Affinage

TP73

Tumor protein p73 · UniProt O15350

Length
636 aa
Mass
69.6 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TP73 encodes a p53-family transcription factor whose TAp73 isoforms function as central integrators of DNA damage signaling, apoptosis, DNA repair, autophagy, and multiciliated cell differentiation. TAp73 transactivates pro-apoptotic targets (PUMA, BAX, Noxa) to trigger mitochondrial cytochrome c release, DNA repair genes (RAD51, BRCA2, LIG4, SMUG1, MUTYH), and developmental regulators (Foxj1, ATG5, POSTN), and its transcriptional activity depends on DNA-binding-domain tetramerization whose efficiency is governed by response-element spacer length (PMID:22474346, PMID:14634023, PMID:19816568, PMID:29511339, PMID:26947080). TAp73 protein stability is controlled by Itch-mediated ubiquitination—counteracted by YAP1 competition, PML-dependent acetylation, and AMPK phosphorylation at S426—while MDM2 inhibits p73 transcriptional activity without promoting degradation, and SIRT1 deacetylation dampens its function (PMID:15678106, PMID:17110958, PMID:15184504, PMID:24874608, PMID:10207051, PMID:16998810). p73 is transcriptionally induced through a Chk1/Chk2–E2F1 axis after DNA damage, is essential for p53-dependent apoptosis, and its DeltaNp73 isoforms act as dominant-negative antagonists of both TAp73 and p53 (PMID:15601819, PMID:11932750, PMID:14634023).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1999 High

    Establishing how MDM2 inhibits p73 resolved a key question about whether p53-family regulation was conserved: MDM2 binds p73 and blocks its transcription by disrupting the p73–p300/CBP interaction, but unlike its action on p53, does not promote p73 degradation, revealing a distinct regulatory logic.

    Evidence Co-immunoprecipitation (in vivo/in vitro), CAT reporter assays, apoptosis assays in p53-null cells

    PMID:10207051

    Open questions at the time
    • Whether MDM2 affects p73 stability under specific stress conditions was not tested
    • Structural basis of the non-degradative MDM2-p73 interaction was not determined
  2. 2000 High

    Demonstrating that oncogenes (E2F1, c-Myc, E1A) activate endogenous p73 and that gain-of-function p53 mutants bind and inhibit p73 established p73 as an independent tumor-suppressive transcription factor operating parallel to p53.

    Evidence Overexpression in p53-null cells, dominant-negative p73 inhibitor, endogenous target induction, domain-mapping Co-IP in cancer cell lines

    PMID:10884390 PMID:11115495

    Open questions at the time
    • Mechanism by which mutant p53 binding disables p73 transactivation was not structurally defined
    • Whether p73 inhibition by mutant p53 is universal across tumor types was untested
  3. 2002 High

    Genetic epistasis showing that combined loss of p63 and p73 abolishes p53-dependent apoptosis established that p73 (with p63) is an obligate co-factor for the p53 apoptotic program, not merely a redundant paralogue.

    Evidence Triple-knockout MEFs, E1A system, in vivo irradiation in mice

    PMID:11932750

    Open questions at the time
    • Individual contributions of p73 vs p63 to apoptosis in different tissues were not separated
    • Whether this requirement applies to all p53-dependent cell death stimuli was unknown
  4. 2002 Medium

    Identifying c-Abl and p38 MAPK as upstream kinases that phosphorylate and stabilize p73 provided the first signaling link from DNA damage sensors to p73 protein accumulation.

    Evidence Kinase assays, p38 pathway inhibitors, p73 stability and transcriptional reporter assays

    PMID:11840343

    Open questions at the time
    • Specific phosphorylation sites on p73 mediating p38-dependent stabilization were not fully mapped
    • Relative contribution of c-Abl vs p38 was not resolved
  5. 2003 High

    Delineation of the TAp73–PUMA–BAX apoptotic axis, and demonstration that DeltaNp73 blocks this pathway, resolved how p73 executes apoptosis and how its dominant-negative isoform confers resistance.

