Affinage

TP53

Cellular tumor antigen p53 · UniProt P04637

Round 2 corrected
Length
393 aa
Mass
43.7 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

p53 is a tetrameric transcription factor and master tumor suppressor that integrates diverse stress signals to execute cell cycle arrest, apoptosis, senescence, and ferroptosis. Its core DNA-binding domain, a zinc-stabilized β-sandwich scaffold, recognizes specific response elements in target genes including p21, PUMA, miR-34a, SLC7A11, and MKP1, while also functioning in a transcription-independent manner by directly activating the proapoptotic protein Bax at mitochondria (PMID:8023157, PMID:14963330, PMID:25799988, PMID:17540599). p53 stability and activity are governed by an elaborate network of post-translational modifications: MDM2-mediated ubiquitination targets p53 for proteasomal degradation, counteracted by deubiquitinases HAUSP and USP10; DNA-damage-induced phosphorylation at Ser15 by ATM and DNA-PK disrupts MDM2 binding; and p300/CBP-mediated acetylation at C-terminal lysines enhances DNA binding, while SIRT1-mediated deacetylation attenuates transcriptional output (PMID:9450543, PMID:11923872, PMID:20096447, PMID:9733515, PMID:9288740, PMID:11672523). TP53 somatic mutations cluster in the conserved DNA-contact and structural residues of the core domain and are found across virtually all human tumor types; viral inactivation occurs through the HPV E6–E6AP ubiquitin ligase complex, while MDM2 gene amplification provides a non-mutational route to p53 inactivation, and alternative p53 isoforms such as Δ133p53 can dominantly antagonize full-length p53 function (PMID:1905840, PMID:2157286, PMID:1614537, PMID:16131611).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1990 High

    Establishing that viral oncoproteins physically target p53 answered how DNA tumor viruses disable tumor suppression, linking p53 to the mechanism of HPV-driven carcinogenesis.

    Evidence Co-immunoprecipitation demonstrating direct HPV E6–p53 binding

    PMID:2157286

    Open questions at the time
    • Mechanism of E6-mediated p53 degradation not yet defined
    • Whether E6 recruits a cellular ubiquitin ligase unknown
  2. 1991 High

    Systematic sequencing of TP53 across tumor types revealed that mutations concentrate in four conserved DNA-binding domain regions with carcinogen-specific spectra, establishing TP53 as the most broadly mutated gene in human cancer.

    Evidence Direct DNA sequencing of TP53 in diverse tumor panels

    PMID:1905840 PMID:2531845

    Open questions at the time
    • Why specific codons are preferential hotspots not structurally explained
    • Functional consequence of individual mutations not biochemically tested
  3. 1992 High

    Discovery that MDM2 binds p53 directly and is amplified in sarcomas identified the principal cellular negative regulator of p53, explaining how tumors inactivate p53 without TP53 mutation.

    Evidence In vitro binding of recombinant proteins; Southern blot showing MDM2 amplification in sarcomas

    PMID:1614537

    Open questions at the time
    • Whether MDM2 degrades p53 or only inhibits transactivation not distinguished
    • Structural basis of binding unknown
  4. 1993 High

    Reconstitution of the E6–E6AP ubiquitin ligase complex degrading p53 established the first defined proteolytic pathway targeting p53 and revealed E6AP as a cellular E3 ligase co-opted by HPV.

    Evidence In vitro ubiquitination with purified E1, E2, E6, E6AP, and p53

    PMID:8221889

    Open questions at the time
    • Whether analogous cellular E3 ligases target p53 in the absence of virus unknown
    • In vivo degradation kinetics not measured
  5. 1994 High

    The crystal structure of the p53 core domain bound to DNA explained why cancer mutations cluster at DNA-contact residues and zinc-coordinating positions, transforming mutational data into a structural framework.

