Affinage

Showing TP73 — P73 is a alias.

TP73

Tumor protein p73 · UniProt O15350

Length
636 aa
Mass
69.6 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TP73 encodes a p53-family transcription factor that operates as a stress-activated transcriptional hub coupling genotoxic and oncogenic signals to apoptosis, DNA repair, and developmental cell-fate programs (PMID:11034214, PMID:12726865, PMID:26947080). Following DNA damage, p73 is induced at the mRNA level through a Chk1/Chk2-E2F1 axis (PMID:15601819), and p73-dependent apoptosis is a shared output with E2F1 (as in TCR-activation-induced T-cell death) that operates independently of p53 (PMID:11034214); p63 and p73 together are required co-factors for p53-mediated apoptosis after DNA damage (PMID:11932750). Once stabilized, TAp73 directly transactivates pro-apoptotic targets including PUMA, Bax, Scotin, and Noxa — the latter requiring NF-κB (p65) (PMID:15865927, PMID:20195489) — and also acts transcription-independently at mitochondria, where caspase-cleaved p73 drives cytochrome c release (PMID:18362891). p73 additionally directs DNA repair, transcribing the base-excision-repair glycosylases SMUG1 and MUTYH via c-Abl-dependent activation (PMID:21891782) and, in complex with Δ133p53, the double-strand-break repair genes RAD51, LIG4, and RAD52 (PMID:29511339). p73 abundance is set by a balance of ubiquitin-dependent turnover and stabilizing modifications: the HECT ligase Itch selectively ubiquitinates p73 for proteasomal degradation and is downregulated upon DNA damage (PMID:15678106), while YAP1 competes with Itch for the p73 PPPY motif to protect it (PMID:17110958) and AMPK phosphorylation at Ser426 prolongs its half-life by reducing Itch-mediated ubiquitination (PMID:24874608). Its transcriptional activity is further restrained by MDM2, which disrupts the p73-p300/CBP interaction (PMID:10207051), by tumor-derived mutant p53 that binds the p73 DNA-binding/oligomerization domains (PMID:10884390), by SIRT1-mediated deacetylation (PMID:16998810), and by WWOX-driven cytoplasmic sequestration (PMID:15070730). Beyond tumor suppression, p73 is a master regulator of multiciliogenesis, directly controlling Foxj1 and >100 cilia genes (PMID:26947080), and is required for ependymal planar cell polarity through non-muscle myosin-II and cytoskeletal dynamics (PMID:30518789) and for Cajal-Retzius cell identity in the developing cortex (PMID:12077194). Crystallographic analysis shows the p73 DNA-binding domain tetramerizes on response elements in a manner acutely sensitive to half-site spacing (PMID:22474346).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Established that p73, despite binding MDM2, is regulated differently from p53 — MDM2 inhibits p73 transcription by displacing p300/CBP rather than degrading it, defining a distinct regulatory loop.

    Evidence Reciprocal Co-IP in vivo/in vitro plus CAT reporter and apoptosis assays in p53-null cells

    PMID:10207051 PMID:10469568

    Open questions at the time
    • Conflicting reports on whether MDM2/MDMX stabilize versus suppress p73 activity
    • Physiological conditions favoring each outcome not defined
  2. 2000 High

    Connected p73 to oncogene- and damage-driven apoptosis independent of p53, showing E2F1/c-Myc/E1A activate endogenous p73 and that p73 is required for TCR-induced T-cell death.

    Evidence Dominant-negative inhibition, genetic E2F1-null and p73-null primary T cells, apoptosis assays

    PMID:10884390 PMID:11034214 PMID:11115495

    Open questions at the time
    • Direct transcriptional targets driving apoptosis not yet enumerated
    • Mechanism by which mutant p53 inhibits p73 mapped only to domains, not at structural resolution
  3. 2002 High

    Showed p63 and p73 are jointly required for p53-dependent apoptosis and that p73 marks Cajal-Retzius cells, establishing both a tumor-suppressor cofactor role and a developmental function.

    Evidence Combinatorial p53-family knockout MEFs/in vivo; immunocytochemistry and ISH in p73-/- cortex

    PMID:11932750 PMID:12077194

    Open questions at the time
    • Molecular basis of p63/p73 cooperativity with p53 not resolved
    • Cajal-Retzius transcriptional targets of p73 unidentified
  4. 2003 High

    Defined p73 as a determinant of chemosensitivity across p53 backgrounds, with mutant p53 acting as an inhibitor that can be relieved to restore drug response.

