Affinage

CDKN2A

Cyclin-dependent kinase inhibitor 2A · UniProt P42771

Round 2 corrected
Length
156 aa
Mass
16.5 kDa
Annotated
2026-04-28
130 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKN2A/p16(INK4a) is a central tumor suppressor and senescence regulator that enforces G1 cell-cycle arrest by binding CDK4 and CDK6 through its ankyrin-repeat domain, blocking their kinase activity toward Rb and displacing cyclin D–p21/p27 complexes to additionally inactivate CDK2 (PMID:8259215, PMID:10207115). The CDKN2A locus encodes two distinct products from alternative first exons: p16(INK4a), which operates in the CDK4/6–Rb pathway, and p14(ARF), which stabilizes p53 by sequestering MDM2, so that loss of the locus simultaneously disables both Rb and p53 tumor-suppressor arms (PMID:7606716, PMID:9529249). Beyond canonical CDK inhibition, p16 suppresses intracellular ROS through a p38-dependent Rb-independent mechanism, stabilizes cyclin D1, E2F1, and p21 mRNAs by inhibiting the AUF1 decay factor, directly interacts with eEF1A2 to suppress translation, and is itself inactivated by cysteine oxidation-driven amyloid formation or cleared by p62-mediated autophagy (PMID:20838381, PMID:21799732, PMID:23444377, PMID:31539802, PMID:32662244). Germline CDKN2A mutations cause familial melanoma susceptibility, and p16-expressing fibroblasts additionally promote epithelial tissue regeneration through a paracrine secretory function (PMID:7987387, PMID:36227993).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1993 High

    The fundamental molecular function of p16 was established: it physically binds CDK4 and inhibits CDK4–cyclin D catalytic activity, placing it as a stoichiometric CDK inhibitor in the Rb pathway.

    Evidence Biochemical binding assays, kinase activity assays, and co-immunoprecipitation in human cell extracts

    PMID:8259215

    Open questions at the time
    • No structural information on the binding interface
    • CDK6 inhibition not yet demonstrated
    • Tumor-suppressive role in vivo unknown
  2. 1994 High

    Positional cloning and cancer genomics established p16/CDKN2A as a bona fide tumor suppressor, with frequent homozygous deletions and point mutations across melanoma, glioma, lung cancer, leukemia, and pancreatic cancer, and germline mutations in familial melanoma kindreds linked p16 to inherited cancer susceptibility.

    Evidence Positional cloning, homozygous deletion mapping, LOH, sequencing across multiple tumor types and melanoma families

    PMID:7726912 PMID:7987387 PMID:8152487 PMID:8153634

    Open questions at the time
    • Relative contributions of p16 vs. overlapping ARF transcript not yet distinguished
    • In vivo mouse knockout data absent
  3. 1995 High

    Discovery of the dual-transcript architecture of the CDKN2A locus revealed that a single gene produces two functionally distinct proteins (p16 from exon 1α and what would become p14ARF from exon 1β), explaining why locus deletions have broader tumor-suppressive consequences than p16 loss alone.

    Evidence Molecular cloning, Northern blot, RT-PCR, and promoter analysis of the INK4a locus

    PMID:7606716

    Open questions at the time
    • Function of the alternative reading-frame product not yet known
    • Tissue-specific promoter regulation not fully mapped
  4. 1996 High

    The role of p16 in replicative senescence was demonstrated: p16 accumulates ~40-fold in senescent human fibroblasts, becomes the dominant inhibitor of both CDK4 and CDK6, and maintains Rb in its growth-suppressive hypophosphorylated form.

    Evidence Immunoprecipitation, immunodepletion, and Western blot in senescent vs. young human diploid fibroblasts

    PMID:8943005

    Open questions at the time
    • Causal requirement for p16 in senescence entry not yet proven by loss-of-function
    • Whether p16 acts independently of telomere shortening unknown
  5. 1997 High

    Genetic epistasis showed p16 is required for oncogene-induced senescence (OIS): oncogenic Ras induces p16 accumulation, and inactivation of p16 prevents Ras-induced arrest, establishing p16 as a critical barrier to oncogene-driven transformation.

