Affinage

NUPR1

Nuclear protein 1 · UniProt O60356

Length
82 aa
Mass
8.9 kDa
Annotated
2026-04-29
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUPR1 is a small, intrinsically disordered, chromatin-associated stress-response protein that functions as a transcriptional cofactor to coordinate cell survival, proliferation, and resistance to multiple forms of cell death. NUPR1 is phosphorylated by PKA at Thr68, which enhances its DNA binding, while its nuclear import through a bipartite NLS is regulated by importin α3 binding that is modulated by Thr68 phosphorylation (PMID:11056169, PMID:32933064); in the nucleus it forms complexes with p53/p300 to transactivate p21 (PMID:18690848), acts as a FoxO3 corepressor to suppress Bnip3-mediated autophagy (PMID:20181828), directly inhibits PARP1 hyperPARylation to protect mitochondrial integrity (PMID:35869257), and transcriptionally activates LCN2 and FTH1 to block iron accumulation and ferroptosis (PMID:33510144, PMID:38802795). Loss of NUPR1 causes mitochondrial failure, ER stress, and necroptotic or hyperPARylation-dependent cell death, while its pharmacological inhibition by ZZW-115—which blocks importin–NLS interaction—suppresses tumor growth in vivo (PMID:30920390, PMID:30451898). NUPR1 also cooperates with oncogenic Kras to bypass senescence through Dnmt1-mediated DNA methylation, and Nupr1 deficiency in mice impairs pancreatic intraepithelial neoplasia formation, cardiac hypertrophic remodeling, renal fibrosis, and hematopoietic stem cell quiescence (PMID:24902898, PMID:17116693, PMID:33617091, PMID:33299232).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 High

    Establishing that NUPR1 is an intrinsically disordered protein with HMG-like properties whose DNA-binding activity is dramatically activated by PKA phosphorylation resolved how a small, largely unstructured protein could function at chromatin.

    Evidence CD, FTIR, NMR, and gel-shift assays with recombinant human NUPR1 ± PKA treatment

    PMID:11056169

    Open questions at the time
    • Identity of the PKA-targeted residue(s) was not fully mapped at this stage
    • In vivo relevance of PKA-dependent activation was not tested
    • Genomic binding sites were unknown
  2. 2002 High

    Demonstrating that p8-null MEFs grow faster (elevated Cdk2/Cdk4, decreased p27), resist apoptosis, and fail to form tumors when transformed established NUPR1 as both a growth suppressor and an essential enabler of tumorigenesis.

    Evidence p8−/− MEFs with kinase assays, apoptosis readouts, soft-agar and nude-mouse tumor assays with p8 re-expression rescue

    PMID:11818333 PMID:11896600

    Open questions at the time
    • Mechanism by which NUPR1 loss blocks transformation despite accelerating proliferation was unexplained
    • Downstream transcriptional targets were unidentified
  3. 2005 High

    Identification of the bipartite NLS and demonstration that nuclear localization is energy-dependent and acetylation-sensitive explained how NUPR1 subcellular distribution is dynamically regulated with the cell cycle.

    Evidence GFP-fusion NLS mutagenesis, pharmacological inhibitors (azide/2-DG, trichostatin A, leptomycin B) in multiple cell lines

    PMID:16294328

    Open questions at the time
    • The acetyltransferase responsible was not identified
    • Export mechanism remained undefined (CRM1-independent)
  4. 2005 High

    Showing that NUPR1 interacts with Jab1 and is required for Jab1-mediated nuclear-to-cytoplasmic translocation and degradation of p27 provided a direct mechanism linking NUPR1 to cell-cycle control.

    Evidence Yeast two-hybrid, Co-IP, His6-pulldown, p27 localization upon siRNA knockdown

    PMID:16300740

    Open questions at the time
    • Whether NUPR1 acts stoichiometrically or catalytically in Jab1 function was unknown
    • Relevance beyond overexpression system not shown
  5. 2006 High

    Discovery of the NUPR1–prothymosin-α complex and its requirement for anti-apoptotic signaling revealed that NUPR1 exerts survival functions through protein–protein interactions beyond chromatin, and that mutual conformational changes accompany binding of two IDPs.

    Evidence NMR, fluorescence, CD for structural changes; siRNA and caspase activity assays for function in HeLa cells

    PMID:16478804

    Open questions at the time
    • Structural details of the complex were limited by disorder
    • Downstream effectors of the anti-apoptotic pathway were not defined
  6. 2006 High

    ChIP evidence that NUPR1 associates with c-Jun-containing AP-1 sites on the ANF, MMP9, and MMP13 promoters in stimulus-dependent fashion, combined with RNAi phenotypes, established NUPR1 as a chromatin cofactor for cardiac hypertrophic and fibroblast remodeling programs.

