Affinage

CDKN1A

Cyclin-dependent kinase inhibitor 1 · UniProt P38936

Length
164 aa
Mass
18.1 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKN1A/p21 is a multifunctional cyclin-dependent kinase inhibitor that couples diverse anti-proliferative and stress signals to cell-cycle arrest, differentiation, and stem-cell quiescence (PMID:8242752, PMID:10710306). It was first defined as a direct transcriptional target of wild-type p53, whose induction following DNA damage mediates growth suppression (PMID:8242752), but it is also induced through p53-independent routes—by serum and growth factors as an immediate-early gene (PMID:8012956), during terminal differentiation of multiple lineages (PMID:7863329), and by an array of transcriptional regulators including Ras/Sp1 (PMID:10597223), BRG1/SWI-SNF (PMID:14729964), Mitf (PMID:15716956), and GADD34-enhanced p53 activity (PMID:14635196); its promoter is conversely silenced by CTIP2-recruited HDACs and SUV39H1-mediated H3K9 trimethylation (PMID:19581932). p21 is built from two functionally separable inhibitory domains: an N-terminal CDK-inhibitory domain and a C-terminal PCNA-binding domain, each of which independently blocks DNA replication (PMID:7753174). Through its N-terminal cyclin (Cy/RXL) and CDK-binding motifs it engages cyclin-CDK complexes—competing with Cdc25A for these complexes (PMID:9234691) and inactivating CDK2 downstream of inducers such as Gax (PMID:9224717)—while its C-terminal domain binds PCNA with nanomolar affinity and displaces Fen1 from the replication complex (PMID:8876181). Beyond G1 control, p21 enforces DNA damage-induced G2 arrest by promoting proteasomal degradation of cyclin B1 (PMID:19158493) and is itself phosphorylated by Cdk1/cyclin B1 at S130 to ensure proper mitotic progression and chromosome segregation (PMID:27384476). p21 abundance and localization are tightly regulated: SCF(Skp2) ubiquitinates it at C-terminal lysines in a cyclin E-CDK2-dependent manner (PMID:16262255), Akt and Pim-1 phosphorylate Thr145 to drive cytoplasmic relocalization and convert p21 into a growth/survival factor (PMID:11231573, PMID:12431783), Cdk5 and Lats2 phosphorylate S130/S146 to trigger its degradation (PMID:27909065, PMID:23886938), and proteolytic cleavage by proteinase 3 strips its nuclear localization and promotes apoptosis (PMID:14675038). This localization control is the key determinant of whether p21 acts as a nuclear tumor suppressor or a cytoplasmic survival factor. Physiologically, p21 is the molecular switch governing hematopoietic stem cell quiescence, with its loss causing HSC over-proliferation and exhaustion under stress (PMID:10710306), and it supports Langerhans cell survival and DNA repair after irradiation (PMID:26343536).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1993 High

    Established the central question of how p53 enforces growth suppression by identifying p21/WAF1 as a direct p53 transcriptional target and growth-suppressive effector.

    Evidence Yeast enhancer trap, promoter-reporter assay, and cDNA overexpression in human tumor cells

    PMID:8242752

    Open questions at the time
    • Did not define the biochemical mechanism by which p21 suppresses growth
    • Did not address p53-independent regulation
  2. 1994 High

    Showed p21 induction is not exclusively a p53/DNA-damage response, separating mitogen-driven immediate-early induction from damage-induced p53-dependent induction.

    Evidence p53-null MEFs with growth-factor stimulation, gamma-irradiation, and mRNA kinetics with cycloheximide

    PMID:8012956

    Open questions at the time
    • Did not identify the transcription factors mediating growth-factor induction
    • Functional consequence of immediate-early induction unresolved
  3. 1995 High

    Resolved how a single inhibitor blocks the cell cycle by dissecting two independent inhibitory domains—an N-terminal CDK-inhibitory module and a C-terminal PCNA-binding module.