    Evidence Transactivation assays, subcellular fractionation (nuclear p73, mitochondrial BAX), cytochrome c release assays

    PMID:14634023

    Open questions at the time
    • Whether p73 activates additional BH3-only proteins besides PUMA was not explored
    • Relative quantitative contribution of DeltaNp73 vs other inhibitory mechanisms was unclear
  6. 2004 High

    Mapping the Chk1/Chk2→E2F1→TAp73 transcriptional induction pathway after DNA damage established how checkpoint signaling specifically upregulates p73 mRNA, completing the signal transduction chain from damage to p73 accumulation.

    Evidence siRNA/dominant-negative of Chk1/Chk2, augmentation experiments, E2F1 binding-site mutagenesis on TAp73 promoter

    PMID:15572378 PMID:15601819

    Open questions at the time
    • Whether other E2F family members contribute redundantly was not fully resolved
    • Chromatin-level regulation of the TAp73 promoter was not addressed
  7. 2004 High

    Discovery that PML nuclear bodies stabilize p73 through a p38-phosphorylation→PML-NB recruitment→p300-acetylation cascade that protects p73 from ubiquitin-dependent degradation revealed how sub-nuclear compartmentalization governs p73 protein levels.

    Evidence Subcellular fractionation, ubiquitination/acetylation assays, Pml−/− primary cells, p38 kinase assays

    PMID:15184504

    Open questions at the time
    • Identity of the E3 ligase blocked by PML-mediated acetylation was not known at the time
    • Whether PML-NB recruitment is required for all p73 target gene programs was untested
  8. 2005 High

    Identification of Itch as the selective E3 ubiquitin ligase for p73 (but not p53), and its downregulation upon DNA damage, explained how p73 protein is kept low basally and rapidly stabilized after genotoxic stress.

    Evidence Co-IP, in vivo ubiquitination assay, proteasome inhibitor, siRNA knockdown of Itch

    PMID:15678106

    Open questions at the time
    • Whether other E3 ligases additionally target p73 for degradation was unknown
    • Mechanism of Itch downregulation upon DNA damage was not defined
  9. 2005 High

    Showing that cdc2/cyclin B phosphorylates p73 at Thr-86 during mitosis, causing chromosome exclusion and loss of transactivation, and that p73 knockdown perturbs mitotic progression via p57/Kip2, extended p73 function beyond apoptosis to cell cycle control.

    Evidence Cell synchronization, phosphorylation analysis, subcellular fractionation, siRNA, dominant-negative mutant

    PMID:15985436

    Open questions at the time
    • Whether p73 directly participates in the spindle assembly checkpoint was not tested
    • Dephosphorylation mechanism during mitotic exit was not identified
  10. 2006 High

    Demonstration that YAP1 stabilizes p73 by competing with Itch for the PPPY motif provided a mechanistic switch for p73 accumulation and apoptosis induction after cisplatin treatment.

    Evidence Competition binding assay, ubiquitination assay, siRNA knockdown of YAP1, apoptosis assays

    PMID:17110958

    Open questions at the time
    • Regulation of YAP1 availability during DNA damage was not fully elucidated
    • Whether Hippo pathway signals modulate YAP-p73 binding during chemotherapy was untested
  11. 2008 High

    Discovery of the PML–YAP–p73 proapoptotic autoregulatory feedback loop (p73/YAP transactivates PML; PML sumoylates/stabilizes YAP; Akt negatively controls the loop) integrated multiple post-translational regulators into a coherent signaling circuit.

    Evidence ChIP on PML promoter, Co-IP (PML-YAP), domain mapping, sumoylation assay, Akt inhibition

    PMID:19111660

    Open questions at the time
    • Quantitative contribution of PML-mediated YAP sumoylation vs other YAP stabilization mechanisms was not defined
    • Whether Akt disrupts the loop by directly phosphorylating p73 was untested
  12. 2009 High

    Genome-wide identification of BRCA2, Rad51, and Mre11 as direct p73/p63 targets, and the development of mammary tumors in p63+/−;p73+/− mice, established p73 as a guardian of genomic integrity through transcriptional control of homologous recombination repair.

    Evidence Microarray after DNA damage, ChIP validation, DNA repair assays, compound heterozygous mouse model

    PMID:19816568

    Open questions at the time
    • Individual tumor-suppressive contribution of p73 vs p63 loss in the compound model was not resolved
    • Whether p73 regulates all HR steps or only specific gene subsets was not comprehensively addressed
  13. 2012 High

    Crystal structures of the p73 DNA-binding domain tetramer on response elements with varying spacer lengths revealed that quaternary structure and transactivation depend on half-site spacing, explaining differential target gene selectivity compared to p53.