    Evidence Retroviral Ras expression in primary cells with dominant-negative p53 and E1A bypass, BrdU incorporation

    PMID:9054499

    Open questions at the time
    • Whether p16 and p53/p21 arms are fully independent or partially redundant in OIS unclear
    • In vivo OIS role of p16 not yet tested
  6. 1998 High

    The second product of the CDKN2A locus, p14ARF, was shown to stabilize p53 by binding and promoting degradation of MDM2, revealing that INK4a-ARF locus deletion simultaneously disables both the CDK4–Rb and MDM2–p53 pathways.

    Evidence Co-immunoprecipitation of ARF with MDM2, p53 stabilization assays, cell cycle arrest rescue, and transformation assays in primary cells

    PMID:9529248 PMID:9529249 PMID:9724636

    Open questions at the time
    • The relative contributions of p16 and ARF to tumor suppression in specific tissues not resolved
    • Whether ARF has p53-independent functions remains open
  7. 1999 High

    Structure–function analysis of cancer-derived p16 mutations pinpointed ankyrin repeats II–III (D84, R87) as the CDK-binding cleft, and the mechanism by which p16–CDK4/6 binding displaces cyclin D–p21/p27 complexes to additionally inactivate CDK2 was established, demonstrating cross-talk between the two CKI families.

    Evidence Systematic mutagenesis with CDK binding, kinase inhibition, and G1 arrest assays; inducible p16 system with co-IP and p21-null genetic epistasis

    PMID:10207115 PMID:10491434

    Open questions at the time
    • Full crystal structure of the p16–CDK4/6 complex not yet solved in this period
    • Whether all cancer-associated mutations act solely through CDK binding loss unclear
  8. 2002 High

    Cell-type specificity of p16 function was established: p16 (not ARF) is specifically required for melanocyte senescence and associated pigmentation, while in vivo mouse models confirmed cooperative p16/ARF and p53 roles in pancreatic tumor suppression.

    Evidence Retroviral p16 vs. ARF rescue in Ink4a/Arf-null melanocytes; compound transgenic/knockout pancreatic cancer models

    PMID:11756558 PMID:11904317

    Open questions at the time
    • Mechanism of p16-dependent melanization unknown
    • Whether p16 has tissue-specific non-CDK functions unresolved
  9. 2004 High

    Single-cell analysis resolved a long-standing question by showing that telomere-dependent senescence operates through ATM–p53–p21 while p16 is activated by a parallel, telomere-independent program, establishing two distinct, coexisting senescence pathways.

    Evidence Multiparameter single-cell imaging with ATM inhibition/knockdown and telomere dysfunction foci quantification

    PMID:15149599

    Open questions at the time
    • The upstream signal activating the telomere-independent p16 pathway not identified
    • Whether the two pathways converge at any point beyond growth arrest unknown
  10. 2006 High

    A transcriptional regulatory hierarchy controlling p16 expression was delineated: c-Myc transcriptionally drives Bmi-1, a Polycomb repressor of the p16 locus; loss of p16 was also shown to cause supernumerary centrosomes through CDK-dependent centriole splitting, revealing a genomic stability function beyond G1 arrest.

    Evidence Targeted c-myc recombination with Bmi-1 ChIP; live imaging and karyotypic analysis of centrosome number in p16-depleted epithelial cells

    PMID:16464125 PMID:16537449

    Open questions at the time
    • Whether Bmi-1 is the sole PcG effector at the p16 locus unclear
    • Whether centrosome defects drive tumorigenesis in p16-null tissues not shown in vivo
  11. 2010 High

    Non-canonical functions and additional transcriptional regulators of p16 were uncovered: p16 suppresses ROS through p38 in an Rb-independent manner, the Hedgehog–GLI2 axis directly represses the p16 promoter, and EBV EBNA3A/3C epigenetically silence p16 through CtBP-dependent H3K27me3 deposition.

