Affinage

CDKN1A

Cyclin-dependent kinase inhibitor 1 · UniProt P38936

Round 2 corrected
Length
164 aa
Mass
18.1 kDa
Annotated
2026-04-28
130 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKN1A (p21/WAF1/CIP1) is a central cell-cycle regulator that integrates DNA damage, mitogenic, differentiation, and stress signals to control proliferation, senescence, and apoptosis. It is transcriptionally induced by p53 through a defined upstream binding site following DNA damage (PMID:8242752) and independently by TGF-β (via Sp1/FoxO–Smad complexes), growth factors, and differentiation cues (PMID:7499379, PMID:15084259, PMID:8012956); it directly inhibits cyclin E–CDK2 and other cyclin–CDK complexes to enforce G1 and G2 arrest, while at substoichiometric levels it promotes cyclin D–CDK4 assembly and nuclear targeting (PMID:8242751, PMID:9106657, PMID:9822382); it also binds PCNA through a C-terminal peptide that masks the polymerase-assembly surface, blocking PCNA-dependent DNA replication and contributing to DNA repair (PMID:7911228, PMID:8861913, PMID:8625293). Beyond cell-cycle control, cytoplasmic p21 inhibits ASK1 and Rho-kinase to suppress apoptosis and remodel actin dynamics (PMID:10064589, PMID:12119358), maintains hematopoietic stem cell quiescence (PMID:10710306), and sustains senescence through a ROS-dependent positive-feedback loop (PMID:20160708).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Identification of p21 as a p53-inducible growth suppressor and universal CDK inhibitor established it as the principal transcriptional effector of p53-dependent cell-cycle arrest, answering how p53 halts proliferation.

    Evidence Subtractive hybridization, yeast two-hybrid, in vitro CDK reconstitution, and co-IP across multiple cyclin–CDK pairs in human tumor and normal cells

    PMID:8101826 PMID:8242751 PMID:8242752 PMID:8259214

    Open questions at the time
    • Structural basis of p21–CDK inhibition not yet defined
    • Whether p21 functions beyond G1 arrest unknown
    • p53-independent regulation of p21 not characterized
  2. 1994 High

    Discovery that p21 directly inhibits PCNA-dependent DNA replication independently of CDK inhibition revealed a second, mechanistically distinct effector arm and linked p21 to the replication machinery.

    Evidence SV40 in vitro replication assay and direct PCNA–p21 binding assay

    PMID:7911228

    Open questions at the time
    • Structural basis of PCNA–p21 interaction unresolved
    • Relevance of PCNA binding to DNA repair not tested
  3. 1994 High

    Demonstration that p21 is induced by growth factors (PDGF, FGF, EGF) in p53-null cells and by differentiation signals established p53-independent transcriptional regulation of p21, broadening its role beyond the DNA damage response.

    Evidence p53 knockout fibroblasts with growth factor stimulation; drug-induced differentiation in hematopoietic cells

    PMID:7936667 PMID:8012956

    Open questions at the time
    • Promoter elements mediating p53-independent induction not fully mapped
    • Physiological significance of transient versus sustained p21 induction unclear
  4. 1995 High

    Mapping of the TGF-β-responsive Sp1-binding element in the p21 promoter defined how TGF-β cytostasis converges on p21 independently of p53, explaining a major growth-inhibitory arm of TGF-β signaling.

    Evidence Promoter deletion/mutation analysis with gel-shift and reporter assays

    PMID:7499379 PMID:7890601

    Open questions at the time
    • Whether Smad proteins directly participate in this complex not yet shown
    • Contribution of other TGF-β-responsive elements not excluded
  5. 1996 High

    The crystal structure of the p21 C-terminal peptide bound to PCNA at 2.6 Å revealed the molecular mechanism by which p21 occludes the polymerase-assembly surface of PCNA, and isogenic p21-null cells showed that this domain is required for DNA repair.

    Evidence X-ray crystallography; damaged-reporter assay in p21+/+ vs. p21−/− HCT116 cells with domain-mutant rescue

    PMID:8625293 PMID:8861913

    Open questions at the time
    • Whether p21 modulates translesion synthesis unclear
    • Full-length p21 structure with PCNA not solved
  6. 1997 High

    Reconstitution kinetics showed p21 promotes cyclin D–CDK4 complex assembly at low stoichiometry (35–80-fold increased Ka) while inhibiting at higher concentrations, resolving the paradox of how a CDK inhibitor can facilitate G1 progression.