    Evidence X-ray crystallography at 2.2 Å resolution

    PMID:8023157

    Open questions at the time
    • Structure of full-length tetrameric p53 not resolved
    • How mutations alter protein stability versus DNA contact not quantified
  6. 1996 High

    The MDM2–p53 co-crystal structure revealed that p53's transactivation helix inserts into a hydrophobic cleft on MDM2, explaining how MDM2 simultaneously blocks transcription and enabling structure-based drug design.

    Evidence X-ray crystallography of MDM2 N-terminal domain bound to p53 peptide

    PMID:8875929

    Open questions at the time
    • Full-length MDM2–p53 complex structure unavailable
    • Whether disrupting this interface suffices for p53 activation in vivo untested
  7. 1997 High

    A suite of discoveries established the core regulatory logic of p53 activation: MDM2 was shown to be a direct E3 ubiquitin ligase for p53; DNA-damage-induced phosphorylation at Ser15/Ser37 by DNA-PK disrupts MDM2 binding; and p300-mediated acetylation of C-terminal lysines stimulates DNA binding — collectively defining the PTM code that toggles p53 between latent and active states.

    Evidence In vitro ubiquitination with MDM2 and cysteine mutagenesis; in vitro DNA-PK phosphorylation with MDM2 co-IP; in vitro p300 acetylation with EMSA

    PMID:9288740 PMID:9363941 PMID:9450543

    Open questions at the time
    • Identity of the in vivo kinase for Ser15 (ATM vs DNA-PK) not resolved
    • Interplay between phosphorylation and acetylation not defined
    • Whether acetylation is required or merely potentiating in vivo unknown
  8. 1997 High

    Demonstration that oncogenic Ras triggers p53-dependent premature senescence in primary cells established senescence as a bona fide p53-mediated tumor-suppressive output distinct from apoptosis.

    Evidence Retroviral Ras expression in primary cells with p53 genetic inactivation

    PMID:9054499

    Open questions at the time
    • Specific p53 target genes mediating senescence not identified
    • Relative contribution of p53 versus p16 not fully dissected
  9. 1998 High

    Identification of ATM as the ionizing-radiation-activated kinase that phosphorylates p53 Ser15 in vivo resolved the upstream kinase question and linked p53 activation to the DNA double-strand break signaling cascade.

    Evidence In vitro kinase assay with immunoprecipitated ATM; reduced Ser15 phosphorylation in ATM-deficient cells

    PMID:9733515

    Open questions at the time
    • Whether ATM phosphorylates p53 directly or through intermediary kinases like Chk2 not fully resolved
    • UV-induced p53 activation pathway still undefined
  10. 2001 High

    Discovery that SIRT1 deacetylates p53 at Lys382 in an NAD-dependent manner established a metabolically-regulated brake on p53 activity, linking cellular metabolic state to tumor suppression.

    Evidence Co-IP; in vitro NAD-dependent deacetylase assay; catalytic-dead mutant enhancing p53-dependent apoptosis

    PMID:11672523

    Open questions at the time
    • In vivo physiological contexts where SIRT1–p53 axis is rate-limiting not defined
    • Whether other sirtuins contribute to p53 deacetylation unknown
  11. 2002 High

    Identification of HAUSP as a deubiquitinase that stabilizes p53 even in the presence of excess MDM2 revealed that p53 levels are set by a balance between ubiquitination and deubiquitination rather than by MDM2 alone.

    Evidence Mass spectrometry of p53 complexes; in vitro DUB assay; catalytic-dead mutant destabilizing p53

    PMID:11923872

    Open questions at the time
    • Whether HAUSP also deubiquitinates MDM2 (creating a regulatory triangle) not addressed
    • Signals that regulate HAUSP activity unknown
  12. 2004 High

    Two breakthroughs expanded p53's functional repertoire and therapeutic tractability: reconstitution of transcription-independent apoptosis via direct p53–Bax interaction at mitochondria, and development of Nutlin small molecules that displace p53 from MDM2 to reactivate the pathway in wild-type TP53 tumors.