    Evidence ROS measurement and p38 inhibition in Cdkn2a-null cells; genome-wide siRNA screen with GLI2 ChIP at p16 promoter; conditional EBNA3C system with histone mark ChIP and CtBP-binding mutants

    PMID:20548956 PMID:20838381 PMID:21095584

    Open questions at the time
    • Rb-independent ROS mechanism downstream of p38 not molecularly defined
    • Whether GLI2-mediated p16 repression is relevant in human tumors with Hedgehog activation not established
  12. 2011 Medium

    p16 was found to regulate mRNA stability by inhibiting the AUF1 decay factor, stabilizing cyclin D1, E2F1, and p21 mRNAs, and to enforce growth arrest independently of the senescence-associated secretory phenotype (SASP), which instead requires DNA damage signaling.

    Evidence AUF1 RNA immunoprecipitation, siRNA epistasis, ARE reporter assays; ectopic p16 vs. p21 expression with cytokine secretion and paracrine activity measurements

    PMID:21799732 PMID:21880712

    Open questions at the time
    • Whether AUF1 regulation by p16 is direct or indirect not fully resolved
    • How p16 separates growth arrest from DDR-driven SASP at the molecular level unclear
  13. 2013 High

    Two new dimensions of p16 regulation and function were revealed: FOXA1 activates p16 transcription during senescence by remodeling nucleosomes, antagonizing Polycomb, and looping a distal enhancer; separately, p16 binds eEF1A2 to directly suppress translation, defining a CDK-independent tumor-suppressive mechanism.

    Evidence ChIP-seq, 3C, and nucleosome assays at the p16 locus; yeast two-hybrid identification of eEF1A2, co-IP, and luciferase translation reporter

    PMID:23443045 PMID:23444377

    Open questions at the time
    • Whether FOXA1-driven enhancer looping is conserved across cell types unknown
    • The eEF1A2 interaction lacks structural detail and independent replication
  14. 2014 High

    Causal proof that p16 epimutation drives tumorigenesis was obtained by engineering targeted p16 promoter methylation in mice, which silenced p16 during aging and increased spontaneous cancer incidence, directly linking epigenetic inactivation to tumor suppressor loss.

    Evidence Targeted genomic DNA methylation in vivo using cis-regulatory elements, bisulfite sequencing, tumor incidence analysis

    PMID:25061879

    Open questions at the time
    • Whether methylation-driven silencing is reversible in established tumors not tested
    • Contribution of concurrent ARF silencing not fully controlled
  15. 2019 High

    A novel inactivation mechanism was defined: oxidation of p16's single cysteine residue drives disulfide-dependent dimerization and amyloid fibril formation, abolishing CDK4/6 inhibitory activity and providing a biochemical link between oxidative stress and p16 tumor-suppressor loss.

    Evidence In-cell and in vitro cysteine oxidation, NMR, electron microscopy of amyloid fibrils, amyloid dye binding, CDK4/6 kinase assays

    PMID:31539802

    Open questions at the time
    • Whether p16 amyloid forms in human tumors in vivo not demonstrated
    • Contribution of the marginal thermodynamic stability of p16 to amyloid propensity in living cells not quantified
  16. 2020 High

    A degradation pathway for p16 was identified: under stress, p16 is recruited to acidic cytoplasmic vesicles and cleared by p62-mediated selective autophagy through the lysosome, providing a regulated turnover mechanism for p16 protein levels.

    Evidence Endogenous p16-mCherry reporter live imaging, lysosomal and autophagy inhibitors, p62 siRNA, LC3-II co-localization

    PMID:32662244

    Open questions at the time
    • Whether autophagic p16 clearance contributes to senescence bypass in tumors unknown
    • The ubiquitin-ligase or signal that triggers p62 recognition of p16 not identified
  17. 2022 High

    Two major conceptual advances redefined p16 biology: ADAR1 was shown to post-transcriptionally suppress p16 translation via a SIRT1–HuR axis during aging, and p16-expressing fibroblasts were found to reside at the epithelial–stromal interface and promote tissue regeneration through a secretory function, demonstrating that p16 has beneficial roles beyond tumor suppression.