    Evidence In vitro kinase reconstitution with kinetic binding analysis and subcellular fractionation

    PMID:9106657

    Open questions at the time
    • In vivo stoichiometric thresholds not quantified
    • Whether p27/p57 are fully redundant in this assembly role not resolved
  7. 1998 High

    Genetic disruption of p21 revealed its requirement for sustaining G2 arrest and preventing endoreduplication after DNA damage, extending p21 function beyond G1 and establishing cyclin E–CDK2 as the critical downstream target.

    Evidence Isogenic p21+/+ and p21−/− HCT116 cells with γ-irradiation and spindle disruption

    PMID:9488034 PMID:9822382 PMID:9858545

    Open questions at the time
    • Mechanism of p21-dependent G2 maintenance versus mitotic entry control not fully delineated
    • How p21 coordinates with 14-3-3σ in G2 arrest unknown
  8. 1999 High

    Discovery that cytoplasmic p21 directly binds and inhibits ASK1 to suppress stress-activated MAPK signaling established a CDK-independent anti-apoptotic function for p21, explaining its cytoprotective role.

    Evidence Co-IP, in vitro kinase inhibition, and ΔNLS-p21 expression in U937 cells

    PMID:10064589

    Open questions at the time
    • Structural basis of p21–ASK1 interaction not determined
    • Whether cytoplasmic p21 functions are relevant in non-hematopoietic cells at physiologic levels unclear
  9. 2000 High

    p21-deficient mice revealed premature HSC exhaustion under serial transplantation, establishing p21 as the molecular switch that restricts stem cell entry into cycle and thereby preserves the long-term repopulating pool.

    Evidence p21 knockout mice with serial bone marrow transplantation and myelotoxic stress

    PMID:10710306

    Open questions at the time
    • Whether p21's HSC role is CDK-dependent or involves cytoplasmic targets not resolved
    • Contribution of p21 to quiescence in non-hematopoietic stem cells not tested
  10. 2002 High

    Identification of Rho-kinase as a second cytoplasmic target of p21 linked the CDK inhibitor to actin dynamics and neurite outgrowth, revealing a role in cytoskeletal remodeling independent of cell-cycle control.

    Evidence Co-IP, in vitro Rho-kinase activity assay, ΔNLS-p21 expression with actin staining in N1E-115, NIH3T3, and hippocampal neurons

    PMID:12119358

    Open questions at the time
    • Whether p21–Rho-kinase interaction is physiologically relevant during differentiation in vivo not shown
    • Structural determinants of the interaction undefined
  11. 2004 High

    The ATM→p53→p21 signaling axis was shown to be continuously required for senescence maintenance at critically short telomeres, and FoxO–Smad complexes were identified as the TGF-β-responsive transcription factor complex on the p21 promoter, completing the upstream signal integration picture.

    Evidence ATM inhibition/siRNA with single-cell analysis; FoxO–Smad co-IP, ChIP, and genetic epistasis

    PMID:15084259 PMID:15149599

    Open questions at the time
    • How p21-mediated arrest transitions to p16-dependent maintenance not mechanistically resolved
    • Relative contribution of FoxO versus Sp1 sites in different tissues not determined
  12. 2005 High

    Identification of the WISp39–Hsp90 complex as a stabilizer of newly synthesized p21 revealed a key post-translational control mechanism: TPR-domain-dependent Hsp90 recruitment prevents proteasomal degradation, and this complex is required for radiation-induced p21 accumulation.

    Evidence Co-IP, WISp39 TPR mutants, siRNA, proteasome inhibitor treatment, radiation cell-cycle assay

    PMID:15664193

    Open questions at the time
    • Identity of the E3 ubiquitin ligase(s) targeting p21 not defined in this context
    • Whether WISp39 modulates p21 in stem cell or senescence settings not tested
  13. 2009 Medium

    hGTSE-1 was identified as a second stabilizer of p21 acting through the WISp39–Hsp90 complex, and p21 was shown to suppress macrophage NF-κB activation independently of CDK inhibition, expanding its functions into innate immunity.