    Evidence Convergent siRNA, dominant-negative, and homologous-recombination loss-of-function chemosensitivity assays

    PMID:12726865

    Open questions at the time
    • Which p73 target genes mediate chemosensitivity not specified
    • Generalizability across tumor types not established
  5. 2004 Medium

    Identified the upstream signaling that induces p73 after DNA damage, placing Chk1/Chk2 and E2F1 stabilization upstream of p73 mRNA accumulation.

    Evidence Kinase interference/augmentation, RT-PCR, E2F1 reporter assays

    PMID:15601819

    Open questions at the time
    • Direct E2F1 occupancy of the p73 promoter not shown here
    • Relative contribution of Chk1 versus Chk2 unresolved
  6. 2004 Medium

    Revealed cytoplasmic sequestration as a control point: WWOX binds p73 and relocalizes it to the cytoplasm, with Src-mediated phosphorylation tuning the interaction.

    Evidence Co-IP, in vitro binding, subcellular fractionation, domain mapping, reporter assays

    PMID:15070730

    Open questions at the time
    • Single-lab finding without reciprocal validation in other systems
    • Physiological signals controlling WWOX-p73 partitioning unclear
  7. 2005 High

    Defined the dominant proteostatic control of p73 — Itch-mediated, p53-sparing ubiquitination and degradation that is relieved by DNA damage.

    Evidence Ubiquitination assays, Co-IP, proteasome inhibition, Itch knockdown

    PMID:15678106 PMID:15865927

    Open questions at the time
    • Signal that downregulates Itch after damage not defined
    • Isoform selectivity of Itch toward TA versus ΔNp73 not addressed
  8. 2006 High

    Mapped the molecular logic of p73 stabilization: YAP1 competes with Itch at the p73 PPPY motif to protect it from degradation, gating cisplatin-induced apoptosis.

    Evidence Competition binding and ubiquitination assays, siRNA, cisplatin treatment

    PMID:16849542 PMID:17110958

    Open questions at the time
    • Upstream regulators of YAP1-p73 binding under damage not defined
    • How p73-driven p53 autoregulation integrates with this axis unclear
  9. 2007 Medium

    Expanded the inhibitory and pharmacological control of p73 — SIRT1 deacetylation and Hck-mediated cytoplasmic retention repress activity, while Nutlin-3 frees p73 from HDM2 to drive apoptosis in p53-null cells.

    Evidence Co-IP, in vitro/in vivo deacetylation, site-directed mutagenesis, endogenous Co-IP, siRNA rescue, target-gene RT-PCR

    PMID:16998810 PMID:17535448 PMID:17700533

    Open questions at the time
    • Each mechanism shown by a single lab without cross-validation
    • In vivo relevance of Hck and SIRT1 control of p73 not established
  10. 2008 Medium

    Demonstrated a transcription-independent, mitochondrial arm of p73 apoptosis, with caspase cleavage products directly triggering cytochrome c release.

    Evidence In vitro caspase cleavage, mitochondrial fractionation and cytochrome c release, transcription-dead mutant, flow cytometry

    PMID:18362891

    Open questions at the time
    • Structural basis of p73 action at mitochondria unknown
    • Relative contribution of transcriptional versus mitochondrial arms in vivo unresolved
  11. 2009 Medium

    Placed NF-κB (p65) as a required cofactor for damage-induced p73 activity and Noxa induction, linking inflammatory signaling to p73-driven apoptosis.

    Evidence p65-null MEFs, microarray and RT-PCR, cytochrome c release

    PMID:20195489

    Open questions at the time
    • Direct physical p65-p73 interaction not demonstrated here
    • Mechanism of p65 requirement (cofactor vs upstream) unclear
  12. 2011 Medium

    Established p73 as a direct transcriptional activator of DNA repair, controlling base-excision-repair glycosylases SMUG1 and MUTYH via c-Abl in genotoxin-exposed epithelium.

    Evidence ChIP, DNA-repair PCR array, reporter assays, c-Abl inhibition, surgical mouse model

    PMID:21891782

    Open questions at the time
    • Breadth of p73-regulated repair genes beyond BER not defined here
    • Single-lab finding in a specialized esophageal context
  13. 2012 High

    Provided the structural basis for p73 DNA recognition, showing tetramerization on response elements is acutely sensitive to half-site spacing — more so than p53.

    Evidence X-ray crystallography of DBD tetramers with varied spacers, transactivation assays

    PMID:22474346

    Open questions at the time
    • Full-length p73 structure and isoform differences not captured
    • How cofactors alter response-element selectivity unknown
  14. 2013 Medium

    Extended p73's reach to metabolism and developmental feedback — driving serine biosynthesis via GLS2 and forming a TRIM32 negative-feedback loop in neural progenitors.