    Evidence X-ray crystallography, transactivation reporter assays with engineered spacer variants

    PMID:22474346

    Open questions at the time
    • Structures with full-length p73 or with chromatin context were not available
    • How spacer-length sensitivity translates to genome-wide target selectivity in vivo was unknown
  14. 2013 High

    Demonstrating that TAp73 directly transactivates ATG5 and that p73-deficient livers show massive lipid accumulation from failed autophagy/lipophagy expanded p73 function to metabolic homeostasis beyond classical tumor suppression.

    Evidence p73-KO mouse liver phenotype, ATG5 promoter transactivation assay, ATG5 gene rescue in hepatocytes

    PMID:23912709

    Open questions at the time
    • Whether other autophagy genes are direct p73 targets was not comprehensively explored
    • Tissue specificity of the TAp73-autophagy axis beyond liver was unclear
  15. 2014 High

    Identification of AMPK-mediated phosphorylation at S426 as a mechanism that prolongs p73 half-life by blocking Itch-mediated ubiquitination linked metabolic stress sensing to p73 stabilization and apoptosis.

    Evidence In vitro kinase assay, S426 site mutagenesis, ubiquitination assay, half-life measurement, nuclear fractionation, apoptosis assays

    PMID:24874608

    Open questions at the time
    • Whether AMPK-p73 axis operates in metabolic tissues (liver, muscle) physiologically was not shown
    • Additional AMPK phosphorylation sites on p73 were not excluded
  16. 2016 High

    ChIP-seq and knockout studies showing p73 directly activates Foxj1 and multiciliogenesis genes, with p73-deficient mice exhibiting hydrocephalus, sterility, and chronic infection, established a non-apoptotic developmental role for p73 in multiciliated cell differentiation.

    Evidence p73-KO mice, ChIP-seq in tracheal cells, phenotypic characterization across organ systems

    PMID:26947080

    Open questions at the time
    • Whether TAp73 or DeltaNp73 is the active isoform driving ciliogenesis was not definitively separated
    • Upstream signals activating p73 in ciliated cell progenitors were not identified
  17. 2018 High

    Showing that Δ133p53 and p73 form a complex that co-occupies DNA repair gene promoters (RAD51, LIG4, RAD52) to synergistically promote DSB repair expanded the repertoire of p73-p53 family cooperativity beyond apoptosis to direct repair pathway regulation.

    Evidence Co-IP, ChIP at repair gene promoters, HR/NHEJ/SSA repair assays, siRNA, γ-irradiation

    PMID:29511339

    Open questions at the time
    • Whether full-length p53 similarly cooperates with p73 at repair loci was not tested
    • In vivo relevance of the Δ133p53-p73 repair axis was not demonstrated
  18. 2018 Medium

    Demonstration that TAp73 regulates planar cell polarity through actin/microtubule cytoskeletal dynamics and non-muscle myosin-II activity in ependymal cells provided a mechanistic basis for the ciliogenesis and neurogenesis defects in p73-deficient mice.

    Evidence Trp73-KO mouse, PCP component localization, actin/microtubule dynamics assays, myosin-II activity measurement

    PMID:30518789

    Open questions at the time
    • Direct transcriptional targets mediating cytoskeletal remodeling were not identified
    • Whether p73-dependent PCP extends to non-neural multiciliated epithelia was untested
  19. 2019 Medium

    Identification of GemC1 as part of a trimeric GemC1–E2F5–p73 complex that activates the p73 promoter and controls chromatin state at p73/Foxj1 loci linked multiciliogenesis initiation to upstream transcriptional control of p73 itself.