    Evidence ADAR1 knockout, HuR RIP, SIRT1 mRNA stability assays in vitro and in vivo; ultrasensitive p16 reporter mouse with cell ablation and lung injury models

    PMID:35851616 PMID:36227993

    Open questions at the time
    • The identity of p16+ fibroblast secreted factors driving regeneration is unknown
    • Whether ADAR1-SIRT1-p16 axis operates in epithelial cells or is fibroblast-specific unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the molecular identity of the telomere-independent signal that activates p16 during aging, the structural basis of the p16–eEF1A2 interaction, whether oxidation-driven p16 amyloid forms in human tumors in vivo, the specific secreted factors from p16+ fibroblasts that promote regeneration, and the extent to which CDK-independent functions of p16 (ROS regulation, mRNA stability, translational suppression) contribute to tumor suppression versus tissue homeostasis.
  • Upstream activator of telomere-independent p16 expression unidentified
  • p16 amyloid not yet detected in tumor tissue
  • Secretome of p16+ regenerative fibroblasts uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005764 lysosome 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1640170 Cell Cycle 6 R-HSA-1643685 Disease 5 R-HSA-4839726 Chromatin organization 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 1
Partners
AUF1BMI1CDK4CDK6EEF1A2FOXA1GLI2SQSTM1

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 p16 (CDKN2A) was identified as a protein that binds specifically to CDK4 and inhibits the catalytic activity of CDK4/cyclin D complexes, acting in a regulatory feedback circuit with CDK4, D-type cyclins, and retinoblastoma protein. Biochemical binding assays, kinase activity assays, co-immunoprecipitation Nature High 8259215
1994 The MTS1/p16 gene was identified as a tumor suppressor frequently deleted or mutated across a wide range of human cancers, and encodes the CDK4 inhibitor p16. Positional cloning, homozygous deletion mapping, PCR, Southern blot, sequencing Science High 8153634
1994 The CDK4-inhibitor gene (p16/CDKN2A) is frequently deleted or rearranged in melanomas, gliomas, lung cancers, and leukemias; germline nonsense mutation was found in dysplastic nevus syndrome, establishing it as a tumor suppressor. PCR, Southern blot, positional cloning, sequencing Nature High 8152487
1994 p16 is frequently somatically mutated (homozygous deletions and point mutations) in pancreatic adenocarcinoma, with coexistent inactivation of p16 and p53 being common, suggesting a role in CDK4/cyclin D regulation in pancreatic cancer. LOH analysis, sequencing, Southern blot, PCR of tumor xenografts and cell lines Nature genetics High 7726912
1994 Germline p16 mutations (missense, nonsense, splice site) were identified in familial melanoma kindreds, establishing p16 as the familial melanoma susceptibility gene. Germline sequencing, SSCP, linkage analysis Nature genetics High 7987387
1995 The p16 locus produces two transcripts from separate promoters: one encoding p16 (using exon 1α) and a previously undescribed form with a different exon 1 (exon 1β), with expression ratios regulated in a tissue-specific and cell-cycle-specific manner; transcription from one promoter is regulated at least in part by retinoblastoma gene product. Molecular cloning, Northern blot, RT-PCR, promoter analysis Cancer research High 7606716
1996 In replicative senescence of human diploid fibroblasts, p16 protein accumulates ~40-fold and forms complexes with both CDK4 and CDK6, becoming the major CDK inhibitor for both kinases and maintaining Rb in its hypophosphorylated (active) state. Immunoprecipitation, immunodepletion, Western blot, radiolabeling of senescent cell extracts Proceedings of the National Academy of Sciences High 8943005
1997 Oncogenic Ras induces premature senescence in primary cells accompanied by accumulation of p53 and p16INK4a; inactivation of either p53 or p16 (or E1A expression) prevents Ras-induced arrest, placing p16 as a required effector of oncogene-induced senescence. Retroviral gene transfer, genetic epistasis with dominant-negative p53 and E1A, cell cycle analysis, BrdU incorporation Cell High 9054499