    Evidence Metabolic profiling, siRNA, ChIP, Co-IP, ubiquitination assays, proliferation under nutrient deprivation

    PMID:23828567 PMID:24186203

    Open questions at the time
    • Direct versus indirect metabolic targets only partially separated
    • Physiological context of TRIM32 feedback beyond neural progenitors unknown
  15. 2014 High

    Identified AMPK Ser426 phosphorylation as a stabilizing signal that opposes Itch and integrates energy stress with p73-dependent apoptosis, and detailed MDM2's differential modulation of mutant-p53/p73 complexes.

    Evidence In vitro/in vivo kinase and ubiquitination assays, half-life measurement, p73 knockdown; Co-IP and reporter assays across p53 mutants

    PMID:24874608 PMID:25417702

    Open questions at the time
    • How AMPK and DNA-damage inputs are prioritized at p73 unclear
    • Trimeric MDM2/mutant-p53/p73 complex stoichiometry not resolved
  16. 2015 Medium

    Refined p73 proteostatic control through metabolism, showing NAMPT inhibition stabilizes p73 via increased acetylation and decreased ubiquitination to drive autophagy and death; ependymal maturation and PCP also depend on p73.

    Evidence NAMPT pharmacological/genetic inhibition with NMN rescue, ubiquitination assays; p73-null mouse SVZ imaging and EM

    PMID:26482843 PMID:26586573

    Open questions at the time
    • Enzyme(s) mediating NAMPT-dependent p73 acetylation not identified
    • Direct p73 targets driving ependymal ciliogenesis not enumerated here
  17. 2016 High

    Defined p73 as the master transcriptional driver of multiciliogenesis through direct control of Foxj1 and cilia genes, and as a pro-invasion factor via POSTN in glioblastoma.

    Evidence ChIP-seq in tracheal cells, knockout mice, reporter assays; ChIP, siRNA, invasion and rescue assays

    PMID:26930720 PMID:26947080

    Open questions at the time
    • Isoform (TA vs ΔN) responsible for cilia program not fully dissected
    • Cofactors directing p73 to cilia versus apoptotic promoters unknown
  18. 2018 Medium

    Established cooperative complexes that diversify p73 output — Δ133p53/p73 promoting DSB repair gene expression, and JNK-driven p53-Thr81 phosphorylation enabling wild-type or mutant p53/p73 dimers with opposite apoptotic outcomes; TAp73 controls ependymal PCP via myosin-II and cytoskeletal dynamics.

    Evidence Co-IP, ChIP, HR/NHEJ/SSA repair assays; phosphomutant Co-IP and apoptosis assays; isoform-specific knockout mice with cytoskeletal imaging