    Evidence Purified p53–Bax mitochondrial permeabilization assay; Nutlin–MDM2 co-crystal structure with xenograft tumor inhibition

    PMID:14704432 PMID:14963330

    Open questions at the time
    • Relative contribution of cytosolic versus nuclear p53 to apoptosis in vivo not quantified
    • Nutlin efficacy in patients not yet demonstrated
  13. 2005 High

    Discovery of alternative p53 isoforms (p53β, Δ133p53) from an internal promoter revealed that the TP53 locus encodes functionally opposing proteins, with Δ133p53 acting as a dominant-negative inhibitor of full-length p53.

    Evidence RT-PCR; reporter assays; antisense inhibition showing dominant-negative effects

    PMID:16131611

    Open questions at the time
    • Relative abundance and tissue specificity of isoforms in normal tissues not systematically mapped
    • Whether isoforms form mixed tetramers with full-length p53 not structurally resolved
  14. 2007 High

    Identification of miR-34a as a direct p53 transcriptional target that mediates widespread gene repression extended the p53 network into non-coding RNA-based gene regulation.

    Evidence ChIP showing p53 binding at miR-34a promoter; miR-34a overexpression with expression arrays and apoptosis readout

    PMID:17540599

    Open questions at the time
    • Whether miR-34a is required for p53-mediated tumor suppression in vivo not tested genetically
    • Other p53-regulated miRNAs not systematically catalogued
  15. 2010 High

    USP10 was identified as a cytoplasmic deubiquitinase that reverses MDM2-mediated p53 ubiquitination and translocates to the nucleus upon ATM-dependent phosphorylation, adding a spatially regulated layer to p53 stabilization after DNA damage.

    Evidence In vitro DUB assay; ATM phosphorylation site mapping; subcellular fractionation; USP10 knockdown

    PMID:20096447

    Open questions at the time
    • Whether USP10 and HAUSP act redundantly or on distinct p53 pools not determined
    • Structural basis of USP10–p53 interaction unknown
  16. 2010 High

    Discovery that p53 induces the long non-coding RNA lincRNA-p21, which recruits hnRNP-K to repress hundreds of genes, established a mechanism for p53-mediated transcriptional repression through lncRNA scaffolding.

    Evidence RNA-seq; RNA immunoprecipitation for hnRNP-K; lincRNA-p21 knockdown with gene expression profiling

    PMID:20673990

    Open questions at the time
    • Whether lincRNA-p21 acts in cis or trans genome-wide not resolved
    • Contribution of lincRNA-p21 to tumor suppression in vivo not tested
  17. 2015 High

    Demonstration that p53 represses SLC7A11 to promote ferroptosis — and that an acetylation-defective p53 mutant retaining this activity still suppresses tumors — identified ferroptosis as a p53-dependent tumor-suppressive program separable from canonical cell-cycle arrest and apoptosis.

    Evidence ChIP; p53 3KR acetylation-defective mutant; SLC7A11 overexpression rescue; xenograft assays; ferroptosis death assays

    PMID:25799988

    Open questions at the time
    • Whether ferroptosis is the critical tumor-suppressive output in specific tissue contexts not defined
    • Mechanism of SLC7A11 transcriptional repression (co-repressor identity) not determined
  18. 2016 High

    Studies of the African-specific p53 S47 variant revealed selective loss of metabolic target gene induction and ferroptosis, while combined TP53/RB1 loss was shown to enable lineage plasticity in prostate cancer through SOX2, expanding p53's tumor-suppressive roles to metabolic regulation and cell fate determination.

    Evidence S47 knockin mice with spontaneous tumors and ferroptosis assays; TP53/RB1 knockout prostate cancer models with SOX2 analysis

    PMID:27034505 PMID:28059768

    Open questions at the time
    • Whether S47 variant affects immune-mediated tumor suppression not tested
    • Mechanistic basis for p53/Rb cooperation in lineage plasticity not molecularly defined
  19. 2019 Medium

    Identification of β-hydroxybutyrylation of p53 by CBP at Lys120/319/370 during ketosis, competing with acetylation and attenuating transcriptional activity, revealed a metabolite-driven mechanism linking fasting to p53 dampening.