    Evidence ChIP (GemC1/E2F5 at p73 promoter), protein interaction assays, GemC1 KO model, epigenetic analysis

    PMID:31028178

    Open questions at the time
    • Whether GemC1 regulation of p73 is restricted to multiciliated cell lineages was unknown
    • The complete set of epigenetic marks controlled by GemC1 at the p73 locus was not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Open questions remain regarding how isoform-specific (TAp73 vs DeltaNp73) transcriptional programs are differentially deployed across tissues, how the multiple post-translational inputs are integrated at the single-cell level, and whether the structural insights from the isolated DNA-binding domain extend to full-length p73 on chromatin.
  • Full-length p73 structure in complex with DNA and co-activators is unavailable
  • Single-cell resolution of isoform-specific expression and function across tissues is lacking
  • Therapeutic modulation of p73 in p53-mutant cancers remains preclinically unvalidated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 5 GO:0005654 nucleoplasm 1
Pathway
R-HSA-5357801 Programmed Cell Death 7 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-73894 DNA Repair 3 R-HSA-1640170 Cell Cycle 2 R-HSA-9612973 Autophagy 1
Partners
E2F1ITCHMDM2PMLSIRT1TP53WWOXYAP1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Combined loss of p63 and p73 abolishes p53-dependent apoptosis in response to DNA damage; p63 and p73 are required for p53 to execute the apoptotic program in E1A-expressing mouse embryo fibroblasts and in vivo irradiation models. Genetic loss-of-function (mouse embryo fibroblasts deficient for p53 family members, E1A oncogene system, in vivo irradiation), epistasis analysis Nature High 11932750
1999 MDM2 binds p73 both in vivo and in vitro, inhibits p73-dependent transcription and apoptosis, but unlike its action on p53, does not promote p73 degradation. Instead, MDM2 disrupts the interaction of p73 with p300/CBP by competing for binding to the p300/CBP N-terminus. Co-immunoprecipitation (in vivo and in vitro), transient transfection transcriptional assays (CAT), apoptosis assays in p53-null cells Molecular and cellular biology High 10207051
2005 The HECT ubiquitin E3 ligase Itch selectively binds and ubiquitinates p73 (but not p53), leading to proteasome-dependent degradation of p73. Upon DNA damage, Itch is downregulated, allowing p73 protein levels to rise. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, siRNA knockdown of Itch, western blotting The EMBO journal High 15678106
2006 YAP1 (Yes-associated protein 1) stabilizes p73 by competing with Itch for binding to the PPPY motif of p73, thereby preventing Itch-mediated ubiquitination and degradation of p73. YAP1 interaction is required for p73 accumulation and apoptosis induction after cisplatin treatment. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of Yap1, competition binding assay, apoptosis assays Cell death and differentiation High 17110958
2003 p73 induces apoptosis via transcriptional activation of PUMA, which in turn causes Bax mitochondrial translocation and cytochrome c release. p73 remains nuclear during apoptosis induction, indicating its effect on Bax translocation is indirect via PUMA. DeltaNp73 inhibits TAp73-induced as well as p53-induced apoptosis by repressing the PUMA/Bax system. Overexpression of p73 isoforms, Bax promoter transactivation assays, subcellular fractionation/localization (nuclear fractionation, mitochondrial translocation assays), cytochrome c release assay, time-course apoptosis analysis The Journal of biological chemistry High 14634023
2004 Checkpoint kinases Chk1 and Chk2 control p73 induction in response to DNA damage by regulating E2F1 stabilization and activity, and E2F1 in turn directs p73 transcriptional expression. Chk1/Chk2 control p73 mRNA accumulation after DNA damage. siRNA/dominant-negative interference with Chk1/Chk2 signaling, augmentation of Chk1/Chk2 activity, mRNA analysis, epistasis in multiple human tumor cell lines Genes & development High 15601819
2003 p73 is a determinant of chemotherapeutic efficacy; blocking p73 function (dominant-negative mutant, siRNA, or homologous recombination) leads to chemoresistance irrespective of p53 status. Mutant p53 can inactivate p73. p73 is induced by a wide variety of chemotherapeutic drugs. Dominant-negative p73 mutant expression, siRNA knockdown, homologous recombination knockout, cell survival/death assays, mutant p53 co-expression Cancer cell High 12726865
2000 Tumor-derived p53 mutants (p53His175 and p53Gly281) physically associate with p73 alpha, beta, gamma, and delta isoforms in vitro and in vivo (including in breast cancer cell lines T47D and SKBR3). The core domain of mutant p53 is sufficient for association with p73; both the DNA-binding and oligomerization domains of p73 are required. This association markedly reduces p73 transcriptional activity. Co-immunoprecipitation in vitro and in vivo, domain mapping with deletion mutants, transcriptional activity assays The Journal of biological chemistry High 10884390