    PMID:29511339 PMID:29615516 PMID:30518789

    Open questions at the time
    • Structural basis of p53-isoform/p73 heterocomplexes not resolved
    • How the same complexes switch between repair and apoptosis outputs unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many competing inputs (Itch/YAP1/AMPK turnover, SIRT1/MDM2/WWOX inhibition, p53-isoform complexes) are integrated to select between p73's apoptotic, DNA-repair, metabolic, and ciliogenic programs in a given cell remains unresolved.
  • No unified model linking post-translational state to target-gene program choice
  • Isoform-resolved (TAp73 vs ΔNp73) genome-wide occupancy across contexts incomplete
  • In vivo hierarchy of stabilizing versus degrading inputs undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-73894 DNA Repair 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 1
Partners
ITCHMDM2SIRT1TP53TP63TRIM32WWOXYAP1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 MDM2 binds p73 both in vivo and in vitro but, unlike with p53, does not promote p73 degradation. Instead, MDM2 suppresses p73 transcriptional activity by disrupting the p73-p300/CBP interaction, competing with p73 for binding to the p300/CBP N-terminus. p73 transcriptionally activates MDM2, forming a regulatory loop distinct from the p53-MDM2 loop. Co-immunoprecipitation (in vivo and in vitro), transient transfection/CAT reporter assays, apoptosis assays in p53-null cells Molecular and cellular biology High 10207051
1999 MDM2 and MDMX bind p73α and p73β and, in contrast to their effect on p53, stabilize p73 protein (increase half-life) and enhance p73-mediated growth suppression and p21 induction. Co-immunoprecipitation, half-life assays, growth suppression assays Current biology : CB Medium 10469568
2000 Tumor-derived p53 mutants (p53His175 and p53Gly281) physically associate with p73α, β, γ, and δ isoforms in vitro and in vivo. The core domain of mutant p53 is sufficient for the association; both the DNA-binding and oligomerization domains of p73 are required. This interaction functionally inhibits p73 transcriptional activity. Co-immunoprecipitation in breast cancer cell lines, in vitro binding, transactivation reporter assays, domain-mapping mutagenesis The Journal of biological chemistry High 10884390
2000 E2F-1, c-Myc, and E1A oncogenes induce and activate endogenous p73α and p73β proteins in p53-deficient tumor cells, leading to p73-dependent transcription (p21, HDM2 induction) and apoptosis. A dominant-negative p73 inhibitor blocks oncogene-induced apoptosis. Western blot, reporter assays, apoptosis assays with dominant-negative p73 inhibitor in p53-null cells The Journal of biological chemistry Medium 11115495
2000 TCR-activation-induced cell death (TCR-AICD) requires both E2F-1 and p73 in a common pathway. E2F-1-null or p73-null primary T cells fail to undergo TCR-mediated apoptosis; dominant-negative E2F-1 or dominant-negative p73 protects T cells, whereas dominant-negative p53 does not. Genetic knockout (E2F-1-null, p73-null primary T cells), dominant-negative protein expression, apoptosis assays Nature High 11034214
2001 p73 transcription is directly induced by p53 and by p73 itself (autoregulation) through a p53-binding site in the p73 promoter; mutant p53(R249S) and transcriptionally inactive p73β292 do not induce p73 expression. Reporter assays with p73 promoter constructs, site-directed mutagenesis of promoter binding site, RT-PCR Oncogene Medium 11314010
2002 Combined loss of p63 and p73 (but not either alone) abolishes p53-dependent apoptosis in response to DNA damage in MEFs expressing E1A and in vivo, demonstrating that p63 and p73 are required co-factors for p53-mediated apoptosis. Mouse embryo fibroblasts deficient for combinations of p53 family members, E1A oncogene system, in vivo apoptosis assays Nature High 11932750
2002 p73 is selectively expressed in Cajal-Retzius (CR) cells of the developing human cortex; in p73-/- mice, Reelin-expressing CR cells are absent at P2 (though early preplate Reelin from calretinin-positive cells remains), indicating p73 is required for CR cell identity/maintenance and cortical hem-derived neocortical development. Immunocytochemistry in human prenatal telencephalon, in situ hybridization in p73-/- mice, comparative analysis of p73-/- vs. wild-type cortex The Journal of neuroscience Medium 12077194
2003 p73 is induced by a broad range of chemotherapeutic drugs; blocking p73 function with dominant-negative mutant, siRNA, or homologous recombination causes chemoresistance regardless of p53 status; mutant p53 can inactivate p73 and downregulation of mutant p53 enhances chemosensitivity. siRNA knockdown, dominant-negative expression, homologous recombination, chemosensitivity assays Cancer cell High 12726865
2004 Checkpoint kinases Chk1 and Chk2 control p73 induction at the mRNA level after DNA damage, acting through E2F1 stabilization. Interference with Chk1/Chk2 reduces p73 accumulation; augmentation increases it. E2F1 directs p73 expression both with and without DNA damage. Multiple experimental systems including kinase interference and augmentation, RT-PCR for p73 mRNA, E2F1 reporter assays Genes & development Medium 15601819