    Evidence Mass spectrometry; CBP in vitro Kbhb assay; BHB-treated cells and fasted mouse thymus; p53 target gene expression

    PMID:30858356

    Open questions at the time
    • Physiological significance of Kbhb versus acetylation competition not quantified at endogenous levels
    • Whether Kbhb has independent signaling functions beyond blocking acetylation unknown
    • Independent replication of Kbhb modification pending
  20. 2021 Medium

    Discovery that ZDHHC1-mediated palmitoylation at three cysteines in the p53 core domain is required for nuclear translocation introduced lipid modification as a regulator of p53 localization, with a reciprocal epigenetic feedback loop silencing ZDHHC1 through p53-recruited DNMT3A.

    Evidence Acyl-RAC assay; cysteine mutagenesis; nuclear fractionation; ChIP for DNMT3A at ZDHHC1 promoter

    PMID:34282274

    Open questions at the time
    • Whether palmitoylation is constitutive or signal-regulated not defined
    • Impact on DNA-binding domain structure (palmitoylated cysteines overlap with zinc-coordinating region) not assessed
    • Independent replication of palmitoylation requirement for nuclear entry pending
  21. 2023 High

    Structural and functional characterization of the African-centric Y107H variant revealed selective loss of PADI4 transactivation and an immune-dependent tumor-suppressive axis, uncovering a p53–PADI4–immune surveillance pathway relevant to immunotherapy response.

    Evidence NMR and crystal structure of Y107H; Y107H knockin mouse tumor models; PADI4 KO mice; immune depletion