1997 In melanoma cell lines, p16 binds CDK4 and CDK6 in vitro and in vivo, inhibiting their kinase activity; mutations that abolish this interaction underlie functional loss of p16 tumor suppressor activity. Immunoprecipitation, Western blot, CDK4/CDK6 co-precipitation assay, Northern blot, methylation PCR Cancer research High 9354451
1998 The ARF product of the CDKN2A locus (p14ARF) activates p53 by binding MDM2 and promoting MDM2 degradation; deletion of the INK4a-ARF locus therefore simultaneously impairs both the p16INK4a/CDK4/RB and ARF/MDM2/p53 tumor suppressor pathways. Co-immunoprecipitation, ectopic expression, cell cycle arrest assays, MDM2 proteolysis assays Cell High 9529249
1998 p19ARF (mouse) and p14ARF (human) physically interact with MDM2, block MDM2's neutralization of p53, and thereby suppress oncogenic transformation; this places INK4a/ARF at the intersection of both the RB and p53 pathways. Co-immunoprecipitation, ectopic expression in primary cells, transformation assays, p53 stabilization assays Cell High 9529248
1998 p14ARF (human CDKN2A beta transcript product) induces p53-dependent cell cycle arrest in both G1 and G2/M by binding MDM2 and stabilizing p53; this arrest is abrogated by HPV E6 but not by dominant-negative p53, and p53 negatively regulates p14ARF expression in a feedback loop. Ectopic expression, co-immunoprecipitation, cell cycle FACS analysis, p53/MDM2 Western blot The EMBO journal High 9724636
1999 Biologic analysis of 16 cancer-associated p16 missense mutants showed that functional defects in CDK binding, kinase inhibition, and G1 arrest are concentrated in ankyrin repeats II and III (especially the D84, R87 region), identifying the CDK-binding cleft of the ankyrin domain as critical for p16 function; some mutants retain CDK4/6 binding but lose G1 arrest activity. CDK4/CDK6 binding assays, kinase inhibition assays, G1 arrest by flow cytometry, mutagenesis Journal of the National Cancer Institute High 10491434
1999 p16(INK4a) inhibition of CDK4/6 displaces cyclin D1, p27, and p21 from CDK4/6 complexes, causing p21 to redistribute to cyclin E-CDK2, inactivating CDK2; p21-mediated inhibition of CDK2 contributes to the cell cycle arrest imposed by p16, demonstrating mechanistic cooperation between the p16/RB and p14ARF/p53 pathways. Inducible p16 expression system, co-immunoprecipitation, kinase assays, p21-null cell lines by homologous recombination, BrdU labeling Molecular and cellular biology High 10207115
1999 Conformational analysis by NMR revealed that p16(INK4a) is marginally stable (ΔG ~1.94 kcal/mol) with limited pico-to-nanosecond flexibility but significant conformational dynamics on the minutes-to-hours timescale detected by H/D exchange, indicating that kinetic rather than thermodynamic stability governs its aggregation tendency. NMR (1H-15N NOE, H/D exchange), denaturation experiments Journal of molecular biology Medium 10556039
2000 p16(INK4a) is required for p53-independent G1 arrest in response to DNA-damaging agents including topoisomerase I and II inhibitors, demonstrating a role for p16 in a DNA-damage checkpoint beyond preventing Rb phosphorylation. Cell cycle analysis, DNA damage treatment of p16-expressing vs. deficient cells Cell biochemistry and biophysics Medium 11325039
2001 Regulatory elements controlling p16(INK4a) overexpression in senescent fibroblasts were mapped to the -622 to -280 bp region of its promoter; a novel negative regulatory element (ITSE, at -491 to -485 bp) binds a 24-kDa protein highly expressed in young cells that represses p16 transcription; a GC-rich positive element at -466 to -451 bp accounts for 91% of promoter activity in senescent cells. EGFP reporter system, 5'-deletion analysis, DNase I footprinting, EMSA, Southwestern blotting The Journal of biological chemistry Medium 11598130
2001 In mammary gland involution, p16(INK4a) directly regulates the transition from E2F3 to E2F4 as the major E2F DNA-binding activity; p16's contribution to growth arrest during involution is independent of cyclin D1, and transgenic cyclin D1 prevents the normal p16 pulse, which is reversible by restoring p16 but not in INK4A/ARF-/- mice. INK4A/ARF knockout mice, cyclin D1 transgenic mice, p16 transgenic mice, E2F EMSA, in vivo mammary gland analysis Cancer research High 11751403