2004 Wwox physically interacts with p73 via its first WW domain; Src kinase phosphorylates Wwox at Tyr33 and enhances its binding to p73. Wwox expression redistributes nuclear p73 to the cytoplasm, suppressing p73 transcriptional activity; cytoplasmic p73 contributes to Wwox pro-apoptotic activity. Co-immunoprecipitation, in vitro binding assays, subcellular fractionation, reporter assays, domain mapping Proceedings of the National Academy of Sciences of the United States of America Medium 15070730
2005 Itch, a HECT ubiquitin-protein ligase, selectively binds and ubiquitinates p73 (but not p53), targeting p73 for rapid proteasome-dependent degradation. Upon DNA damage, Itch is downregulated, allowing p73 protein levels to rise. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, Itch knockdown, Western blot for p73 stability The EMBO journal High 15678106
2005 TAp73 induces apoptosis via: (i) direct transactivation of Scotin, causing ER stress; (ii) transactivation of PUMA (strong, lethal) and Bax promoters (weak, insufficient alone); and (iii) potential activation of the CD95 death receptor pathway. TAp73 also transactivates the DeltaNp73 promoter, creating a negative feedback. Promoter transactivation reporter assays, apoptosis assays in cell culture Biochemical and biophysical research communications Medium 15865927
2006 YAP1 (Yes-associated protein 1) interacts with p73 via the p73 PPPY motif and competes with Itch for the same binding site on p73, thereby preventing Itch-mediated ubiquitination and proteasomal degradation of p73. YAP1 knockdown reduces p73 accumulation and apoptosis after cisplatin treatment. Co-immunoprecipitation, competition binding assays, ubiquitination assays, siRNA knockdown, cisplatin treatment Cell death and differentiation High 17110958
2006 p73 (or p53) directly transactivates endogenous p53 expression through binding to a defined p53-binding site in the p53 promoter; siRNA silencing of p73 reduces p53 transcription, and disruption of p53 autoregulation impairs cell cycle checkpoints and p53-mediated apoptosis. siRNA knockdown, reporter assays with p53 promoter mutants, RT-PCR for endogenous p53 mRNA, inducible interfering RNA Cancer research Medium 16849542
2007 SIRT1 physically binds p73 and suppresses p73-dependent transcriptional activity; SIRT1 deacetylates p73 both in vivo and in vitro, partially inhibiting p73-induced apoptosis. Co-immunoprecipitation, deacetylation assays in vivo and in vitro, reporter assays, apoptosis assays Journal of cellular physiology Medium 16998810
2007 Nutlin-3 disrupts endogenous TAp73α-HDM2 binding in p53-null cells, leading to increased p73 transcriptional activity (Noxa, PUMA, p21 upregulation), prolonged p73 half-life, and enhanced apoptosis; p73 siRNA rescues Nutlin-3-treated cells, confirming p73 dependence. Co-immunoprecipitation, siRNA knockdown, RT-PCR for target genes, apoptosis assays, p73 half-life measurement Oncogene Medium 17700533
2007 Hck (Src-family kinase) interacts with p73 via its SH3 domain and phosphorylates p73 at Tyr28 (distinct from c-Abl which phosphorylates Tyr99). Hck co-expression stabilizes p73 in the cytoplasm (kinase-dependent) and represses p73 transcriptional activity and p73-mediated apoptosis through SH3-domain-dependent mechanisms. Co-immunoprecipitation, in vitro binding, site-directed mutagenesis of phosphorylation sites, subcellular fractionation, reporter assays, RT-PCR, apoptosis assays BMC molecular biology Medium 17535448
2008 p73 is cleaved by caspase-3 and caspase-8 during apoptosis induced by DNA-damaging drugs and TRAIL. TAp73 and caspase-cleavage products localize to mitochondria; recombinant p73 directly induces cytochrome c release from isolated mitochondria. A transcription-deficient TAp73 mutant enhances TRAIL-induced apoptosis, demonstrating transcription-independent pro-apoptotic function. In vitro caspase cleavage assays, subcellular fractionation, mitochondria isolation with cytochrome c release assay, siRNA knockdown, flow cytometry Oncogene Medium 18362891
2009 DNA damage-induced p73 activation and subsequent Noxa expression require NF-κB (p65); in p65-null MEFs, genotoxin treatment cannot induce p73 activity or Noxa mRNA expression, and cytochrome c release is compromised. p65-null MEFs, microarray gene profiling, RT-PCR, cytochrome c release assays Aging Medium 20195489
2011 p73 selectively activates DNA damage repair in esophageal cells exposed to bile acids in acidic conditions via c-Abl kinase-dependent activation; p73 transcriptionally regulates base excision repair glycosylases SMUG1 and MUTYH. p73 deficiency in mice recapitulating bile acid exposure results in increased DNA damage. Human DNA repair PCR array, chromatin immunoprecipitation, reporter assays, c-Abl kinase inhibition, organotypic/traditional cell culture, surgical mouse model FASEB journal Medium 21891782
2012 Crystal structures of the p73 DNA-binding domain (DBD) tetramer bound to response elements with different spacer lengths reveal that the compact tetramer interface is determined by half-site spacing; a 2-bp spacer unwinds DNA and reduces the tetramerization interface, while a 4-bp spacer prevents tetramerization. Functionally, p73 is more sensitive to spacer length than p53: a 1-bp spacer reduces p73 transactivation by 90%. X-ray crystallography, transactivation reporter assays Proceedings of the National Academy of Sciences of the United States of America High 22474346