    Evidence Co-IP with domain mapping and paclitaxel resistance assay; p21 KO macrophages with LPS, IκB kinase assay, and NF-κB reporter

    PMID:19224635 PMID:20018861

    Open questions at the time
    • Mechanism by which p21 inhibits IκBα kinase activity not determined
    • hGTSE-1 findings from a single lab, not independently replicated
  14. 2010 High

    A positive feedback loop was defined in which sustained p21 activation drives mitochondrial ROS through GADD45–p38MAPK–TGF-β signaling; these ROS maintain DNA damage foci and DDR, explaining how senescence becomes self-sustaining.

    Evidence siRNA knockdown, ROS measurement, live-cell microscopy, stochastic modeling

    PMID:20160708

    Open questions at the time
    • Whether this loop operates in vivo during organismal aging not tested
    • Quantitative thresholds of p21 needed to initiate versus maintain the loop undefined
  15. 2013 High

    Lats2 was identified as a kinase that phosphorylates p21 at Ser146 following UV irradiation, promoting p21 degradation and a switch from arrest to apoptosis, revealing how the Hippo pathway impinges on the p53–p21 axis.

    Evidence In vitro kinase assay with phospho-specific antibodies, co-IP, caspase activity assay

    PMID:23886938

    Open questions at the time
    • In vivo validation of Lats2–p21 axis in tumor models not performed
    • Whether other Hippo pathway kinases also target p21 unknown
  16. 2017 Medium

    Two additional regulatory layers were revealed: TRF2-mediated recruitment of the REST–coREST–LSD1 repressor complex to a G-quadruplex in the CDKN1A promoter silences p21 transcription in cancer cells, and p21 prevents CDK-mediated SMAD3 phosphorylation to drive CX3CR1 expression on myeloid-derived suppressor cells.

    Evidence ChIP and G-quadruplex mutational analysis for TRF2; p21 KO mice in tumor models with SMAD3 phosphorylation analysis