2004 WWOX physically interacts with p73 via its first WW domain; Src kinase phosphorylates WWOX at Tyr33 in the first WW domain and enhances its binding to p73. WWOX expression triggers redistribution of nuclear p73 to the cytoplasm, suppressing p73 transcriptional activity, while cytoplasmic p73 contributes to WWOX's proapoptotic activity. Co-immunoprecipitation, in vitro binding assays, domain mapping (WW domain), kinase assay (Src phosphorylation), subcellular fractionation/localization, transcriptional reporter assays Proceedings of the National Academy of Sciences of the United States of America High 15070730
2004 p38 MAP kinase-mediated phosphorylation of p73 is required for p73 recruitment into PML-nuclear bodies (PML-NB). PML modulates p73 stability by inhibiting its ubiquitin-proteasome-dependent degradation in a PML-NB-dependent manner. p300-mediated acetylation of p73 protects it against ubiquitination, and PML regulates p73 stability by positively modulating its acetylation levels. Subcellular fractionation, co-immunoprecipitation, ubiquitination assays, PML-NB localization studies, Pml-/- primary cells, p38 kinase assays, acetylation assays The Journal of experimental medicine High 15184504
2008 PML and YAP form a proapoptotic autoregulatory feedback loop with p73: p73/YAP transactivates PML (a direct transcriptional target); PML and YAP physically interact through their PVPVY and WW domains respectively, causing PML-mediated sumoylation and stabilization of YAP, thereby amplifying p73 proapoptotic activity. This loop is under negative control of Akt/PKB kinase. ChIP (p73/YAP on PML promoter), co-immunoprecipitation (PML-YAP), domain mapping, sumoylation assays, reporter assays, Akt inhibition experiments Molecular cell High 19111660
2002 c-Abl induces phosphorylation of p73 on threonine residues adjacent to prolines, and the p38 MAP kinase pathway mediates this response. Activation of p38 is sufficient to enhance p73 stability, and c-Abl-dependent transcriptional activation of p73 requires p38 kinase activity. Kinase assays, p38 pathway inhibitors, p38 activation, p73 phosphorylation and stability assays, transcriptional reporter assays Oncogene Medium 11840343
2007 SIRT1 binds to p73, suppresses p73-dependent transcriptional activity, and deacetylates p73 both in vivo and in vitro, partially inhibiting p73-induced apoptosis. Co-immunoprecipitation, in vitro and in vivo deacetylation assays, transcriptional reporter assays, apoptosis assays Journal of cellular physiology Medium 16998810
2005 p73 is phosphorylated at Thr-86 by the p34cdc2/cyclin B complex at the G2/M transition, which is associated with exclusion of p73 from condensed chromosomes and loss of DNA binding and transcriptional activation ability. Hypo-phosphorylated p73 reappears during mitotic exit, relocalizes to telophase nuclei, and recovers transcriptional activity. siRNA knockdown of p73 alters mitotic progression (accumulation of ana-telophase cells, aberrant late mitotic figures). p73 transactivation of cyclin-dependent kinase inhibitor Kip2/p57 mediates the mitotic exit phenotype. siRNA knockdown of p73, cell synchronization, subcellular fractionation/localization (chromatin exclusion), phosphorylation analysis, transcriptional reporter assays, dominant-negative p73 mutant The Journal of biological chemistry High 15985436
2007 Nutlin-3 disrupts endogenous binding between TAp73alpha and HDM2 in p53-null cells, leading to increased p73 transcriptional activity with upregulation of target genes noxa, puma and p21, enhanced apoptosis, and prolonged p73 protein half-life. p73 siRNA rescues Nutlin-3-treated cells from apoptosis. Co-immunoprecipitation (endogenous p73-HDM2), siRNA knockdown of p73, transcriptional target gene analysis, cell viability/apoptosis assays, p73 half-life determination Oncogene High 17700533
2012 Crystal structure of the p73 DNA-binding domain tetramer bound to response elements with spacers of different length reveals that the quaternary structure and transactivation activity are determined by the distance between half-sites. Zero and one base-pair spacers produce compact tetramers with large tetramerization interfaces; a two base-pair spacer causes DNA unwinding and smaller interface; a four base-pair spacer hinders tetramerization. p73 is more sensitive to spacer length than p53. X-ray crystallography, transactivation assays (reporter assays with different spacer response elements) Proceedings of the National Academy of Sciences of the United States of America High 22474346
2000 E2F1, c-Myc, and E1A oncogenes up-regulate endogenous p73alpha and p73beta proteins in p53-deficient cells, leading to activation of p73 transcription function (p21, HDM2 induction) and apoptosis. A dominant-negative p73 inhibitor blocks oncogene-induced apoptosis. Adenoviral overexpression, reporter assays, endogenous target gene induction (p21, HDM2), dominant-negative p73 inhibitor, apoptosis assays in SaOs-2 cells The Journal of biological chemistry High 11115495