2002 In melanocytes, p16 (not ARF) is specifically required for replicative senescence and associated hyperpigmentation; restoration of p16 in Ink4a/Arf-/- melanocytes induced growth arrest, heavy melanization, and beta-galactosidase expression, whereas ARF restoration caused apoptosis without senescence. Retroviral gene restoration, senescence assays (beta-gal, growth curves), pigmentation spectrophotometry, immunoblotting Journal of the National Cancer Institute High 11904317
2002 In pancreatic neoplasia driven by TGF-alpha in mice, p16(Ink4a) inactivation (by LOH, intragenic mutation, or promoter hypermethylation) was a common feature; compound mutant mice with both Ink4a/Arf and p53 mutations showed synergistic tumor development, establishing obligate roles for p16(Ink4a) and p19(Arf)-p53 in pancreatic tumor suppression. Compound transgenic/knockout mouse crosses, LOH analysis, methylation PCR, histopathology, tumor incidence statistics Molecular and cellular biology High 11756558
2003 p16(INK4a) induces erythroid differentiation and apoptosis in erythroid lineage cells (K562) by arresting the cell cycle at G0/G1, with apoptosis associated with downregulation of bcl-x and nuclear NF-κB; these effects were not observed with other G1-arresting agents, indicating a specific p16 function beyond G1 arrest. INK4a gene transfection, flow cytometry, Western blot for bcl-x and NF-κB, differentiation assays Experimental hematology Medium 12763133
2004 p16(INK4a) deficiency contributes to, but is not solely required for, replicative senescence in human fibroblasts; p16-defective fibroblasts (from CDKN2A mutation carriers) have extended lifespan but arrest at an intermediate state between M1 and M2, demonstrating p16 cooperates with other factors in implementing the senescent state. Primary fibroblasts from CDKN2A mutation carriers, Bmi1 and DNA tumor virus oncoprotein bypass experiments, growth curve analysis Experimental cell research Medium 15265701
2004 Telomere shortening triggers senescence through ATM-p53-p21, but not p16; p16 is upregulated in a telomere- and DNA damage-independent manner in a subset of cells, demonstrating that distinct, parallel senescence programs (telomere-dependent and p16-dependent) co-exist in senescent cultures. Multiparameter single-cell detection, ATM inhibition/knockdown, telomere dysfunction foci, p16 immunofluorescence Molecular cell High 15149599
2006 Loss of p16(INK4a) generates supernumerary centrosomes through centriole pair splitting, leading to multipolar spindles, aneuploidy, and genomic instability; p16 cooperates with p21 through CDK activity regulation to prevent centriole splitting. Immunocytochemistry, quantitative immunofluorescence, karyotypic analysis, time-lapse microscopy in human diploid epithelial cells and fibroblasts PLoS biology High 16464125
2006 Reduced c-Myc signaling triggers telomere-independent senescence mediated by p16(INK4a); c-Myc directly transcriptionally controls Bmi-1, a Polycomb repressor of the p16 locus; reduced Myc reduces Bmi-1, thereby de-repressing p16 expression and promoting senescence. Targeted homologous recombination of c-myc, Bmi-1 ChIP and expression analysis, p16 knockdown experiments Proceedings of the National Academy of Sciences High 16537449
2010 p16(INK4a) has an Rb-independent role in regulating intracellular reactive oxygen species (ROS); knockdown of p16 increased ROS and oxidative DNA damage in a p38 stress kinase-dependent and Rb-independent manner; this effect was particularly pronounced in melanocytes, potentially explaining melanoma predisposition. siRNA knockdown, ROS measurement, 8-oxoguanine quantification, Cdkn2a-deficient mouse fibroblasts, Rb knockdown comparison Oncogene Medium 20838381
2010 The Hedgehog pathway component SUFU suppresses p16(INK4a); a fragment of the Hh-responsive GLI2 transcription factor directly binds and inhibits the p16 promoter; cells with primary cilia (PC) have lowest p16 expression; Hh suppresses p16 through both PC-dependent and -independent routes. Genome-wide siRNA screen, ChIP of GLI2 at p16 promoter, primary cilium identification by immunofluorescence, p16 reporter assays Molecular cell High 21095584