    PMID:28912501 PMID:29234059

    Open questions at the time
    • G-quadruplex-mediated regulation observed in single lab; generalizability across tumor types untested
    • Whether p21–SMAD3–CX3CR1 axis functions outside myeloid lineage not examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structural basis of p21 within multi-subunit cyclin–CDK–PCNA complexes, quantitative in vivo stoichiometric thresholds that determine the switch between assembly promotion and CDK inhibition, and the relative contributions of nuclear versus cytoplasmic p21 pools in stem cell maintenance and senescence in organismal contexts.
  • No full-length p21 structure in complex with cyclin–CDK or ternary with PCNA
  • In vivo stoichiometric tipping points for assembly versus inhibition undefined
  • Compartment-specific p21 functions not dissected in conditional knockin models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-1640170 Cell Cycle 7 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-73894 DNA Repair 1
Partners
ASK1CDK2GTSE1LATS2PCNAROCK1TP53WISP39
Complex memberships
Cyclin D–CDK4–p21 complexCyclin E–CDK2–p21–PCNA quaternary complexWISp39–Hsp90–p21 stabilization complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 WAF1 (CDKN1A/p21) was identified as a gene directly transcriptionally induced by wild-type p53 via a p53-binding site 2.4 kb upstream of its coding sequence; introduction of WAF1 cDNA suppressed growth of human brain, lung, and colon tumor cells. Subtractive hybridization, yeast enhancer trap, reporter gene assay, cell growth suppression assay Cell High 8242752
1993 p21 (CIP1) is a potent, tight-binding inhibitor of multiple cyclin-CDK complexes (cyclin A-Cdk2, cyclin E-Cdk2, cyclin D1-Cdk4, cyclin D2-Cdk4), inhibiting phosphorylation of Rb; it was found in cyclin A, D1, E, and Cdk2 immunoprecipitates. Two-hybrid screen, co-immunoprecipitation, in vitro CDK kinase assay, cotransfection growth assay Cell High 8242751
1993 p21 is a universal inhibitor of cyclin kinase family members; in normal cells p21 exists in quaternary complexes with CDK, cyclin, and PCNA, and overexpression of p21 inhibits mammalian cell proliferation. In vitro reconstitution showed p21 inhibits every CDK/cyclin pair tested. Molecular cloning, in vitro reconstitution of quaternary complexes, CDK kinase assay, cell proliferation assay Nature High 8259214
1993 In normal human diploid fibroblasts, p21 exists in quaternary complexes with cyclins A, B, D, CDKs, and PCNA; upon SV40 transformation these complexes are disrupted and p21 dissociates from cyclin-CDK complexes, indicating p21 complex formation is altered during cellular transformation. Co-immunoprecipitation, Western blot, subunit composition analysis of CDK complexes Genes & development High 8101826
1994 WAF1/CIP1 protein is localized to the nucleus of cells with wild-type p53, is induced by DNA-damaging agents in a p53-dependent manner, accumulates in cyclin E-containing complexes following DNA damage with decreased CDK activity, and is induced during both p53-associated G1 arrest and apoptosis. Immunolocalization, Western blot, CDK kinase assay, co-immunoprecipitation Cancer research High 8118801
1994 p21 directly inhibits PCNA-dependent DNA replication in vitro independent of cyclin/CDK by blocking PCNA activation of DNA polymerase delta; this results from a direct interaction between p21 and PCNA. SV40 in vitro DNA replication assay, direct protein interaction assay, DNA polymerase delta activity assay Nature High 7911228
1994 p21 (Sdi1/CIP1) is identified as a senescent cell-derived inhibitor of DNA synthesis; Sdi1 expression increases 10–20-fold in senescent versus young cells and its sustained expression correlates with the senescent phenotype and loss of proliferation. Expression screen (tritiated thymidine autoradiography), Northern blot, cDNA cloning Experimental cell research High 8125163
1994 p53-dependent G1 arrest in normal human fibroblasts after gamma radiation correlates with long-term elevation of p53 protein, Cip1 mRNA, and Cip1 protein, supporting Cip1 as the downstream effector of p53-mediated permanent arrest; the checkpoint is only active before the G1 restriction point. Gamma irradiation dose-response, cell cycle analysis, Northern/Western blot Genes & development High 7958916
1994 p21 induction is triggered by multiple differentiation-inducing agents through a p53-independent pathway in hematopoietic and hepatoma cells, occurring as an immediate early response and coupled to early differentiation markers. Drug treatment, Northern/Western blot, p53-independent context confirmed Oncogene Medium 7936667
1994 p21/WAF1/CIP1 is induced by growth factors (PDGF, FGF, EGF but not insulin) in a p53-independent pathway in p53-null embryonic fibroblasts, functioning as an immediate-early gene induced transiently at G1 entry; DNA damage-induced p21 induction requires p53. p53 knockout mouse fibroblasts, serum/growth factor stimulation, Northern blot, cycloheximide chase Cancer research High 8012956
1996 Crystal structure of the C-terminal 22-residue peptide of p21(WAF1/CIP1) bound to human PCNA at 2.6 Å resolution revealed 1:1 stoichiometry, beta-sheet formation with the PCNA interdomain connector loop, and masking of elements on PCNA required for binding other polymerase assembly components, explaining p21's inhibition of PCNA function. X-ray crystallography at 2.6 Å resolution Cell High 8861913
1995 TGF-beta activates the p21 promoter through a 10-bp TGF-beta-responsive element that binds Sp1 and Sp3 transcription factors; deletion/mutation analysis defined this element as necessary and sufficient for TGF-beta-mediated p21 transcription. Promoter deletion and mutation analysis, reporter gene assay, gel shift assay The Journal of biological chemistry High 7499379
1995 TGF-beta-induced p21 upregulation leads to physical association of p21 with cyclin E, reduced cyclin E-associated kinase activity, and suppression of Rb phosphorylation, mediating cellular sensitivity to TGF-beta cytoinhibition. Western blot, co-immunoprecipitation, in vitro CDK kinase assay, Rb phosphorylation assay The Journal of biological chemistry High 7890601