    PMID:37140445

    Open questions at the time
    • How PADI4-mediated citrullination connects to immune recognition not molecularly defined
    • Whether the p53-PADI4 signature generalizes beyond the cohorts tested unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: how the relative contributions of p53's diverse outputs (arrest, apoptosis, senescence, ferroptosis, immune surveillance) are determined in a tissue- and context-specific manner; the full structural basis of tetrameric p53 on chromatin with co-regulators; and how the many post-translational modifications are integrated combinatorially to specify target gene selection.
  • Full-length p53 tetramer structure on DNA with cofactors not resolved
  • Combinatorial PTM code for target gene selectivity not decoded
  • Tissue-specific determinants of p53 output choice not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1643685 Disease 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-73894 DNA Repair 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 1
Partners
BAXEP300HAUSPMDM2SIRT1TP53BP2UBE3AUSP10
Complex memberships
p53 homotetramer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 p53 mutations occur in diverse human tumor types and are concentrated in four highly conserved regions of the DNA-binding domain, with mutational spectra that differ by tumor type and correlate with carcinogen exposure (e.g., G:C to T:A transversions in lung/liver cancers, C-to-T transitions at CpG hotspots in colon/brain tumors, codon 249 hotspot in aflatoxin-associated liver cancer). Direct DNA sequencing across multiple tumor types Science High 1905840 2531845
1994 The crystal structure of the p53 core domain (residues 102–292) bound to DNA revealed a β-sandwich scaffold supporting two large loops (held together by a zinc atom) and a loop-sheet-helix motif that forms the DNA-binding surface; tumor-derived mutations cluster in these conserved structural elements, explaining their loss of DNA-binding activity. X-ray crystallography at 2.2 Å resolution; structural analysis of tumor mutant positions Science High 8023157
1990 HPV-16 and HPV-18 E6 oncoproteins physically associate with the p53 tumor suppressor protein; this interaction correlates with the transforming activity of different HPV types, providing a mechanism for viral inactivation of p53. Co-immunoprecipitation / in vitro binding assay Science High 2157286
1993 The HPV E6–E6AP complex functions as a ubiquitin-protein ligase (E3) that ubiquitinates p53, targeting it for proteasomal degradation; E6AP itself possesses intrinsic ubiquitin ligase activity independent of E6. In vitro ubiquitination reconstitution with purified E1, E2, E6, E6-AP and p53 Cell High 8221889
1992 MDM2 protein binds directly to p53 in vitro; the MDM2 gene is amplified in over one-third of human sarcomas, providing a mechanism for functional inactivation of p53 without mutation of TP53 itself. In vitro binding of recombinant proteins; Southern blot/gene amplification analysis of sarcoma samples Nature High 1614537
1996 Crystal structure of the MDM2 N-terminal domain bound to the p53 transactivation domain peptide revealed that p53 binds as an amphipathic α-helix inserting into a deep hydrophobic cleft on MDM2; three p53 residues (Phe19, Trp23, Leu26) make critical contacts, and this surface overlaps with p53's transactivation domain, explaining how MDM2 inhibits p53 transcriptional activity. X-ray crystallography of MDM2–p53 peptide complex Science High 8875929
1997 MDM2 is a ubiquitin ligase (E3) that polyubiquitinates p53 in the presence of E1 and UbcH5 (E2); a cysteine residue in the C-terminus of MDM2 is essential for this E3 activity, providing the primary mechanism for p53 proteasomal degradation in cells lacking viral E6. In vitro ubiquitination assay with purified recombinant proteins; cysteine mutagenesis FEBS letters High 9450543
1997 DNA damage-induced phosphorylation of p53 at Ser15 (and Ser37) by DNA-PK reduces p53's interaction with MDM2, thereby alleviating MDM2-mediated inhibition of p53 transcriptional activity; this phosphorylation induces a conformational change in p53. In vitro phosphorylation with purified DNA-PK; co-immunoprecipitation; transcription reporter assays in cells Cell High 9363941
1997 p53 can be acetylated in vitro and in vivo by the coactivator p300 at C-terminal lysine residues; this acetylation dramatically stimulates p53 sequence-specific DNA-binding activity, indicating a novel activation pathway through acetylation-induced conformational change. In vitro acetylation assay with purified p300 and p53; DNA-binding EMSA; in vivo acetylation detection Cell High 9288740