    Evidence Domain deletion/overexpression in mammalian cells plus in vitro PCNA-dependent replication and CDK inhibition assays

    PMID:7753174

    Open questions at the time
    • Did not quantify PCNA binding affinity
    • Did not establish which domain dominates in physiological contexts
  4. 1995 High

    Extended p21 function beyond proliferation control to terminal differentiation, showing p53-independent expression across lineages and that MyoD is sufficient but dispensable for myogenic induction.

    Evidence p53-null and MyoD/myogenin double-knockout mice with in situ hybridization and developmental expression analysis

    PMID:7863329

    Open questions at the time
    • Did not identify the factors driving p21 in non-myogenic differentiation
    • Causal role of p21 in differentiation vs. correlation not fully resolved
  5. 1996 High

    Defined the molecular basis of C-terminal replication inhibition by showing p21 binds PCNA at nanomolar affinity and competitively displaces Fen1 from the replication complex.

    Evidence In vitro Kd measurement, co-IP in cell extracts, and in vivo overexpression

    PMID:8876181

    Open questions at the time
    • Did not address competition with other PCNA partners in vivo
    • Did not link Fen1 displacement to specific repair outcomes
  6. 1997 Medium

    Connected upstream developmental signaling to p21-mediated CDK2 inactivation, showing Gax induces p21 p53-independently and that p21 is required for Gax-driven arrest.

    Evidence Adenoviral Gax overexpression, p21-null fibroblasts, CDK2 activity assay, and co-IP

    PMID:9224717

    Open questions at the time
    • Mechanism of Gax-driven p21 transcription not defined
    • Single-lab study
  7. 1997 High

    Refined the N-terminal mechanism by showing p21 and Cdc25A compete for cyclin-CDK complexes through the Cy motif, establishing a regulatory tug-of-war over CDK activation.

    Evidence In vitro binding, Cy-motif mutagenesis, competitive peptide inhibition, and Xenopus extract replication assay

    PMID:9234691

    Open questions at the time
    • In vivo stoichiometry of the competition not established
    • Did not connect to specific physiological arrest signals
  8. 1998 Medium

    Identified a naturally occurring C-terminally truncated p21 variant lacking PCNA-binding and NLS, linking loss of these domains to monomeric, cytoplasmic, non-inhibitory p21 in transformed cells.

    Evidence SDS-PAGE mobility shift, co-IP with Cdk2/PCNA, gel filtration, and subcellular fractionation

    PMID:9546435

    Open questions at the time
    • Protease/mechanism generating p21delta not identified
    • Functional contribution to transformation not directly tested
  9. 1999 Medium

    Mapped a transcriptional route for oncogenic Ras to p21 via Sp1-binding promoter elements and a separate MAPK-dependent posttranscriptional route.

    Evidence Conditional Ras expression, promoter deletion/point mutants, luciferase reporter, and EMSA

    PMID:10597223

    Open questions at the time
    • Did not resolve the posttranscriptional MAPK mechanism
    • Single-lab study
  10. 2000 High

    Established p21 as the physiological switch for hematopoietic stem cell quiescence, defining an organismal role distinct from acute damage responses.

    Evidence p21-knockout mice, serial bone marrow transplantation, cell cycle analysis, and myelotoxic injury

    PMID:10710306

    Open questions at the time
    • Upstream signals setting p21 levels in HSCs not defined
    • Did not address localization control in stem cells
  11. 2000 Medium

    Revealed reciprocal p21–c-Myc antagonism, showing p21 both inhibits PCNA-dependent polymerase delta and blocks c-Myc-Max transcriptional activation.

    Evidence Reciprocal co-IP, in vitro DNA synthesis assay, EMSA, and reporter assay

    PMID:10744738

    Open questions at the time
    • In vivo significance of the Myc interaction not established
    • Single-lab study
  12. 2001 High

    Identified phosphorylation-driven relocalization as the basis of p21's dual identity: Akt phosphorylates Thr145 to send p21 to the cytoplasm and convert it into a growth promoter.