1997 p21 promotes assembly of active cyclin D/CDK4 complexes at low concentrations (acting as an adaptor) while inhibiting activity at higher concentrations; p21, p27, and p57 all promote cdk4/cyclin D association with a 35- to 80-fold increase in Ka (decreased Koff); p21 also targets CDK4 and cyclin D1 to the nucleus. In vitro kinase reconstitution, kinetic binding assays, immunodepletion, subcellular fractionation, mammalian cell cotransfection Genes & development High 9106657
1998 p53 and p21 are both required to sustain G2 arrest after DNA damage; disruption of either gene allows gamma-irradiated cells to progress into mitosis and fail cytokinesis, demonstrating p21 is essential for maintaining the G2 checkpoint through p53-dependent transcriptional activation. Targeted gene disruption of p53 and p21 in HCT116 cells, cell cycle analysis, gamma irradiation Science High 9822382
1999 Cytoplasmic p21(Cip1/WAF1) forms a complex with ASK1 (apoptosis signal-regulating kinase 1) and inhibits the stress-activated MAP kinase cascade; a deletion mutant lacking the nuclear localization signal (ΔNLSp21) did not induce cell cycle arrest but bound and inhibited ASK1, conferring apoptosis resistance. Biochemical co-immunoprecipitation, in vitro kinase inhibition, deletion mutant analysis, ectopic expression in U937 cells The EMBO journal High 10064589
1999 p21-mediated inhibition of cyclin E/Cdk2 activity is the mechanism by which p21 prevents endoreduplication after mitotic spindle disruption; p21 did not directly regulate cyclin D1-dependent kinase or cyclin B1/Cdc2, and a threshold level of p21 is required for negative regulation of cyclin E/Cdk2. Isogenic p21+/+ and p21-/- HCT116 cells, inducible p21 expression (HIp21), CDK kinase assay, PCNA binding assay, flow cytometry Molecular and cellular biology High 9858545
1999 p16(INK4a) displaces p21 and p27 from cyclin D1/CDK4/6 complexes, leading to a posttranscriptional increase in total cellular p21 that then associates with and inactivates cyclin E-CDK2, causing cell cycle arrest; p21-null HCT116 cells were resistant to p16-mediated arrest, demonstrating p21-CDK2 inhibition is a critical effector of p16. Inducible p16 expression, co-immunoprecipitation, CDK kinase assay, p21-null HCT116 cells, DNA synthesis assay Molecular and cellular biology High 10207115
1999 Ciz1, a novel zinc-finger protein, binds the N-terminal CDK2-interacting domain of p21; coexpression of Ciz1 with p21 induces cytoplasmic redistribution of otherwise nuclear p21, and the interaction is disrupted by CDK2 overexpression. Co-immunoprecipitation, pulldown, coexpression/localization studies in U2-OS cells Biochemical and biophysical research communications Medium 10529385
2000 p21 stimulates transcriptional activation by p300 and CBP through derepression of a novel transcriptional repression domain (CRD1) within p300, independent of p300 HAT activity and of the previously reported cyclinE-Cdk2 binding site; this effect is core-promoter dependent. Transient transfection, luciferase reporter, domain deletion analysis, co-immunoprecipitation Molecular and cellular biology Medium 10733570
2000 p21(WAF1/CIP1) overexpression (N-terminal 91 amino acids containing CDK-inhibitory activity) inhibits DR4 TRAIL receptor-induced proximal caspase (CASP8 and CASP10) cleavage, revealing that p21 can suppress apoptosis by blocking initiator caspase activation. Adenoviral overexpression, caspase cleavage assay, PARP cleavage assay, domain truncation Biochemical and biophysical research communications Medium 10694497
2000 p21 mediates hematopoietic stem cell (HSC) quiescence; p21-deficient mice show increased HSC number and proliferation under normal conditions, and p21-/- mice suffer premature HSC exhaustion and hematopoietic failure upon serial transplantation or myelotoxic stress, establishing p21 as the molecular switch governing HSC cell cycle entry. p21 knockout mice, HSC isolation, serial bone marrow transplantation, myelotoxic stress model, BrdU incorporation Science High 10710306
2001 c-Myc represses p21(WAF1/CIP1) promoter transcription through interaction with Sp1/Sp3; the central region of c-Myc interacts with the zinc finger domain of Sp1, and this repression does not require canonical Myc DNA-binding sites or HDAC activity. Co-immunoprecipitation, GST pulldown, reporter gene assay, MycER inducible system Proceedings of the National Academy of Sciences of the United States of America High 11274368
2002 Cytoplasmic p21(Cip1/WAF1) forms a complex with Rho-kinase and inhibits its activity in vitro and in vivo; ectopic expression of p21 lacking the NLS in N1E-115 and NIH3T3 cells alters actin structure consistent with Rho inactivation and promotes neurite outgrowth and branching in hippocampal neurons. Co-immunoprecipitation, in vitro Rho-kinase activity assay, ectopic expression of ΔNLS-p21, actin staining, neurite morphology assay The Journal of cell biology High 12119358
2002 LKB1-mediated G1 arrest requires cytoplasmic (not exclusively nuclear) LKB1 kinase activity and is p53-dependent; LKB1 specifically upregulates p21(WAF1/CIP1) protein levels and p21 promoter activity, and the arrest can be bypassed by cyclin D1 or cyclin E overexpression. Reintroduction of LKB1 in LKB1-deficient cells, NLS-disruption constructs, reporter assay, p21 promoter activity, epistasis with cyclins Human molecular genetics Medium 12045203
2004 Telomere shortening triggers senescence through ATM→p53→p21(CIP1) signaling to cause G1 arrest; inhibition of ATM expression or activity allows cell cycle re-entry, demonstrating continuous ATM→p53→p21 signaling is required to maintain stable arrest. p16 upregulation occurs independently. Single-cell multiparameter detection, ATM inhibitor/siRNA, cell cycle analysis, immunofluorescence Molecular cell High 15149599
2004 Smad proteins activated by TGF-beta form a complex with FoxO transcription factors to activate p21Cip1 transcription; FoxG1 binds to FoxO-Smad complexes and blocks p21Cip1 expression; PI3K negatively controls this through FoxO nuclear exclusion. Co-immunoprecipitation, reporter assay, ChIP, genetic epistasis in neuroepithelial and glioblastoma cells Cell High 15084259