2013 TAp73 activates serine biosynthesis in cancer cells not by directly regulating serine metabolic enzymes but by transcriptionally controlling glutaminase-2 (GLS2), a key glutaminolysis enzyme. p73-driven GLS2 expression converts glutamine to glutamate, which drives serine biosynthesis and GSH synthesis. TAp73 depletion abolishes cancer cell proliferation under serine/glycine deprivation. Metabolic profiling, siRNA knockdown, reporter assays, cell proliferation assays under nutrient deprivation Oncogene Medium 24186203
2013 TRIM32 (E3 ubiquitin ligase) is a direct transcriptional target of TAp73 in neural progenitor cells; TRIM32 in turn physically interacts with TAp73 and promotes its ubiquitination and degradation, establishing a negative feedback loop. ΔNp73 represses TRIM32 expression. ChIP, reporter assays, Co-immunoprecipitation, ubiquitination assays, Western blot Cell death & disease Medium 23828567
2014 AMPK phosphorylates p73 on Ser426 in vitro and in vivo. AMPK activation prolongs p73 half-life, increases nuclear p73, and reduces Itch-mediated ubiquitination of p73. Chronic AMPK activation leads to p73-dependent apoptosis only in p53-expressing cells; p73 is required for p53 stabilization under AMPK activation but not under DNA damage. In vitro kinase assay, in vivo phosphorylation assay, half-life measurement, ubiquitination assays, p73 knockdown, co-immunoprecipitation Cell death and differentiation High 24874608
2014 MDM2 differentially regulates mutant p53 interactions with p63 and p73: MDM2 inhibits p63 binding to p53R175H (conformational mutant) but enhances the weaker p53R273H/p73 interaction. MDM2 can relieve p63 inhibition by p53R175H but forms a trimeric complex with p73 and p53R273H/R175H to enhance p73 inhibition. Co-immunoprecipitation, reporter assays, domain mapping Oncogene Medium 25417702
2015 NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, leading to enhanced autophagy and cancer cell death; these effects are reversed by NMN (the NAMPT enzymatic product), establishing a NAMPT-p73 nexus in cancer cell viability. NAMPT pharmacological inhibition and siRNA knockdown, p73 overexpression/knockdown, ubiquitination assays, Western blot, cell viability assays Cell death and differentiation Medium 26586573
2015 p73 is required for ependymal cell maturation and planar cell polarity establishment in the developing SVZ; p73-deficient ependymal cells have impaired ciliogenesis and fail to organize into pinwheels, disrupting SVZ niche architecture and neurogenesis. Genetic knockout mouse model (p73-null), immunofluorescence, electron microscopy, neurogenesis assays Developmental neurobiology Medium 26482843
2016 p73 is expressed in multiciliated cells (MCCs) and is required for MCC differentiation; p73 directly regulates Foxj1 (a master transcriptional regulator of multiciliogenesis) and >100 cilia-associated target genes. Loss of p73 causes defects in ciliogenesis explaining hydrocephalus, hippocampal dysgenesis, sterility, and chronic inflammation in p73-null mice. ChIP-seq (p73 and p63) in murine tracheal cells, genetic knockout mice, reporter assays, immunofluorescence Cell reports High 26947080
2016 TAp73 directly activates POSTN (periostin) transcription in glioblastoma cells, conferring an invasive phenotype. POSTN overexpression rescues the reduced invasiveness caused by p73 knockdown, placing POSTN downstream of TAp73 in a pro-invasion pathway. ChIP, reporter assays, siRNA knockdown, invasion assays, rescue experiments with POSTN overexpression Oncotarget Medium 26930720
2018 Δ133p53 forms a complex with p73 upon γ-irradiation; co-expression of Δ133p53 and p73 synergistically promotes DNA DSB repair (HR, NHEJ, SSA) by jointly binding to both a Δ133p53-responsive element and a p73-RE in the promoters of RAD51, LIG4, and RAD52. Loss of p73 increases DNA damage accumulation and leads to cell cycle arrest and senescence. Co-immunoprecipitation, ChIP, reporter assays, γ-irradiation, HR/NHEJ/SSA repair assays, siRNA knockdown Cell death and differentiation Medium 29511339
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. Wild-type p53/p73 dimerization facilitates expression of apoptotic target genes (PUMA, BAX) and promotes apoptosis; mutant p53/p73 complex suppresses apoptosis. Co-immunoprecipitation, phosphorylation assays, structural modeling, reporter assays, apoptosis assays, site-directed mutagenesis of Thr81 Science signaling Medium 29615516
2018 TAp73 is an essential regulator of ependymal planar cell polarity (PCP) by modulating actin and microtubule cytoskeleton dynamics. TAp73 regulates translational PCP and actin dynamics through modulation of non-muscle myosin-II activity and controls asymmetric localization of PCP-core signaling modules and polarized microtubule dynamics for rotational PCP. TAp73-specific knockout mice, immunofluorescence for PCP proteins and cytoskeletal markers, analysis of myosin-II activity Cell death & disease Medium 30518789