    Evidence Co-IP, dominant-negative Akt rescue, phosphorylation mapping, fractionation/IF in HER-2/neu cells

    PMID:11231573

    Open questions at the time
    • Did not define cytoplasmic effectors mediating growth promotion
    • Quantitative contribution vs. nuclear pool unclear
  13. 2002 High

    Generalized Thr145-driven relocalization by identifying Pim-1 as a second kinase that phosphorylates this site and drives cytoplasmic p21.

    Evidence In vitro kinase assay, pull-down, co-transfection with WT/kinase-dead Pim-1, phosphoamino acid analysis, and localization

    PMID:12431783

    Open questions at the time
    • Relative contribution of Akt vs. Pim-1 in vivo not resolved
    • Downstream cytoplasmic function not addressed
  14. 2003 Medium

    Placed GADD34 upstream of p21 by showing it enhances p53 Ser15 phosphorylation and p53-dependent p21 transcription.

    Evidence GADD34 transfection, p53 Ser15 phosphorylation assay, p21 promoter reporter, and GADD34-null MEFs

    PMID:14635196

    Open questions at the time
    • Mechanism by which GADD34 promotes p53 phosphorylation not detailed
    • Single-lab study
  15. 2004 Medium

    Showed chromatin remodeling drives p21 induction, with BRG1/SWI-SNF activating pRb through p21 upregulation to enforce growth arrest and senescence.

    Evidence BRG1 expression, p21 promoter analysis, CDK/cyclin measurements, and senescence/growth-arrest assays

    PMID:14729964

    Open questions at the time
    • Direct BRG1 occupancy at the p21 promoter not shown
    • Single-lab study
  16. 2004 Medium

    Demonstrated proteolytic regulation of p21 localization, with proteinase 3 cleavage between Thr80/Gly81 stripping nuclear p21 and promoting endothelial apoptosis.

    Evidence Immunoblotting, IF, flow cytometry, PR3 treatment of HUVECs, and cleavage-site mapping

    PMID:14675038

    Open questions at the time
    • Physiological context of PR3-mediated cleavage limited to endothelium
    • In vivo relevance not established
  17. 2005 High

    Defined degradative control of p21 by showing SCF(Skp2) ubiquitinates C-terminal lysines in a manner requiring cyclin E-CDK2 docking through the RXL and FNF motifs.

    Evidence In vitro and in vivo ubiquitination assays with mutagenesis of recruitment motifs and lysines

    PMID:16262255

    Open questions at the time
    • Cell-cycle timing of Skp2-mediated turnover not fully defined
    • Other ubiquitin ligases not excluded
  18. 2005 Medium

    Added a lineage-specific transcriptional inducer by showing Mitf activates p21 and induces Rb-dependent G1 arrest, cooperating with Rb1.

    Evidence Mitf overexpression, p21 promoter reporter, Mitf-Rb1 co-IP, and cell cycle analysis

    PMID:15716956

    Open questions at the time
    • Direct Mitf occupancy at the endogenous promoter not shown
    • Single-lab study
  19. 2007 Medium

    Uncovered p53-independent control of Rb by p21, showing ectopic p21 drives both Rb dephosphorylation and proteasomal Rb depletion.

    Evidence Ectopic p21 in multiple lines, proteasome inhibitor, p21 shRNA, and transdominant p53 inhibitor

    PMID:17486059

    Open questions at the time
    • Ubiquitin ligase mediating Rb depletion not identified
    • Single-lab study
  20. 2009 Medium

    Extended p21's arrest function into G2 by showing it sustains DNA damage-induced G2 arrest through proteasomal degradation of cyclin B1.

    Evidence p21-null cells, DNA damage, cyclin B1 measurement, proteasome inhibitor rescue, and cell cycle analysis

    PMID:19158493

    Open questions at the time
    • Mechanism linking p21 to cyclin B1 degradation not defined
    • Single-lab study
  21. 2009 Medium

    Defined epigenetic silencing of p21 by CTIP2-recruited HDACs and SUV39H1 deposition of H3K9me3 at the promoter.