2010 EBV proteins EBNA3A and EBNA3C cooperate to epigenetically repress p16(INK4a) by maintaining H3K27me3 (repressive) and reducing H3K4me3 (activating) marks at the p16 locus; this repression requires interaction of both EBNA3A and EBNA3C with the co-repressor CtBP. Conditional EBNA3C LCL system, ChIP for H3K27me3/H3K4me3, recombinant EBV with EBNA3A/3C CtBP-binding mutants PLoS pathogens High 20548956
2011 p16(INK4a) induces senescence growth arrest without a senescence-associated secretory phenotype (SASP); the SASP is a DNA damage response separable from p16-mediated growth arrest; p16 expression during replicative senescence indirectly suppresses the SASP by limiting DNA damage accumulation. Ectopic p16 and p21 expression, ionizing radiation and oncogenic RAS senescence models, cytokine secretion assays, paracrine activity assays The Journal of biological chemistry High 21880712
2011 p16(INK4a) positively regulates cyclin D1 and E2F1 expression by suppressing the mRNA decay-promoting protein AUF1; AUF1 binds cyclin D1 and E2F1 mRNAs and promotes their degradation; p16 inhibits AUF1, stabilizing these mRNAs; E2F1 downstream of p16/AUF1 mediates p16-dependent regulation of apoptosis. AUF1-RNA immunoprecipitation, siRNA knockdowns, genome-wide microarray, E2F1 3'UTR ARE reporter assays PloS one Medium 21799732
2013 FOXA1 activates p16(INK4a) transcription during senescence through multiple mechanisms: direct sequence-specific transcriptional activation, reduction of nucleosome density at the p16 promoter, antagonism of Polycomb repression at the p16 locus, and looping of a ~150 kb distal enhancer to the promoter. ChIP-seq, chromatin conformation capture (3C), nucleosome remodeling assays, knockdown in senescent fibroblasts The EMBO journal High 23443045
2013 p16(INK4a) interacts directly with the translation elongation factor eEF1A2 (identified by yeast two-hybrid screening); ectopic p16 decreases eEF1A2 expression and inhibits protein synthesis; p16-eEF1A2 interaction suppresses cancer cell growth by downregulating translational activity. Yeast two-hybrid screening, co-immunoprecipitation, luciferase translation reporter, Xenopus embryo microinjection, morpholino knockdown Journal of cell science Medium 23444377
2013 p16(INK4a) positively regulates p21(WAF1) expression by suppressing AUF1-dependent degradation of CDKN1A mRNA; AUF1 binds CDKN1A mRNA in a p16-dependent manner via AU-rich elements in the 3'UTR; concurrent knockdown of both AUF1 and p16 restores normal p21 expression. AUF1 RNA immunoprecipitation with qRT-PCR, siRNA co-knockdown, ARE-EGFP reporter, ectopic p16 expression PloS one Medium 23894605
2014 Targeted p16(Ink4a) promoter hypermethylation in mice in vivo led to transcriptional suppression during aging, increased incidence of spontaneous cancers, and accelerated tumor onset when combined with a germline p16 mutation, providing direct causal evidence that p16 epimutation drives tumorigenesis. Targeted genomic DNA methylation in vivo using cis-acting regulatory elements, tumor incidence statistics, bisulfite sequencing The Journal of clinical investigation High 25061879
2015 p16(INK4a) represses α-klotho promoter activity by blocking E2F function; ablation of p16(INK4a) restores α-klotho expression in hypomorphic kl(kl/kl) mice and rescues accelerated aging phenotypes; p16 and klotho expression are inversely correlated during aging, revealing a new regulatory role for p16 in aging via klotho suppression. p16 knockout crosses with klotho mutant mice, promoter reporter assays, expression correlation during aging Nature communications High 25923845
2015 MIR31HG lncRNA represses p16(INK4a) expression by recruiting Polycomb group proteins to the INK4A locus; during oncogene-induced senescence, MIR31HG relocates to the cytoplasm, relieving PcG repression of INK4A, allowing p16 upregulation. ChIP for PcG marks, CHART-seq of MIR31HG genomic interactions, knockdown and OIS induction experiments Nature communications High 25908244