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 700 11932750
2000 The p53/p63/p73 family of transcription factors: overlapping and distinct functions. Journal of cell science 445 10769197
2002 On the shoulders of giants: p63, p73 and the rise of p53. Trends in genetics : TIG 430 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
1999 MDM2 suppresses p73 function without promoting p73 degradation. Molecular and cellular biology 298 10207051
2000 A common E2F-1 and p73 pathway mediates cell death induced by TCR activation. Nature 281 11034214
2005 The ubiquitin-protein ligase Itch regulates p73 stability. The EMBO journal 279 15678106
2003 Functional regulation of p73 and p63: development and cancer. Trends in biochemical sciences 247 14659698
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 209 15070730
2004 p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2. Genes & development 194 15601819
2006 The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73. Cell death and differentiation 176 17110958
2007 HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene 158 17700533
2002 Expression of p73 and Reelin in the developing human cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 147 12077194
2002 Role of p73 in malignancy: tumor suppressor or oncogene? Cell death and differentiation 142 11859406
2005 p73 induces apoptosis by different mechanisms. Biochemical and biophysical research communications 128 15865927
2011 p73 in Cancer. Genes & cancer 127 21779517
2000 p63 and p73 transactivate differentiation gene promoters in human keratinocytes. Biochemical and biophysical research communications 124 10873608
2000 Oncogenes induce and activate endogenous p73 protein. The Journal of biological chemistry 124 11115495
2016 p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network. Cell reports 123 26947080
2007 One, two, three--p53, p63, p73 and chemosensitivity. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 120 17287142
1999 MDM2 and MDMX bind and stabilize the p53-related protein p73. Current biology : CB 119 10469568
2014 How the TP53 family proteins TP63 and TP73 contribute to tumorigenesis: regulators and effectors. Human mutation 116 24488880
2009 p63 and p73 transcriptionally regulate genes involved in DNA repair. PLoS genetics 115 19816568
2005 p73, a sophisticated p53 family member in the cancer world. Cancer science 114 16271066
2008 The impact of p53 and p73 on aneuploidy and cancer. Trends in cell biology 112 18406616
2007 SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity. Journal of cellular physiology 112 16998810
2013 p73 regulates serine biosynthesis in cancer. Oncogene 110 24186203
1999 Structure, function and regulation of p63 and p73. Cell death and differentiation 108 10637429
2000 Evolution of functions within the p53/p63/p73 family. Annals of the New York Academy of Sciences 105 11193045
2001 p53, p63 and p73--solos, alliances and feuds among family members. Biochimica et biophysica acta 104 11825686
2014 Functional interplay between MDM2, p63/p73 and mutant p53. Oncogene 96 25417702
2006 p73 or p53 directly regulates human p53 transcription to maintain cell cycle checkpoints. Cancer research 91 16849542
2001 From p63 to p53 across p73. FEBS letters 84 11223031
2004 p53 protein variants: structural and functional similarities with p63 and p73 isoforms. Oncogene 83 14737098
2001 p73 is transcriptionally regulated by DNA damage, p53, and p73. Oncogene 83 11314010
2000 Mutation analysis of P73 and TP53 in Merkel cell carcinoma. British journal of cancer 79 10732753
1998 Loss of imprinting and allele switching of p73 in renal cell carcinoma. Oncogene 70 9796703
2011 p73: a multifunctional protein in neurobiology. Molecular neurobiology 68 21380933
1999 Elevated and biallelic expression of p73 is associated withprogression of human bladder cancer. Cancer research 66 10383132
2017 TP73-AS1 promotes breast cancer cell proliferation through miR-200a-mediated TFAM inhibition. Journal of cellular biochemistry 65 28639399
1999 Comparative analysis of p73 and p53 regulation and effector functions. The Journal of cell biology 65 10562283
2007 Wild-type p53 and p73 negatively regulate expression of proliferation related genes. Oncogene 62 17982488
2005 Regulation of the p73 protein stability and degradation. Biochemical and biophysical research communications 60 15865926
2001 Acquired expression of transcriptionally active p73 in hepatocellular carcinoma cells. Oncogene 60 11526499
2012 Regulation of p73 activity by post-translational modifications. Cell death & disease 58 22419114
2001 p73 in apoptosis. Apoptosis : an international journal on programmed cell death 56 11595834
2018 p73 coordinates with Δ133p53 to promote DNA double-strand break repair. Cell death and differentiation 54 29511339
2018 p73 Alternative Splicing: Exploring a Biological Role for the C-Terminal Isoforms. Journal of molecular biology 54 29733853
2015 The NAD(+) salvage pathway modulates cancer cell viability via p73. Cell death and differentiation 54 26586573