    Evidence ChIP, SUV39H1 inhibitor (chaetocin), promoter reporter, and co-IP of CTIP2 with HDACs/SUV39H1

    PMID:19581932

    Open questions at the time
    • Signals recruiting CTIP2 to the promoter not defined
    • Single-lab study
  22. 2012 Medium

    Placed Trim71 upstream of Cdkn1a in ESC cell-cycle control, repressing p21 via Argonaute2/miRNA to promote the G1-S transition.

    Evidence Trim71-Ago2 co-IP, Trim71 knockdown, Cdkn1a reporter, cell cycle analysis, and epistasis rescue by Cdkn1a depletion

    PMID:22735451

    Open questions at the time
    • Specific miRNAs targeting Cdkn1a not identified
    • Single-lab study
  23. 2013 Medium

    Linked p21 turnover to apoptosis decisions, showing Chk1-activated Lats2 phosphorylates S146 after UV to degrade p21 and de-repress caspase-3.

    Evidence In vitro kinase assay, site mutagenesis, UV irradiation, caspase activity assays, and overexpression/knockdown

    PMID:23886938

    Open questions at the time
    • Generality beyond UV stress not established
    • Single-lab study
  24. 2016 Medium

    Showed S130 phosphorylation by Cdk1/cyclin B1 during mitosis tunes p21 stability and CDK affinity to ensure proper mitotic duration and chromosome segregation.

    Evidence In vitro kinase assay, S130A mutant, mitotic duration, and chromosome segregation analysis

    PMID:27384476

    Open questions at the time
    • In vivo phenotype of S130 phosphorylation loss not assessed in animals
    • Single-lab study
  25. 2016 Medium

    Identified Cdk5 as a Cdk2-independent S130 kinase that degrades nuclear p21 in S-phase to promote cancer cell growth.

    Evidence In vitro kinase assay, S130A mutant, proteasome inhibitor, growth assay, fractionation, and clinical correlation

    PMID:27909065

    Open questions at the time
    • Relationship between Cdk5- and Cdk1-mediated S130 phosphorylation not resolved
    • Single-lab study
  26. 2016 Medium

    Demonstrated a non-canonical survival role, with p21 required for Langerhans cell survival, DNA repair, migration, and Treg induction after irradiation.

    Evidence Cdkn1a-/- mice, IR, apoptosis and DNA-damage markers, MHC-II expression, lymph node migration, and Treg quantification

    PMID:26343536

    Open questions at the time
    • Molecular basis of the survival/repair function in LCs not defined
    • Single-lab study
  27. 2021 Medium

    Added RNA-level control by showing NSUN2-deposited m5C and the ALYREF reader promote CDKN1A mRNA nuclear export and p21 protein expression.

    Evidence NSUN2 knockdown, ALYREF-CDKN1A RIP, nuclear/cytoplasmic fractionation, Western blot, and cell cycle analysis