1997 Oncogenic Ras expression in primary human or rodent cells induces a permanent G1 arrest (premature senescence) accompanied by accumulation of p53 and p16INK4a; inactivation of either p53 or p16 prevents this arrest, establishing that p53 is required for Ras-induced oncogene senescence. Retroviral expression of oncogenic Ras in primary cells; genetic inactivation of p53 and p16; cell cycle analysis Cell High 9054499
1998 ATM kinase is activated by ionizing radiation and directly phosphorylates p53 at Ser15 in a manganese-dependent manner; ionizing radiation (but not UV) rapidly enhances ATM's p53-directed kinase activity, and phosphorylation of p53 Ser15 is reduced in ataxia telangiectasia cells, establishing ATM as a kinase that phosphorylates p53 in vivo after ionizing radiation. In vitro kinase assay with immunoprecipitated ATM; phosphorylation mapping; ATM-deficient cell lines Science High 9733515
2001 hSIRT1 (hSIR2) binds p53 and deacetylates it in an NAD-dependent manner with specificity for Lys382; wild-type hSIRT1 expression reduces p53 transcriptional activity, while a catalytically inactive mutant potentiates p53-dependent apoptosis and radiosensitivity. Co-immunoprecipitation; in vitro deacetylase assay; transcription reporter assays; catalytic mutant expression Cell High 11672523
2002 HAUSP (herpesvirus-associated ubiquitin-specific protease) was identified by mass spectrometry as a p53-interacting protein; HAUSP specifically deubiquitinates p53 both in vitro and in vivo, stabilizing p53 even in the presence of excess MDM2 and inducing p53-dependent growth repression and apoptosis; a catalytically inactive HAUSP mutant increases p53 ubiquitination and destabilizes p53. Mass spectrometry of affinity-purified p53 complexes; Co-IP; in vitro deubiquitination assay; catalytic point mutant; cell growth/apoptosis assays Nature High 11923872
2004 Small-molecule MDM2 antagonists (Nutlins) that bind the p53-binding pocket of MDM2 (confirmed by co-crystal structures) activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and inhibition of tumor xenograft growth in vivo. X-ray crystallography of MDM2–Nutlin complexes; cell-based p53 pathway activation; xenograft tumor growth inhibition Science High 14704432
2004 Cytosolic p53 directly activates the proapoptotic Bcl-2 protein Bax in the absence of other proteins, sufficient to permeabilize mitochondria and engage apoptosis; this transcription-independent mechanism operates similarly to BH3-only proteins and also releases Bcl-xL-sequestered proapoptotic factors. In vitro mitochondrial permeabilization assay with purified proteins; cytosolic fractionation; transcription-deficient p53 mutant analysis Science High 14963330
2005 p53 has an alternative internal promoter in intron 3 (conserved from Drosophila to humans) and produces multiple splice variants including p53β and Δ133p53; p53β can enhance p53 target gene expression in a promoter-dependent manner, while Δ133p53 acts as a dominant-negative inhibitor of full-length p53-mediated apoptosis. RT-PCR; reporter assays; antisense inhibition; expression in tumor vs. normal tissue Genes & Development High 16131611
2007 p53 transactivates miR-34a directly after DNA damage; miR-34a expression causes widespread reprogramming of gene expression enriched for cell-cycle, apoptosis, DNA repair, and angiogenesis genes, and promotes apoptosis, establishing miR-34a as a component of the p53 transcriptional network. Global miRNA expression profiling; promoter characterization; p53 ChIP; miR-34a overexpression with gene expression arrays; apoptosis assays Molecular Cell High 17540599
2010 USP10, a cytoplasmic deubiquitinase, deubiquitinates p53 and reverses MDM2-induced p53 nuclear export and degradation; after DNA damage, USP10 is stabilized and a fraction translocates to the nucleus to activate p53; ATM phosphorylates USP10 at Thr42 and Ser337 to regulate this translocation and stabilization. Co-IP; in vitro deubiquitination assay; subcellular fractionation; ATM kinase assay; USP10 KD with p53 stability readouts Cell High 20096447
2010 lincRNA-p21 is transcriptionally induced by p53 and serves as a transcriptional repressor in the p53 response; it physically associates with hnRNP-K, and this interaction is required for proper genomic localization of hnRNP-K at repressed genes; lincRNA-p21 knockdown de-represses hundreds of p53-repressed genes and reduces apoptosis. RNA-seq; RIP (RNA immunoprecipitation) for hnRNP-K; lincRNA-p21 knockdown with gene expression profiling; ChIP Cell High 20673990