    Evidence ChIP and RNAi in primary cardiomyocytes and cardiac fibroblasts treated with endothelin/α-adrenergic agonist/TNF

    PMID:17116693

    Open questions at the time
    • Whether NUPR1 is recruited by c-Jun directly or through intermediary factors was not resolved
    • In vivo cardiac remodeling phenotype of Nupr1 KO was not yet reported
  7. 2008 Medium

    Demonstration that NUPR1 complexes with p53 and p300 on the p21 promoter, upregulates Bcl-xL and phospho-Rb, and confers chemoresistance linked NUPR1's transcriptional cofactor role to a defined drug-resistance mechanism.

    Evidence Co-IP, ChIP at p21 promoter, luciferase reporter, siRNA knockdown with doxorubicin/Taxol sensitivity assays

    PMID:18690848

    Open questions at the time
    • Whether NUPR1 binds p53 directly or via p300 was unresolved
    • Single-lab study without independent replication
  8. 2009 High

    Identification of NUPR1 as a FoxO3 corepressor that limits Bnip3 transcription and autophagy, validated by p8−/− mouse cardiac phenotype (elevated autophagy, impaired function), established NUPR1 as a negative regulator of stress-induced autophagy.

    Evidence ChIP for FoxO3 at Bnip3 promoter ± p8, RNAi/Atg5 siRNA epistasis, p8−/− mouse cardiac phenotyping

    PMID:20181828

    Open questions at the time
    • Direct vs. indirect nature of NUPR1–FoxO3 interaction not biochemically resolved
    • Autophagy regulation in non-cardiac tissues not examined
  9. 2009 High

    Showing that NUPR1 binds p300, co-occupies the myogenin promoter with MyoD/p68, and is required for chromatin remodeling and myogenic differentiation broadened NUPR1's cofactor role to a developmental differentiation context.

    Evidence Co-IP, ChIP at myogenin promoter, siRNA in C2C12 myoblasts with differentiation readout

    PMID:19723804

    Open questions at the time
    • Whether NUPR1 is a general p300-scaffold or promoter-selective was unknown
    • Relevance in vivo during muscle development not tested
  10. 2014 High

    Genetic demonstration that Nupr1 cooperates with Kras(G12D) to bypass senescence and drive PanIN formation, via the FoxO3a–Skp2–p27–pRb–E2F axis, positioned NUPR1 as a critical node in pancreatic cancer initiation.

    Evidence Pdx1-Cre;LSL-KrasG12D;Nupr1−/− mouse model with β-galactosidase staining and pathway analysis

    PMID:24902898

    Open questions at the time
    • Mechanism of NUPR1 action on Skp2 was indirect
    • Human pancreatic cancer genetics for NUPR1 not established
  11. 2015 High

    Identification of Dnmt1 as a NUPR1-regulated target that mediates genome-wide DNA methylation changes to bypass Kras-induced senescence provided an epigenetic mechanism for NUPR1's oncogenic cooperation.

    Evidence Nupr1−/− × KrasG12D mice, DNA methylation analysis, Dnmt1 expression and RNAi in human pancreatic cancer cells

    PMID:26617245

    Open questions at the time
    • Whether NUPR1 directly binds the Dnmt1 promoter was not shown by ChIP
    • Causal ordering of methylation changes vs. senescence not fully resolved
  12. 2017 High

    NMR mapping of the NUPR1–RING1B interaction to the hydrophobic '30s region' (Ala33) with ~10 µM affinity, and its inhibition by trifluoperazine, linked NUPR1 to Polycomb-mediated chromatin regulation and opened a pharmacological strategy.

    Evidence NMR chemical shift perturbation, ITC, site-directed mutagenesis (Ala33Gln, Thr68Gln), protein ligation assay in cellulo

    PMID:28720707

    Open questions at the time
    • Functional consequence of NUPR1–RING1B interaction on gene silencing not demonstrated
    • Whether this interaction occurs on chromatin was unknown
  13. 2018 High

    Demonstration that NUPR1 inactivation causes mitochondrial failure, ER stress, and necroptotic cell death (rescued by necrostatin-1 but not caspase inhibitors) established the mechanistic basis for NUPR1's pro-survival role and the lethal consequence of its loss.