    PMID:34570675

    Open questions at the time
    • m5C site mapping on CDKN1A mRNA not detailed
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the many competing inputs—transcriptional inducers/silencers, RNA-export control, multi-site phosphorylation, ubiquitination, and proteolysis—are quantitatively integrated to set the nuclear vs. cytoplasmic p21 pool that decides between tumor suppression and survival in a given cell.
  • No unified quantitative model of p21 localization control
  • Context-dependent dominance of competing kinases/ligases unknown
  • Cytoplasmic anti-apoptotic effectors not molecularly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-69306 DNA Replication 2
Partners
AKT1CDC25ACDK2FEN1PCNAPIM1SKP2TP53
Complex memberships
PCNA (binding partner)SCF(Skp2) ubiquitin ligase (substrate)cyclin E-Cdk2 complex (binding partner)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 WAF1/p21 is a direct transcriptional target of wild-type p53: a p53-binding site was identified 2.4 kb upstream of WAF1 coding sequences, and the WAF1 promoter conferred p53-dependent inducibility upon a heterologous reporter gene. Introduction of WAF1 cDNA suppressed growth of human tumor cells in culture. Yeast enhancer trap, promoter-reporter assay, cDNA overexpression in human tumor cell lines Cell High 8242752
1995 p21Cip1 contains two functionally independent cell-cycle inhibitory domains: an N-terminal CDK-inhibitory domain and a C-terminal PCNA-binding/inhibitory domain. When separately overexpressed in mammalian cells, each domain independently prevents DNA replication. Domain deletion/overexpression in mammalian cells, in vitro PCNA-dependent DNA replication assay, CDK inhibition assay Nature High 7753174
1994 p21/WAF1/CIP1 can be induced through a p53-independent pathway: serum and growth factors (PDGF, FGF, EGF but not insulin) induce WAF1 in quiescent p53-deficient fibroblasts as an immediate-early gene, whereas DNA damage (gamma-irradiation) induces WAF1 via a p53-dependent pathway. p53 knockout mouse embryonic fibroblasts, growth factor stimulation, gamma-irradiation, mRNA kinetics with cycloheximide Cancer research High 8012956
1995 p21Cip1 is expressed in a p53-independent manner during terminal differentiation of multiple cell lineages (skeletal muscle, cartilage, skin, nasal epithelium). MyoD is sufficient but not necessary for p21 induction in myogenic cells, as p21 is still expressed in MyoD/myogenin double-knockout mice. p53 knockout and MyoD/myogenin knockout mice, in situ hybridization, expression analysis during development Science High 7863329
2001 Akt phosphorylates p21Cip1/WAF1 at threonine 145, resulting in cytoplasmic localization of p21 and promotion of cell growth. HER-2/neu-mediated activation of Akt drives this phosphorylation; blocking Akt with dominant-negative Akt restores nuclear localization and growth-inhibiting activity of p21. Co-IP, dominant-negative Akt expression, phosphorylation assay, subcellular fractionation/immunofluorescence, HER-2/neu-overexpressing cell lines Nature cell biology High 11231573
1996 p21Cip1/WAF1 competes with Fen1 for binding to PCNA: p21 binds PCNA with Kd ~10 nM (3 molecules per PCNA trimer) and prevents formation of a PCNA-Fen1 complex, thereby disrupting Fen1 recruitment to the DNA replication complex. Overexpression of p21 disrupts Fen1-PCNA interaction in vivo. In vitro binding assay (Kd measurement), co-immunoprecipitation in cell extracts, overexpression in vivo Proceedings of the National Academy of Sciences of the United States of America High 8876181
2002 Pim-1 kinase associates with p21Cip1/WAF1 and phosphorylates it at Thr145 in vivo, resulting in cytoplasmic localization of p21. Co-transfection of kinase-dead Pim-1 results in nuclear localization of p21, whereas wild-type Pim-1 drives cytoplasmic localization. In vitro kinase assay, pull-down assay, immunoprecipitation, co-transfection with wild-type and kinase-dead Pim-1, phosphoamino acid analysis, subcellular localization Biochimica et biophysica acta High 12431783
2000 p21cip1/waf1 functions as the molecular switch governing hematopoietic stem cell (HSC) quiescence: p21-knockout mice show increased HSC proliferation and number under homeostasis, and serial transplantation of p21-/- bone marrow leads to HSC exhaustion and hematopoietic failure under stress. p21 knockout mice, serial bone marrow transplantation, cell cycle analysis, myelotoxic injury model Science High 10710306