2005 WISp39, a TPR-domain protein, stabilizes newly synthesized p21 by preventing its proteasomal degradation; WISp39, p21, and Hsp90 form a trimeric complex in vivo; point mutations in WISp39's TPR domain abolish Hsp90 binding and p21 stabilization without disrupting p21 binding; WISp39 siRNA prevents p21 accumulation and cell cycle arrest after ionizing radiation. Co-immunoprecipitation, siRNA knockdown, proteasome inhibitor, WISp39 TPR mutants, radiation cell cycle assay Molecular cell High 15664193
2005 The CDK-inhibitory domain (54 amino acids containing cyclin-CDK interaction motif) of p21 is responsible for its protection against cisplatin cytotoxicity; the PCNA-binding C-terminal domain and procaspase-3-interactive N-terminal domain contribute little; cisplatin activates CDK2 and a CDK2 dominant-negative also protects cells. Adenoviral domain-deletion constructs, in vitro CDK2 kinase assay, CDK2 dominant-negative, cell viability assay American journal of physiology. Renal physiology High 15840769
2007 p21 mediates Rb degradation via the proteasome in addition to Rb dephosphorylation; ectopic p21 expression caused Rb depletion that was proteasome-dependent and p53-independent; p27 also caused Rb depletion but p16 did not; Rb depletion after DNA damage required p21. Ectopic expression, proteasome inhibitor, p21 shRNA, transdominant p53 inhibitor, Western blot in HT1080 and HCT116 cells Oncogene Medium 17486059
2009 CTIP2 is recruited to the p21 gene promoter and silences p21 transcription through interactions with histone deacetylases and methyltransferases; CTIP2 and SUV39H1 cooperatively inhibit p21 transcription through H3K9 trimethylation; treatment with chaetocin (SUV39H1 inhibitor) represses H3K9me3 at the p21 promoter and induces p21 expression and cell cycle arrest. Chromatin immunoprecipitation, reporter assay, siRNA, pharmacological inhibition (chaetocin), ChIP Oncogene High 19581932
2010 A feedback loop is necessary for stable cellular senescence: long-term CDKN1A (p21) activation induces mitochondrial dysfunction and ROS production via GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta signaling; these ROS replenish DNA damage foci and maintain ongoing DDR. This loop is both necessary and sufficient for the stability of growth arrest. Interactome analysis, siRNA knockdown, stochastic modeling, live-cell microscopy, ROS measurements Molecular systems biology High 20160708
2013 Lats2 phosphorylates p21 at Ser146 following UV irradiation (Lats2 itself phosphorylated by Chk1 at Ser835); phosphorylation of p21 by Lats2 induces p21 degradation, activation of caspase-3 and caspase-9, and promotes apoptosis. In vitro kinase assay, phospho-specific antibodies, co-immunoprecipitation, caspase activity assay, overexpression and knockdown Journal of cell science High 23886938
2004 Proteinase 3 (PR3) cleaves p21 between Thr80 and Gly81, causing loss of nuclear p21, cytoplasmic sequestration, and depletion from cyclin/CDK complexes, leading to endothelial cell apoptosis; Granzyme B also cleaves p21 between Asp62 and Phe63. Immunoblotting with PR3 treatment, immunofluorescence, flow cytometry, site identification by mass spectrometry Kidney international Medium 14675038
1996 p21 deficiency is associated with a defect in DNA repair: p21-/- HCT116 cells show reduced repair of UV- or cisplatinum-damaged reporter DNA and increased mutation frequency; reintroduction of wild-type p21, but not a C-terminal truncation mutant lacking the PCNA-interaction domain, restored repair capacity, implicating the PCNA-binding domain in p21's repair function. Isogenic p21+/+ and p21-/- HCT116 cells, damaged reporter assay, 6-TG resistance colony assay, mutant p21 reintroduction Cancer research High 8625293
1998 CDK-binding/inhibitory activity of p21 is required to prevent apoptosis in human colorectal carcinoma cells: p21 mutants at codon 46 or 140 that lack CDK-binding failed to inhibit CDK activity, bind CDK2, suppress apoptosis, or enhance survival after irradiation or adriamycin, whereas wild-type p21 did all of these. Inducible (LacSwitch) expression of wild-type and point-mutant p21, CDK kinase assay, co-immunoprecipitation, clonogenic survival, apoptosis assay Oncogene High 9488034
2017 In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p21(Cip1/Waf1) stimulates CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3; deletion of p21 reduces CX3CR1 expression and inhibits Mo-MDSC accumulation in tumors expressing CX3CL1. p21 and p16 knockout mice, tumor models, CX3CR1 expression assay, SMAD3 phosphorylation analysis Nature communications Medium 29234059
2009 p21 inhibits macrophage activation by suppressing NF-κB activity; p21-deficient peritoneal macrophages show increased LPS-induced NF-κB activation, elevated IκBα kinase activity, and increased IκBα phosphorylation/degradation, leading to elevated TNF-alpha and IL-1beta production; this is independent of p21's cell-cycle inhibitory role. p21 knockout mice, LPS stimulation, NF-κB reporter, IκB kinase assay, ELISA European journal of immunology Medium 19224635
2017 TRF2 binds the CDKN1A promoter G-quadruplex and recruits the REST-coREST-LSD1 repressor complex, causing altered histone marks and transcriptional repression of p21; TRF2-mediated p21 repression attenuates drug-induced G2/M arrest in cancer cells. ChIP, promoter reporter, mutational analysis of G-quadruplex, REST complex co-immunoprecipitation Scientific reports Medium 28912501
2009 hGTSE-1 protein stabilizes p21(CIP1/WAF1) by protecting it from proteasome-dependent degradation as part of a functional complex with WISp39 and Hsp90; the N-terminal portion of hGTSE-1 is sufficient for p21 binding and stabilization; hGTSE-1-mediated p21 stabilization contributes to cellular resistance to paclitaxel. Co-immunoprecipitation, proteasome inhibitor treatment, domain deletion analysis, paclitaxel cytotoxicity assay The Journal of biological chemistry Medium 20018861