2003 p73 and p63 protein stability: the way to regulate function? Biochemical pharmacology 54 14555234
2008 P73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis. Oncogene 51 18362891
2015 Structure and apoptotic function of p73. BMB reports 50 25441426
2003 Differential regulation of p63 and p73 expression. Oncogene 50 12944917
2008 Contribution of p53, p63, and p73 to the developmental diseases and cancer. Neoplasma 49 18348649
2008 Therapeutic prospects for p73 and p63: rising from the shadow of p53. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 49 18801697
2000 Enhanced p73 expression during differentiation and complex p73 isoforms in myeloid leukemia. Biochemical and biophysical research communications 48 11027640
2014 Alterations of p63 and p73 in human cancers. Sub-cellular biochemistry 46 25201187
2006 p53 and p73 display common and distinct requirements for sequence specific binding to DNA. Nucleic acids research 45 17170001
2022 Structural diversity of p63 and p73 isoforms. Cell death and differentiation 44 35314772
2015 p73 is required for ependymal cell maturation and neurogenic SVZ cytoarchitecture. Developmental neurobiology 43 26482843
2011 p73 protein regulates DNA damage repair. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 21891782
2007 Overexpressed TP73 induces apoptosis in medulloblastoma. BMC cancer 41 17626635
2004 p73 and p63: why do we still need them? Cell cycle (Georgetown, Tex.) 41 15254416
2012 Structure of p73 DNA-binding domain tetramer modulates p73 transactivation. Proceedings of the National Academy of Sciences of the United States of America 40 22474346
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
2018 TP73 G4C14-A4T14 polymorphism and cancer susceptibility: evidence from 36 case-control studies. Bioscience reports 39 30420492
2014 AMPK couples p73 with p53 in cell fate decision. Cell death and differentiation 39 24874608
2011 Targeting p73 in cancer. Cancer letters 39 21903324
2008 In good times and bad: p73 in cancer. Cell cycle (Georgetown, Tex.) 38 18583938
2006 The role of p73 in hematological malignancies. Leukemia 37 16541141
1999 Mutation and expression analysis of the p73 gene in prostate cancer. The Prostate 37 10221564
2019 Tissue-specific roles of p73 in development and homeostasis. Journal of cell science 36 31582429
2014 TP63 and TP73 in cancer, an unresolved "family" puzzle of complexity, redundancy and hierarchy. FEBS letters 36 24983500
2012 Role of p53 family members p73 and p63 in human hematological malignancies. Leukemia & lymphoma 36 22497596
2006 p63 and p73: life and death in squamous cell carcinoma. Cell cycle (Georgetown, Tex.) 36 16687923
2000 Differential expression of p73 splice variants and protein in benign and malignant ovarian tumours. International journal of cancer 36 10962441
2018 Mutant and wild-type p53 form complexes with p73 upon phosphorylation by the kinase JNK. Science signaling 35 29615516
2007 p73: a chiaroscuro gene in cancer. European journal of cancer (Oxford, England : 1990) 35 17428654
2016 p73 promotes glioblastoma cell invasion by directly activating POSTN (periostin) expression. Oncotarget 34 26930720
2005 p73-induced apoptosis: a question of compartments and cooperation. Biochemical and biophysical research communications 34 15865923
2018 p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton. Cell death & disease 33 30518789
2011 p73 as a pharmaceutical target for cancer therapy. Current pharmaceutical design 33 21391908
2009 Activation of p73 and induction of Noxa by DNA damage requires NF-kappa B. Aging 33 20195489
2003 p73 Overexpression and angiogenesis in human colorectal carcinoma. Japanese journal of clinical oncology 33 12865464
2004 Mechanism of induction of apoptosis by p73 and its relevance to neuroblastoma biology. Annals of the New York Academy of Sciences 32 15650240
2018 Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury. Acta neuropathologica communications 30 29482641
2013 Regulatory feedback loop between TP73 and TRIM32. Cell death & disease 30 23828567
2008 YAP and p73: a complex affair. Molecular cell 30 19111652
2004 TP73 allelic expression in human brain and allele frequencies in Alzheimer's disease. BMC medical genetics 30 15175114
2019 The long noncoding RNA TP73-AS1 promotes tumorigenicity of medulloblastoma cells. International journal of cancer 29 31081944
2015 p53- and p73-independent activation of TIGAR expression in vivo. Cell death & disease 29 26247727
2012 Tissue-specific expression of p73 C-terminal isoforms in mice. Cell cycle (Georgetown, Tex.) 29 23159862
2006 Regulating p73 isoforms in human tumours. The Journal of pathology 29 17044134
2001 Choosing between growth arrest and apoptosis through the retinoblastoma tumour suppressor protein, Abl and p73. Biochemical Society transactions 29 11709051
2015 How Does p73 Cause Neuronal Defects? Molecular neurobiology 28 26266644
2007 Regulation of p73 by Hck through kinase-dependent and independent mechanisms. BMC molecular biology 28 17535448

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