1997 p21CIP1 mediates G1-S cell cycle arrest downstream of the homeodomain protein Gax: Gax overexpression induces p53-independent upregulation of p21, leading to p21 association with cdk2 complexes and decreased cdk2 activity. Fibroblasts deficient in p21 are not susceptible to growth inhibition or cdk2 inactivation by Gax. Recombinant adenovirus-mediated Gax overexpression, p21 knockout fibroblasts, cdk2 activity assay, co-immunoprecipitation Genes & development Medium 9224717
1997 p21CIP1 and Cdc25A compete for binding to cyclin-cdk complexes via a cyclin-binding Cy motif. A p21-derived Cy-motif peptide competitively disrupts Cdc25A-cyclin-cdk2 association and inhibits cdk2 dephosphorylation. p21 inhibits Cdc25A-mediated cyclin E-cdk2 association, while Cdc25A protects cyclin-cdk from p21 inhibition. In vitro binding assay, Cy-motif mutagenesis, competitive peptide inhibition, Xenopus egg extract DNA replication assay, co-immunoprecipitation Molecular and cellular biology High 9234691
2000 c-Myc directly binds the C-terminal region of p21 and partially relieves p21-mediated inhibition of PCNA-dependent DNA polymerase delta activity. Conversely, p21 binding to the Myc box II region of c-Myc blocks c-Myc-Max complex formation on E-box elements, suppressing c-Myc transcriptional activation. Co-immunoprecipitation, in vitro DNA synthesis assay, electrophoretic mobility shift assay (EMSA), transcription reporter assay The Journal of biological chemistry Medium 10744738
2005 SCF(Skp2) ubiquitin ligase ubiquitinates p21Cip1/WAF1 in a manner that requires functional interaction of p21 with the cyclin E-Cdk2 complex. Mutation of both the cyclin E recruitment motif (RXL) and the Cdk2-binding motif (FNF) at the N-terminus of p21 abolishes ubiquitination; ubiquitination occurs at four C-terminal lysine residues. In vitro ubiquitination assay, site-directed mutagenesis of p21, co-immunoprecipitation, in vivo ubiquitination assay Biochemistry High 16262255
2009 p21Cip1/WAF1 mediates DNA damage-induced G2 cell cycle arrest by promoting proteasomal degradation of cyclin B1. Cells lacking p21 or unable to upregulate p21 fail to downregulate cyclin B1 after DNA damage, cannot sustain G2 arrest, and accumulate >4N DNA content. p21-null cells, DNA damage treatment, cyclin B1 protein level analysis, proteasome inhibitor rescue, cell cycle analysis Cell cycle Medium 19158493
2007 p21(Waf1) promotes proteasomal degradation of the retinoblastoma protein Rb in a p53-independent manner: ectopic p21 in HT1080 and HCT116 cells causes both Rb dephosphorylation (activation) and Rb protein depletion via proteasome. Rb depletion after DNA damage does not occur in the absence of p21. Ectopic p21 expression, p53-independent context, proteasome inhibitor, p21 shRNA knockdown, transdominant p53 inhibitor Oncogene Medium 17486059
2013 Lats2 kinase phosphorylates p21/CDKN1A at S146 in response to UV irradiation (after being activated by Chk1 phosphorylation at S835). This phosphorylation induces degradation of p21, releases procaspase-3 inhibition, and promotes apoptosis via caspase-3 and caspase-9 activation. In vitro kinase assay, site-directed mutagenesis, UV irradiation, caspase activity assay, overexpression and knockdown Journal of cell science Medium 23886938
2016 Cdk1/cyclin B1 phosphorylates p21 at S130 during mitosis, which reduces p21 stability and its binding affinity to Cdk1/cyclin B1. Interfering with this phosphorylation (S130A mutant) results in extended mitotic duration and defective chromosome segregation. In vitro kinase assay, S130A phospho-mutant expression, mitotic duration measurement, chromosome segregation analysis Oncotarget Medium 27384476
2016 Cdk5 directly phosphorylates p21CIP1 at S130 in a Cdk2-independent manner, triggering proteasome-dependent degradation of nuclear p21 primarily in S-phase and promoting cancer cell growth. S130A-p21 mutant blocks both p21 degradation and Cdk5-induced cancer cell growth increase. In vitro kinase assay, S130A mutant, proteasome inhibitor, cell growth assay, subcellular fractionation, clinical sample correlation Cancer research Medium 27909065
2004 BRG1-containing SWI/SNF complexes activate pRb by inducing its hypophosphorylation through upregulation of p21CIP1/WAF1/SDI1. The physical interaction between BRG1 and pRb is not required for cell growth arrest or E2F target gene repression; instead, BRG1 acts via p21 induction to activate pRb. p21 upregulation by BRG1 is necessary to induce growth arrest and cell senescence. BRG1 expression in cells, p21 promoter analysis, CDK2/cyclin E/cyclin D measurement, cell senescence assay, growth arrest assay Molecular and cellular biology Medium 14729964