    Evidence shRNA/siRNA knockdown, mitochondrial membrane potential/ROS/ATP assays, necrostatin-1 and Z-VAD-FMK rescue, pancreatitis mouse model

    PMID:30451898

    Open questions at the time
    • Identity of the necroptotic executors downstream of mitochondrial failure was not defined
    • Whether ER stress is cause or consequence of mitochondrial failure was unclear
  14. 2019 High

    Development of ZZW-115, which binds NUPR1 near Thr68 and blocks importin-mediated nuclear translocation, causing tumor regression in vivo, validated NUPR1's nuclear function as druggable and established a pharmacological tool compound.

    Evidence ITC/fluorescence binding, nuclear translocation assay, xenograft regression, necroptosis characterization

    PMID:30920390

    Open questions at the time
    • Off-target effects of ZZW-115 not comprehensively profiled
    • Pharmacokinetic and toxicity profile limited
  15. 2020 High

    Structural demonstration that Thr68 phosphorylation induces a turn conformation in the NLS peptide and reduces importin α3 binding resolved the apparent paradox that PKA phosphorylation enhances DNA binding but may limit nuclear entry, revealing a regulatory switch.

    Evidence 2D ¹H-NMR NOE, ITC with importin α3, phospho-mimetic peptides

    PMID:32933064

    Open questions at the time
    • In vivo phosphorylation dynamics during stress were not measured
    • Whether this phospho-switch operates under all stress conditions was untested
  16. 2020 High

    Proteomic identification of importin partners and demonstration that NUPR1 directly stimulates SUMOylation in a cell-free system linked NUPR1 to the DNA damage response and explained how ZZW-115 sensitizes cells to genotoxic agents.

    Evidence MS interactome, cell-free SUMOylation reconstitution with recombinant NUPR1, genotoxicity assays

    PMID:32780723

    Open questions at the time
    • SUMOylation substrates specifically dependent on NUPR1 were not fully catalogued
    • Mechanism by which NUPR1 stimulates the SUMO machinery unknown
  17. 2021 High

    Establishing the NUPR1→LCN2 transcriptional axis as the primary mechanism of ferroptosis resistance, validated by genetic epistasis and conditional KO mice, unified NUPR1's survival role with iron metabolism.

    Evidence shRNA + LCN2 rescue, pancreas-specific Lcn2 conditional KO mice, erastin treatment, pancreatitis models

    PMID:33510144

    Open questions at the time
    • Whether NUPR1 directly binds the LCN2 promoter via ChIP was not shown in this study
    • LCN2-independent ferroptosis regulation by NUPR1 not excluded
  18. 2021 High

    Showing that Nupr1 mediates TGF-β/Smad3-driven myofibroblast activation and that Nupr1-null mice are protected from renal fibrosis extended NUPR1's pathological relevance to fibrotic disease.

    Evidence Nupr1−/− UUO mouse model, Smad3 phosphorylation analysis, trifluoperazine pharmacological rescue

    PMID:33617091

    Open questions at the time
    • Whether NUPR1 is a direct Smad3 transcriptional target or responds indirectly was not resolved
    • NUPR1 interaction with Smad3 at the protein level not demonstrated
  19. 2022 High

    In vitro reconstitution showing NUPR1 directly binds and inhibits PARP1, and that NUPR1 loss triggers hyperPARylation-dependent mitochondrial catastrophe (rescued by olaparib), identified a fundamentally new molecular activity for NUPR1 as a PARP1 inhibitor.

    Evidence Co-IP, in vitro PARP1 activity assay with recombinant NUPR1 and Ala33/Thr68 mutants, NAD+/NADH measurements, olaparib/NMN rescue

    PMID:35869257

    Open questions at the time
    • Structural basis of PARP1 inhibition not determined
    • Whether NUPR1 inhibits other PARP family members was untested
    • Relative contribution of PARP1 inhibition vs. transcriptional programs to survival unclear
  20. 2024 High

    ChIP-validated direct binding of NUPR1 to the FTH1 promoter, promoting iron storage and ferroptosis resistance, established a second iron-metabolism arm (alongside LCN2) of the NUPR1 anti-ferroptosis program.