2001 p53DINP1, a p53-inducible nuclear protein, is required for Ser46 phosphorylation of p53 and for induction of p53AIP1 and apoptosis in response to DNA double-strand breaks; overexpression of p53DINP1 synergizes with DNA damage to enhance Ser46 phosphorylation; the protein complex associated with p53DINP1 can phosphorylate p53 at Ser46, placing p53DINP1 as a cofactor for the Ser46 kinase. Differential display; antisense oligonucleotide inhibition; overexpression; in vitro kinase assay with p53DINP1-associated complex Molecular Cell Medium 11511362
2002 E2F1, unlike E2F2, specifically signals p53 phosphorylation (modifications resembling DNA damage response) in a p19ARF-independent manner; this phosphorylation is required for E2F1-mediated apoptosis; caffeine (PI3K-related kinase inhibitor) abolishes both p53 phosphorylation and E2F1-mediated apoptosis, and co-expression of a p53 phosphorylation-site mutant compromises apoptosis. Adenoviral expression of E2F1 in p19ARF-null cells; Western blot for phospho-p53; apoptosis assays; caffeine inhibition; phospho-site mutant p53 Molecular and Cellular Biology Medium 12101227
2013 OTUD5, a deubiquitinase, interacts directly with p53 and deubiquitinates it; OTUD5 is required for rapid activation of p53-dependent transcription and p53-dependent apoptosis in response to DNA damage. Co-IP; in vitro deubiquitination assay; OTUD5 knockdown with p53 ubiquitination and apoptosis readouts PLoS ONE Medium 24143256
2014 USP11, an ubiquitin-specific protease, forms a specific complex with p53 and stabilizes it by deubiquitination; USP11 knockdown markedly attenuates p53 induction in response to DNA damage. Co-IP; deubiquitination assay; USP11 knockdown with p53 stability readout Journal of Zhejiang University. Science. B Medium 25471832
2015 p53 suppresses ferroptosis resistance by repressing SLC7A11 (a key component of the cystine/glutamate antiporter), thereby inhibiting cystine uptake and sensitizing cells to ferroptotic death under ROS stress; an acetylation-defective p53 mutant (3KR) that cannot induce cell-cycle arrest, senescence, or apoptosis retains this SLC7A11-repression activity and tumor suppressive function in xenograft models. ChIP; reporter assays; p53 3KR acetylation mutant; SLC7A11 overexpression rescue; xenograft tumor growth assays; ferroptosis cell death assays Nature High 25799988
2016 NAT10 acetylates p53 at K120 and promotes p53 stabilization by counteracting MDM2; additionally, NAT10 promotes MDM2 degradation via its intrinsic E3 ligase activity; after DNA damage, NAT10 translocates from nucleolus to nucleoplasm to activate p53-mediated cell cycle control and apoptosis. Co-IP; in vitro acetylation assay; in vitro ubiquitination assay; subcellular fractionation/localization; KD with p53 target gene expression and cell cycle/apoptosis readouts EMBO Reports Medium 26882543
2016 Loss of TP53 and RB1 function enables lineage plasticity in prostate cancer through increased SOX2 expression, allowing tumor cells to shift from AR-dependent luminal to AR-independent basal-like phenotype; restoration of TP53 and RB1 function or SOX2 inhibition reverses this plasticity and restores drug sensitivity. In vitro and in vivo human prostate cancer models with TP53/RB1 knockout/restoration; SOX2 knockdown; lineage marker analysis Science High 28059768
2016 The p53 isoform Δ133p53β promotes cancer cell invasion and EMT (epithelial-to-mesenchymal transition) regardless of TP53 mutation status; depletion of endogenous Δ133p53β prevents invasiveness without affecting full-length mutant p53 expression, explaining why wild-type TP53 can promote invasion in some contexts. Isoform-specific siRNA depletion; overexpression; invasion assays; EMT marker analysis in breast and colon cell lines eLife Medium 27630122
2019 p53 is modified by β-hydroxybutyrylation (Kbhb) at Lys120, Lys319, and Lys370, catalyzed by CBP; p53 Kbhb results in reduced acetylation levels and decreased expression of p53 target genes (p21, PUMA), as well as reduced cell growth arrest and apoptosis; this mechanism is activated by elevated β-hydroxybutyrate (BHB) during starvation. Mass spectrometry identification of modification sites; CBP in vitro Kbhb assay; BHB treatment of cells and fasted mouse thymus; p53 target gene expression; apoptosis/growth arrest assays Cell Death & Disease Medium 30858356
2019 FBW7α targets p53 for proteasomal degradation via Lys-48-linked polyubiquitylation at Lys-132; this requires phosphorylation of p53 at Ser33 (by GSK3β) and Ser37 (by DNA-PK) creating a phosphodegron that enhances p53 binding to FBW7α; FBW7α-mediated degradation occurs during and after DNA double-strand breaks, and its abrogation enhances p53 tumor-suppressive function. Co-IP; in vitro ubiquitination assay; phospho-site mutagenesis; kinase inhibitor treatments; FBW7α domain mutants; DNA damage assays Journal of Biological Chemistry Medium 31346036