2004 Checkpoint kinase signaling activates E2F1, which directly drives TAp73 promoter activation. E1A expression activates the TAp73 promoter via p300- and pRB-binding sites and through E2F1-binding sites in the TAp73 promoter; mutations in E2F1 binding sites impair E1A-mediated TAp73 promoter activation. TAp73 promoter-reporter assays with E1A mutants, E2F1 binding site mutation analysis, mRNA and protein analysis of endogenous TAp73 The Journal of biological chemistry Medium 15572378
2016 p73 is expressed in multiciliated cells, is required for multiciliated cell (MCC) differentiation, and directly regulates transcriptional modulators of multiciliogenesis including Foxj1. Loss of p73 causes hydrocephalus, hippocampal dysgenesis, sterility, and chronic inflammation/infection attributable to loss of ciliary biogenesis. p73 knockout mice (phenotypic characterization), p73 and p63 ChIP-seq in murine tracheal cells, validation of direct transcriptional target genes (Foxj1 and other cilia-associated genes) Cell reports High 26947080
2018 JNK-mediated phosphorylation of Thr81 in the proline-rich domain of p53 enables wild-type p53 (as well as mutant p53) to form a complex with p73. Dimerization of wild-type p53 with p73 facilitates expression of apoptotic target genes (PUMA, BAX) and apoptosis induction in response to JNK activation. Co-immunoprecipitation, site-directed mutagenesis (Thr81), JNK activation assays, structural algorithms, target gene expression analysis, apoptosis assays Science signaling Medium 29615516
2018 Δ133p53 forms a complex with p73 upon γ-irradiation. Co-expression of Δ133p53 and p73 synergistically promotes DNA double-strand break repair (HR, NHEJ, SSA) by jointly binding to Δ133p53-responsive elements and p73-responsive elements in the promoters of RAD51, LIG4, and RAD52. Depletion of p73 reduces early-stage apoptosis and increases later-stage DNA DSB accumulation. Co-immunoprecipitation, ChIP (p73 and Δ133p53 at repair gene promoters), DNA repair assays (HR, NHEJ, SSA), siRNA knockdown, γ-irradiation model Cell death and differentiation High 29511339
2013 TAp73 directly transactivates the ATG5 promoter, and the TAp73-ATG5 axis is required for autophagy and macrolipophagy in liver. Livers of p73-deficient mice show massive lipid droplet accumulation, low autophagy, and blocked triglyceride hydrolysis. ATG5 gene transfer corrects autophagy defects in p73-deficient hepatocytes. p73-deficient mice (liver phenotype), promoter-transactivation assay (ATG5 promoter), ATG5 gene rescue experiment, autophagy/lipophagy assays Cell death and differentiation High 23912709
2009 p63 and p73 directly regulate DNA repair genes BRCA2, Rad51, and Mre11. Cells deficient for p63 and p73 are impaired in DNA repair, and p63+/-;p73+/- mice develop mammary tumors. Genome-wide transcriptomic analysis after DNA damage in p53-family deficient cells, ChIP validation of direct target genes, DNA repair functional assays, p63/p73 compound heterozygous mouse model PLoS genetics High 19816568
2004 p73 plays a role in thyroid hormone-induced oligodendrocyte precursor cell (OPC) differentiation and in PDGF-withdrawal-induced OPC differentiation. Both p53 and p73, but not p63, are involved in TH-induced OPC differentiation in vitro. Dominant-negative p53 family inhibitor in purified OPC cultures, loss-of-function experiments distinguishing p53 family members, differentiation assays with thyroid hormone and PDGF withdrawal Development (Cambridge, England) Medium 14960496
2015 p73 is required for ependymal cell maturation and SVZ neurogenic niche architecture. p73 deficiency halts the transition of radial glia into ependymal cells, results in impaired ciliogenesis, disrupted pinwheel organization, and loss of translational planar cell polarity, leading to impaired neurogenesis. p73-deficient mouse model, immunohistochemistry, cell type characterization, ciliogenesis analysis, SVZ niche structure analysis Developmental neurobiology Medium 26482843
2018 TAp73 regulates ependymal planar cell polarity (PCP) through modulation of actin and microtubule cytoskeleton dynamics. TAp73 regulates translational PCP and actin dynamics through modulation of non-muscle myosin-II activity, and is required for asymmetric localization of PCP-core and global signaling modules and polarized microtubule dynamics. Trp73 knockout mouse model, subcellular localization studies of PCP components, actin/microtubule dynamics assays, non-muscle myosin-II activity measurements, immunofluorescence Cell death & disease Medium 30518789
2013 TAp73 directly binds to the TRIM32 promoter and activates TRIM32 expression in neural progenitor cells. In turn, TRIM32 physically interacts with TAp73 and promotes its ubiquitination and degradation, creating a regulatory feedback loop. DNp73 represses TAp73-induced TRIM32 expression. ChIP (p73 binding to TRIM32 promoter), co-immunoprecipitation (TRIM32-TAp73), ubiquitination assays, promoter-reporter assays, neural progenitor cell model Cell death & disease Medium 23828567
