquitin ligase, acting downstream of CSN6, negatively regulates p27Kip1 stability; CSN6 interacts with p27 and facilitates its ubiquitin-mediated degradation. COP1 overexpression leads to cytoplasmic distribution of p27 via COP1 nuclear export signal, accelerating p27 degradation. Co-immunoprecipitation, ubiquitination assay, CSN6 knockdown, COP1 overexpression, subcellular fractionation Cell cycle Medium 25945542
2009 AP-1 transcription factor complex (Jun/Fos heterodimer) mediates transcriptional down-regulation of the p27Kip1 gene in response to mitogenic stimulation; an AP-1 binding element at position -469 is required, and both MAPK and PI3K signaling pathways mediate this transcriptional repression. Promoter-reporter luciferase assay with AP-1 site mutation, in vitro DNA binding assay, chromatin immunoprecipitation, enforced Jun/Fos expression The Journal of biological chemistry Medium 19959471
2008 c-Myc inhibits FOXO3a-mediated transcriptional activation of the p27Kip1 promoter by forming a functional association with FOXO3a on a proximal Forkhead binding element; this involves the Myc box II domain of c-Myc and the N-terminal DNA-binding portion of FOXO3a. Co-immunoprecipitation, oligonucleotide precipitation assay, chromatin immunoprecipitation, promoter-reporter assay Journal of cellular biochemistry Medium 18393360

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 2092 8033212
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2014 The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. The Lancet. Oncology 1528 25524798
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1999 SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nature cell biology 1362 10559916
1997 New functional activities for the p21 family of CDK inhibitors. Genes & development 1269 9106657
2002 Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 1243 11961546
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1996 Translational control of p27Kip1 accumulation during the cell cycle. Science (New York, N.Y.) 824 8596954
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
1997 Cyclin E-CDK2 is a regulator of p27Kip1. Genes & development 802 9192873
1996 Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 793 8684460
2004 IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 784 15084260
2002 PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nature medicine 784 12244302
2007 The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nature cell biology 747 17237771
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2007 Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. The EMBO journal 677 17627278
2008 Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell 665 18805092
2002 PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nature medicine 664 12244301
1996 Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle. Science (New York, N.Y.) 658 8629023
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2007 HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer cell 645 17418410
2000 Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. The EMBO journal 642 10790373
2008 MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. The Journal of biological chemistry 634 18708351
1997 Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. The EMBO journal 602 9311993
2002 Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nature medicine 580 12244303
1999 p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development (Cambridge, England) 453 10079221
2004 Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase. Nature cell biology 356 15531880
1997 Accumulation of the cyclin-dependent kinase inhibitor p27/Kip1 and the timing of oligodendrocyte differentiation. The EMBO journal 291 9029151
1999 Cyclins D1 and D2 mediate myc-induced proliferation via sequestration of p27(Kip1) and p21(Cip1). The EMBO journal 276 10508164
1998 Cooperation between the Cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development. Genes & development 269 9784491
2000 Multiple functions of p27(Kip1) and its alterations in tumor cells: a review. Journal of cellular physiology 251 10699962
2001 p27(Kip1): regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. Experimental cell research 246 11237531
2011 p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell stem cell 228 21885020
2001 Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 226 11313917
2007 Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. The Journal of clinical endocrinology and metabolism 192 17519308
2010 Ubiquitylation and proteasomal degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK inhibitors. Cell cycle (Georgetown, Tex.) 190 20519948
1996 p27/Kip1 mutation found in breast cancer. Cancer research 169 8625318
2001 Role for p27(Kip1) in Vascular Smooth Muscle Cell Migration. Circulation 163 11413088
2001 ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways. Cancer research 162 11522658
2000 p27(Kip1) regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina. Developmental biology 143 10694424
2004 Protection of p27(Kip1) mRNA by quaking RNA binding proteins promotes oligodendrocyte differentiation. Nature neuroscience 142 15568022
2001 Requirement for p27(KIP1) in retinoblastoma protein-mediated senescence. Molecular and cellular biology 134 11340156
2008 Post-translational regulation of the tumor suppressor p27(KIP1). Cellular and molecular life sciences : CMLS 117 18636226
2006 Cyclin D1 induction of cellular migration requires p27(KIP1). Cancer research 113 17047061
2006 Reduction of cytosolic p27(Kip1) inhibits cancer cell motility, survival, and tumorigenicity. Cancer research 111 16489017
2002 Understanding p27(kip1) deregulation in cancer: down-regulation or mislocalization. Cell cycle (Georgetown, Tex.) 109 12548012
2012 MiR-196a is upregulated in gastric cancer and promotes cell proliferation by downregulating p27(kip1). Molecular cancer therapeutics 108 22343731
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