2009 CTIP2 recruits histone deacetylases and the methyltransferase SUV39H1 to the p21(WAF1) promoter, silencing p21 transcription via H3K9 trimethylation. Inhibition of SUV39H1 with chaetocin reduces H3K9me3 at the p21 promoter and stimulates p21 expression. ChIP assay, SUV39H1 inhibitor treatment, promoter reporter assay, co-immunoprecipitation of CTIP2 with HDACs and SUV39H1 Oncogene Medium 19581932
2004 Proteinase 3 (PR3) cleaves p21 between Thr80 and Gly81 in endothelial cells, causing loss of nuclear p21, cytoplasmic sequestration, and depletion of p21 from cyclin/CDK complexes, thereby promoting endothelial cell apoptosis. Granzyme B cleaves p21 at a different site (between Asp62 and Phe63). Immunoblotting, immunofluorescence, flow cytometry, treatment of HUVECs with PR3, cleavage site mapping Kidney international Medium 14675038
2005 Mitf (microphthalmia-associated transcription factor) activates p21(Cip1) gene expression and induces G1 cell-cycle arrest in a p21-dependent manner. Cooperation between Mitf and retinoblastoma protein Rb1 potentiates Mitf-mediated transcriptional activation. Mitf-mediated p21 induction leads to Rb1 hypophosphorylation. Mitf overexpression, p21 promoter reporter assay, co-immunoprecipitation of Mitf with Rb1, cell cycle analysis Nature Medium 15716956
1999 Ras induces p21Cip1/Waf1 transcriptionally through Sp1-binding sites (positions -83 to -54) in the p21 promoter. Mutation of both Sp1-binding sites 2 and 4 abolishes Ras-induced promoter activity. In conditional Ras-expressing cells, p21 induction is posttranscriptional via the MAPK pathway. Conditional Ras expression, p21 promoter deletion and point mutants, luciferase reporter, EMSA for Sp1/Sp3 binding Oncogene Medium 10597223
2003 GADD34 promotes p53 phosphorylation at Ser15 in a dose-dependent manner and enhances p21/WAF1 transcription via p53-dependent activation of the p21 promoter. p21 promoter activity is very low in GADD34-deficient MEFs and is restored by GADD34 transfection. GADD34 transfection, p53 phosphorylation assay (Ser15), p21 promoter-reporter assay, GADD34-deficient MEFs Journal of cellular biochemistry Medium 14635196
2021 NSUN2-mediated m5C modification of CDKN1A mRNA promotes its nuclear export via the ALYREF m5C reader, thereby upregulating p21 protein expression. NSUN2 deficiency reduces ALYREF recognition of CDKN1A mRNA, decreases mRNA export to cytoplasm, reduces p21 translation, accelerates cell cycle, and promotes adipogenesis. NSUN2 knockdown, RIP (RNA immunoprecipitation) for ALYREF-CDKN1A mRNA interaction, mRNA nuclear/cytoplasmic fractionation, Western blot, cell cycle analysis RNA biology Medium 34570675
2012 Trim71 associates with Argonaute2 and microRNAs and represses Cdkn1a expression, promoting the G1-S transition in embryonic stem cells. Trim71 knockdown prolongs G1 phase and slows ESC proliferation; this phenotype is rescued by Cdkn1a depletion, placing Trim71 upstream of Cdkn1a in the ESC cell cycle regulatory pathway. Co-immunoprecipitation of Trim71 with Ago2, Trim71 knockdown, Cdkn1a reporter assay, cell cycle analysis, epistasis rescue by Cdkn1a depletion Nature communications Medium 22735451
2016 CDKN1A/p21 is required for Langerhans cell (LC) survival and DNA repair after ionizing radiation (IR). Cdkn1a-/- LCs undergo apoptosis and accumulate DNA damage after IR, and fail to upregulate MHC class II, migrate to draining lymph nodes, or induce Treg cell accumulation, unlike wild-type LCs. Cdkn1a-/- mice, IR treatment, apoptosis assay, DNA damage markers, MHC class II expression, lymph node migration assay, Treg quantification Nature immunology Medium 26343536
2020 TFEB directly regulates basal and DNA damage-induced p21/WAF1 expression in a p53-dependent manner. TFEB depletion dramatically reduces basal p21 levels; TFEB overexpression increases p21 and delays G2/M arrest during doxorubicin-induced DNA damage, promoting cell survival. Pharmacological inhibition of p21 abrogates TFEB-mediated cell protection. TFEB knockdown and overexpression, p21 promoter reporter (implied by p53-dependent effect), doxorubicin treatment, cell cycle analysis, pharmacological p21 inhibition Cells Low 32397616
1998 A C-terminally truncated form of p21 (p21delta, lacking ~10 C-terminal amino acids including the PCNA-binding domain, second cyclin-binding domain, and NLS) is found in transformed cell lines and after high-dose UV. Unlike full-length p21, p21delta is not associated with Cdk2 or PCNA, is monomeric by gel filtration, and localizes predominantly to the cytoplasm rather than the nucleus. SDS-PAGE mobility shift analysis, co-immunoprecipitation with Cdk2 and PCNA, gel filtration chromatography, subcellular fractionation/immunofluorescence Oncogene Medium 9546435