2014 AMPK phosphorylates p73 on a novel residue S426 in vitro and in vivo. Following AMPK activation, p73 protein half-life is prolonged, p73 accumulates in the nucleus, and escapes Itch E3 ligase-mediated ubiquitination and proteasomal degradation. Chronic AMPK activation leads to p73-dependent apoptosis, and p73 is required for p53 stabilization and accumulation under AMPK-induced metabolic stress. In vitro kinase assay (AMPK phosphorylating p73), site-directed mutagenesis (S426), co-immunoprecipitation, ubiquitination assays, p73 half-life measurement, nuclear localization by fractionation, apoptosis assays Cell death and differentiation High 24874608
2019 GemC1 regulates transcriptional activation of p73 by acting in a trimeric complex with E2F5 and p73, and this complex activates the p73 promoter. GemC1 is necessary for p73 expression in different multiciliated epithelia and regulates multiciliogenesis through control of chromatin organization and epigenetic marks at the p73 and Foxj1 loci. ChIP (GemC1, E2F5 at p73 promoter), promoter-reporter assays, protein-protein interaction assays (trimeric complex), in vivo GemC1 KO model, epigenetic analysis of p73 and Foxj1 loci Journal of cell science Medium 31028178
2011 p73 (but not p53 or p63) is selectively activated by c-Abl kinase in response to bile acid-induced DNA damage in esophageal cells. Activated p73 induces DNA damage repair by transcriptionally regulating multiple DNA repair genes, including glycosylases SMUG1 and MUTYH (base excision repair). p73 deficiency in a mouse surgical bile acid reflux model increases DNA damage. c-Abl kinase activation assays, p73 activation in esophageal cell lines, human DNA repair PCR array, transcriptional regulation assays for SMUG1 and MUTYH, p73-deficient mouse model with bile acid reflux surgery FASEB journal Medium 21891782
2007 Hck (Src family kinase) interacts with p73 via its SH3 domain and phosphorylates p73 at Tyr-28 (distinct from c-Abl which phosphorylates Tyr-99). Hck stabilizes p73 protein in the cytoplasm in a kinase-dependent manner, but represses p73 transcriptional activity via SH3 domain-dependent interactions. Hck also interacts with YAP, which modulates p73 transcriptional activity. Co-immunoprecipitation (in vivo and in vitro), SH3 domain binding assay, site-directed mutagenesis (Tyr-28 phosphorylation site), kinase assay, transcriptional reporter assays, shRNA knockdown of YAP, apoptosis assays BMC molecular biology Medium 17535448
2006 p73 directly transactivates the human p53 promoter and maintains p53 expression. Silencing p73 by RNA interference significantly suppresses p53 transcription, and impaired p73-mediated autoregulation results in aberrant cell cycle regulation and suppression of p53-mediated apoptosis. ChIP (p73/p53 binding to p53 promoter), siRNA knockdown, p53 promoter mutational analysis, inducible interfering RNA for p53 autoregulation, cell cycle and apoptosis analysis Cancer research Medium 16849542
2020 FDXR regulates p73 expression via IRP2: loss of FDXR increases IRP2 expression (via FDX2), which destabilizes TP73 mRNA through an iron response element (IRE) in its 3'UTR. This FDXR-IRP2-p73 axis regulates aging and tumor suppression. Genetically modified mouse models (Fdxr-/+, Trp73-/+, compound mice), MEF cell assays, IRP2 expression analysis, TP73 3'UTR IRE mutagenesis, mRNA stability assays The Journal of pathology Medium 32304229
2016 TAp73 directly activates POSTN (periostin) expression by binding to the POSTN promoter (demonstrated by ChIP and reporter assays), conferring an invasive phenotype in glioblastoma cells. POSTN overexpression rescues the invasive phenotype after p73 knockdown. ChIP (p73 binding to POSTN promoter), promoter-reporter assays, siRNA knockdown of p73, invasion assays, POSTN rescue experiment Oncotarget Medium 26930720
2009 NF-kappaB is required for genotoxin-induced p73 activation and subsequent p73-dependent Noxa expression. In cells lacking NF-kappaB (p65-null MEFs), genotoxin treatment cannot induce p73 activation or Noxa mRNA, impairing cytochrome c release and apoptosis. p65-null MEF genetic model, microarray gene profiling, Noxa promoter analysis, mRNA analysis of p73 and Noxa induction, cytochrome c release assay Aging Medium 20195489
2006 p19ras (an alternative splice isoform of H-ras) binds to p73beta in vivo and in vitro, stimulates p73 transcriptional activity, and competes with MDM2 binding to p73beta, relieving MDM2-mediated transcriptional repression of p73. This p19ras-p73-MDM2 interaction occurs exclusively in the nucleus. Yeast two-hybrid screening, co-immunoprecipitation (in vivo and in vitro), transcriptional reporter assays, subcellular localization analysis, competition assay (p19ras vs MDM2 binding to p73) The Journal of biological chemistry Medium 16436381