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 WAF1, a potential mediator of p53 tumor suppression. Cell 8151 8242752
1993 The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 5537 8242751
1997 Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 4238 9054499
1993 p21 is a universal inhibitor of cyclin kinases. Nature 3348 8259214
1998 Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science (New York, N.Y.) 2593 9822382
1994 WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer research 2215 8118801
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
1994 The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 1669 7911228
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
2005 Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature genetics 1390 15765097
1994 Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Experimental cell research 1375 8125163
2016 Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic acids research 1364 26861625
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
1997 New functional activities for the p21 family of CDK inhibitors. Genes & development 1269 9106657
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
2000 Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science (New York, N.Y.) 1051 10710306
1994 DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes & development 1030 7958916
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2004 Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Molecular cell 1014 15149599
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
1994 Induction of WAF1/CIP1 by a p53-independent pathway. Cancer research 888 8012956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2004 Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 837 15084259
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2010 Feedback between p21 and reactive oxygen production is necessary for cell senescence. Molecular systems biology 775 20160708
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1996 Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA. Cell 696 8861913
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
1994 Induction of p21 (WAF-1/CIP1) during differentiation. Oncogene 582 7936667
1993 Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes & development 569 8101826
1999 Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. The EMBO journal 521 10064589
1995 Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter. The Journal of biological chemistry 403 7499379
2002 Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts. Cancer letters 365 11880176
2001 Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Proceedings of the National Academy of Sciences of the United States of America 348 11274368
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