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 WAF1, a potential mediator of p53 tumor suppression. Cell 8153 8242752
2000 Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science (New York, N.Y.) 1053 10710306
1995 p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science (New York, N.Y.) 1048 7863329
2001 Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nature cell biology 932 11231573
1994 Induction of WAF1/CIP1 by a p53-independent pathway. Cancer research 889 8012956
1995 Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1. Nature 536 7753174
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
2010 Multiple microRNAs modulate p21Cip1/Waf1 expression by directly targeting its 3' untranslated region. Oncogene 319 20190813
2005 Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression. Nature 308 15716956
1996 P21Waf1/Cip1/Sdi1 and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 297 8756825
1996 The absence of p21Cip1/WAF1 alters keratinocyte growth and differentiation and promotes ras-tumor progression. Genes & development 287 8957006
2007 Histone deacetylase inhibitors: signalling towards p21cip1/waf1. The international journal of biochemistry & cell biology 228 17412634
2019 The Multifaceted p21 (Cip1/Waf1/CDKN1A) in Cell Differentiation, Migration and Cancer Therapy. Cancers 224 31438587
2000 Laminar shear stress inhibits vascular endothelial cell proliferation by inducing cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1). Circulation research 209 10666414
2002 Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochimica et biophysica acta 173 12431783
1994 Evidence for a p53-independent pathway for upregulation of SDI1/CIP1/WAF1/p21 RNA in human cells. Molecular carcinogenesis 170 7522462
1997 p21CIP1-mediated inhibition of cell proliferation by overexpression of the gax homeodomain gene. Genes & development 155 9224717
2011 p21Cip1/Waf1 protein and its function based on a subcellular localization [corrected]. Journal of cellular biochemistry 143 21815189
2012 Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation. Nature communications 131 22735451
1996 p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex. Proceedings of the National Academy of Sciences of the United States of America 121 8876181
1997 Expression of p21 (waf1/cip1/sdi1), but not p53 protein, is a factor in the survival of patients with advanced gastric carcinoma. Cancer 119 9179052
2000 Reciprocal regulation via protein-protein interaction between c-Myc and p21(cip1/waf1/sdi1) in DNA replication and transcription. The Journal of biological chemistry 116 10744738
2015 CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation. Nature immunology 112 26343536
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1997 p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases. Molecular and cellular biology 98 9234691
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1999 Tranilast inhibits vascular smooth muscle cell growth and intimal hyperplasia by induction of p21(waf1/cip1/sdi1) and p53. Circulation research 55 10082476
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1996 Novel form of p21(WAF1/CIP1/SDI1) protein in phorbol ester-induced G2/M arrest. The Journal of biological chemistry 55 8939883
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2004 Proteinase 3 sidesteps caspases and cleaves p21(Waf1/Cip1/Sdi1) to induce endothelial cell apoptosis. Kidney international 52 14675038
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1998 Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells. Oncogene 49 9546435
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