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 699 11932750
2000 The p53/p63/p73 family of transcription factors: overlapping and distinct functions. Journal of cell science 444 10769197
2002 On the shoulders of giants: p63, p73 and the rise of p53. Trends in genetics : TIG 429 11818141
2000 P63 and P73: P53 mimics, menaces and more. Nature reviews. Molecular cell biology 419 11252895
2004 p63 and p73: roles in development and tumor formation. Molecular cancer research : MCR 392 15280445
2003 Chemosensitivity linked to p73 function. Cancer cell 367 12726865
2003 p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. The Journal of biological chemistry 307 14634023
1999 MDM2 suppresses p73 function without promoting p73 degradation. Molecular and cellular biology 296 10207051
2005 The ubiquitin-protein ligase Itch regulates p73 stability. The EMBO journal 278 15678106
2003 Functional regulation of p73 and p63: development and cancer. Trends in biochemical sciences 247 14659698
2008 PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Molecular cell 221 19111660
2007 p63 and p73 in human cancer: defining the network. Oncogene 213 17334395
2000 Physical and functional interaction between p53 mutants and different isoforms of p73. The Journal of biological chemistry 211 10884390
2004 Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proceedings of the National Academy of Sciences of the United States of America 208 15070730
2000 A ribonucleotide reductase gene is a transcriptional target of p53 and p73. Oncogene 196 10980602
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2000 Oncogenes induce and activate endogenous p73 protein. The Journal of biological chemistry 124 11115495
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2017 TP73-AS1 promotes breast cancer cell proliferation through miR-200a-mediated TFAM inhibition. Journal of cellular biochemistry 64 28639399
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2005 Expression of p63 and p73 in ameloblastomas. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 40 15752257
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2005 A role of p73 in mitotic exit. The Journal of biological chemistry 34 15985436
2020 FDXR regulates TP73 tumor suppressor via IRP2 to modulate aging and tumor suppression. The Journal of pathology 33 32304229
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2019 The long noncoding RNA TP73-AS1 promotes tumorigenicity of medulloblastoma cells. International journal of cancer 29 31081944
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