2021 ZDHHC1 palmitoyltransferase palmitoylates p53 at Cys135, Cys176, and Cys275; this palmitoylation is required for nuclear translocation of p53; p53 in turn recruits DNMT3A to the ZDHHC1 promoter, creating an epigenetic feedback loop that silences ZDHHC1. Acyl-RAC palmitoylation assay; site-directed mutagenesis of cysteine residues; nuclear fractionation; ChIP for DNMT3A Oncogene Medium 34282274
2004 p53 transactivates the MKP1 phosphatase through two p53 responsive elements—one in the second intron and a newly identified one in the third exon of MKP1; both elements bind p53 in vitro (gel shift) and in vivo (ChIP), and mutation of either element reduces reporter activity ~50% while loss of both completely abolishes p53-dependent MKP1 transcription. Reporter gene assays; EMSA (gel shift); ChIP; site-directed mutagenesis of p53 responsive elements Cancer Biology & Therapy Medium 15611668
2020 A mouse model of the human TP53 R181C germline mutation (p53 R178C knockin) revealed a novel lipolytic activity of p53: mutant mice are lean with increased lipolysis and fatty acid metabolism in white adipose tissue; ChIP-seq showed mutant p53 bound and transactivated the ADRB3 (Beta-3-Adrenergic Receptor) gene, which promotes lipolysis. Knockin mouse model; body composition analysis; gene expression profiling; ChIP-seq Cell Reports Medium 31968253
2023 The African-centric TP53 Y107H variant is structurally similar to wild-type p53 (by NMR and crystal structure) but is specifically impaired for transactivation of a small subset of target genes including PADI4; PADI4 (a citrullinating enzyme) is itself tumor suppressive and requires an intact immune system for this function; a p53-PADI4 gene signature predicts cancer survival and response to immune-checkpoint inhibitors. NMR structure; crystal structure; transcriptional reporter assays; Y107H knockin mouse tumor models; PADI4 KO mouse; immune depletion experiments Cancer Discovery High 37140445
2016 An African-specific p53 variant S47 (Pro47Ser) shows selective impairment in transactivating metabolic target genes GLS2 and SCO2 and is markedly defective in inducing ferroptotic cell death; S47 mice develop spontaneous cancers of diverse histological types. Human cell lines and knockin mouse model; p53 target gene expression profiling; cell death assays with multiple genotoxic agents; ferroptosis assays Genes & Development Medium 27034505
2001 Deoxycholic acid (DCA) suppresses p53 protein levels by stimulating proteasome-mediated degradation via the nuclear export protein CRM1/ERK signaling pathway; this occurs post-transcriptionally (DCA actually induces p53 mRNA) and is blocked by the proteasome inhibitor lactacystin, CRM1 inhibitor leptomycin B, or ERK pathway inhibitors. HCT116 cell line; p53 mRNA vs. protein analysis; proteasome/CRM1/ERK inhibitors; p53 transcriptional activity assays Carcinogenesis Medium 11375905

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 p53 mutations in human cancers. Science (New York, N.Y.) 7714 1905840
1997 Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 4238 9054499
2004 In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science (New York, N.Y.) 3869 14704432
1990 Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science (New York, N.Y.) 3180 1978757
1989 Mutations in the p53 gene occur in diverse human tumour types. Nature 2953 2531845
2004 Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science (New York, N.Y.) 2764 14976264
2015 Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2746 25799988
2009 Blinded by the Light: The Growing Complexity of p53. Cell 2583 19410540
2015 Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. The New England journal of medicine 2459 26061751
1990 Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science (New York, N.Y.) 2366 2157286
2001 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2263 11672523
1997 Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 2223 9288740
1994 Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science (New York, N.Y.) 2211 8023157
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
1993 The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 2052 8221889
2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 1945 23788249
1992 Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 1933 1614537
1996 Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science (New York, N.Y.) 1841 8875929
1997 DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 1783 9363941
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