2016 BMP-SMAD-ID signaling suppresses p16/INK4a-mediated cellular senescence, which is a major barrier to iPSC reprogramming; FOP patient fibroblasts (ACVR1 R206H hyperactivation of BMP-SMAD) show enhanced reprogramming efficiency by suppressing p16-mediated senescence via ID genes. iPSC reprogramming efficiency assays, BMP-SMAD inhibitors, inhibitory SMAD overexpression, p16 expression analysis Proceedings of the National Academy of Sciences Medium 27794120
2016 Lactate-induced Snail directly binds and inhibits the p16INK4a promoter (demonstrated by ChIP), allowing premalignant cells to escape oncogene-induced senescence; this links tumor metabolic reprogramming to p16-mediated senescence bypass. SA-β-gal assay, ChIP of Snail at p16 promoter, dual luciferase reporter, Ras activity assay Journal of experimental & clinical cancer research Medium 29482580
2016 p16INK4a induces senescence partly through upregulation of miR-141 and miR-146b-5p, which repress the mRNA-binding/decay protein AUF1; AUF1 in turn stabilizes ZEB1 mRNA, so p16-miRNA-AUF1 axis suppresses EMT by reducing ZEB1; this mechanistically links p16-mediated senescence to inhibition of cell migration. miRNA overexpression/inhibition, AUF1 RIP, ZEB1 expression analysis, wound-healing and invasion assays, AUF1 rescue experiments Molecular carcinogenesis Medium 27596953
2018 Methionyl-tRNA synthetase (MRS) stabilizes CDK4 by enhancing its interaction with a chaperone complex; p16INK4a competes with MRS for CDK4 binding, so MRS effects on CDK4 are more prominent in p16-negative cancer cells; MRS knockdown reduces CDK4 levels and causes G0/G1 arrest. CDK4 co-immunoprecipitation, MRS knockdown, cell cycle analysis, in vivo xenograft tumor assay ACS pharmacology & translational science Medium 32219202
2019 Oxidation of the single cysteine residue in p16INK4a leads to disulfide-dependent dimerization and a dramatic structural rearrangement producing amyloid fibrils (confirmed by cross-β sheet structure, diagnostic dye binding, and electron microscopy); amyloid formation abolishes p16's CDK4/6 inhibitory activity, providing a mechanism by which oxidative stress inactivates p16. In-cell and in vitro cysteine oxidation assays, NMR, electron microscopy, amyloid dye binding, CDK4/6 kinase inhibition assays Redox biology High 31539802
2020 p16INK4a is degraded by the autophagy-lysosomal pathway; stress stimuli recruit p16 to acidic cytoplasmic vesicles within 4 hours; lysosomal protease inhibitors accumulate p16 in lysosomes; p62 knockdown attenuates p16 aggregation in autolysosomes, implicating p62 as a chaperone targeting p16 to autophagosomes. Time-lapse fluorescence microscopy with endogenous p16-mCherry reporter, lysosomal inhibitors, autophagy blockers, p62 siRNA knockdown, LC3-II co-localization Aging cell High 32662244
2022 ADAR1 is post-transcriptionally downregulated by autophagic degradation during senescence; ADAR1 loss promotes senescence through p16INK4a upregulation via an RNA-editing-independent mechanism: ADAR1 sustains SIRT1 mRNA stability through HuR, and SIRT1 antagonizes p16INK4a mRNA translation; ADAR1 knockdown drives p16-dependent senescence. ADAR1 siRNA and in vivo Adar1 knockout, p16 translational reporter, HuR RIP, SIRT1 mRNA stability assays, in vivo mouse tissue aging Nature cell biology High 35851616
2022 p16INK4a expression is required in fibroblasts to enhance epithelial regeneration; p16INK4a+ fibroblasts reside in the basement membrane adjacent to epithelial stem cells and have enhanced secretory capacity to promote regeneration in response to inflammation. Ultrasensitive p16 reporter mouse engineering, cell ablation, lung injury models, flow cytometry, transcriptomics of sorted p16+ fibroblasts Science High 36227993

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 7256 17554300
1997 Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 4238 9054499
1993 A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 3482 8259215
1994 A cell cycle regulator potentially involved in genesis of many tumor types. Science (New York, N.Y.) 2777 8153634
2007 Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science (New York, N.Y.) 2225 17463246
2016 Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 2142 26840489
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