    Evidence ChIP at FTH1 promoter, NUPR1 knockdown/overexpression, ZZW-115, xenograft model, circPIAS1/miR-455-3p epistasis

    PMID:38802795

    Open questions at the time
    • Whether NUPR1 coordinately regulates LCN2 and FTH1 or these are context-dependent was not addressed
    • Iron-independent functions of FTH1 induction not examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of NUPR1's interaction with PARP1 and the SUMO machinery, the relative contributions of its transcriptional vs. enzymatic-inhibitory functions to cell survival, whether NUPR1 acts as a general chromatin scaffold or is promoter-selective, and its precise mechanism of nuclear export.
  • No high-resolution structure of any NUPR1 complex exists
  • Genome-wide ChIP-seq for NUPR1 chromatin occupancy has not been reported
  • In vivo phosphorylation stoichiometry at Thr68 under stress is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1643685 Disease 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1640170 Cell Cycle 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 2 R-HSA-73894 DNA Repair 1
Partners
COPS5EP300FOXO3KPNA4PARP1PTMARING1TP53

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Human NUPR1 (p8) has properties of HMG-I/Y proteins, is monomeric and partially unfolded in solution, binds DNA weakly, and is a substrate for protein kinase A (PKA); phosphorylation by PKA increases secondary structure content and dramatically enhances DNA binding. Circular dichroism, FTIR, NMR spectroscopy, electrophoretic gel shift assay, in vitro PKA phosphorylation assay The Journal of biological chemistry High 11056169
2006 NUPR1 (p8) forms a complex with the antiapoptotic protein prothymosin alpha (ProTalpha); the interaction induces conformational changes in both proteins and both must be co-expressed for the antiapoptotic response to staurosporine in HeLa cells. Yeast two-hybrid, fluorescence spectroscopy, circular dichroism, NMR spectroscopy, siRNA knockdown/overexpression, caspase 3/7 and 9 activity assay Proceedings of the National Academy of Sciences of the United States of America High 16478804
2008 NUPR1 forms a complex with p53 and p300, binds the p21 promoter, and transcriptionally upregulates p21 expression; it also promotes phosphorylation of Rb and upregulation of Bcl-xL, conferring resistance to doxorubicin and Taxol. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, Western blot Current cancer drug targets Medium 18690848
2002 p8-deficient mouse embryonic fibroblasts grow more rapidly due to elevated Cdk2/Cdk4 activity and decreased p27 levels, and are more resistant to adriamycin-induced apoptosis; p8 overexpression increases p53 protein level and trans-activation capacity, and p53 negatively trans-activates p8, forming an autoregulatory loop. p8-/- mouse embryonic fibroblasts, kinase activity assay, Western blot, reporter assay, apoptosis assay Oncogene High 11896600
2006 p8 is required for endothelin- and alpha-adrenergic agonist-induced cardiomyocyte hypertrophy and for TNF-stimulated induction of MMP9 and MMP13 in cardiac fibroblasts; p8 associates with chromatin at c-Jun-containing sites on the ANF, MMP9 and MMP13 promoters in a stimulus-dependent manner. Chromatin immunoprecipitation (ChIP), RNAi knockdown, gene expression analysis, primary cardiomyocyte and fibroblast assays Molecular and cellular biology High 17116693
2005 p8 interacts with Jab1; this interaction is required for Jab1-induced translocation of p27 from nucleus to cytoplasm and its subsequent degradation; knockdown of p8 strongly inhibits Jab1 activity. Yeast two-hybrid, His6-pulldown, co-immunoprecipitation, co-localization, siRNA knockdown, p27 localization assay Biochemical and biophysical research communications High 16300740
2009 p8 (NUPR1) acts as a corepressor of FoxO3 transcription factor; p8 knockdown increases FoxO3 nuclear localization, increases FoxO3 association with the Bnip3 promoter, and elevates Bnip3 levels, leading to increased autophagy and apoptosis. p8-/- mice show elevated cardiac autophagy, higher Bnip3, and impaired cardiac function. RNAi in cardiomyocytes/H9C2/U2OS cells, FoxO3 transcriptional activity assay, ChIP, p8-/- mouse cardiac phenotyping, pharmacological autophagy inhibitors, Atg5 siRNA Molecular biology of the cell High 20181828
2009 p8 (NUPR1) binds to histone acetyltransferase p300 and co-occupies the myogenin promoter together with p300, MyoD, and p68 (Ddx5); p8 knockdown compromises chromatin association of all four proteins, impairs p300-dependent events (Myc expression, histone acetylation, MyoD acetylation) and severely impairs myogenic differentiation. Co-immunoprecipitation, ChIP, siRNA knockdown, differentiation assays in C2C12 myoblasts Journal of cell science High 19723804
2006 Com-1 (NUPR1) interacts with estrogen receptor-beta (ER-beta) in breast cancer cells as shown by co-immunoprecipitation; ER-beta and Com-1 share identical nuclear localization; 17-beta-estradiol stimulation reduces nuclear Com-1 staining in a ubiquitin-proteasome pathway-dependent manner. Co-immunoprecipitation, immunocytochemistry, ribozyme transgene knockdown, ubiquitin/proteasome inhibitor treatment Biochemical and biophysical research communications Medium 15781258
2006 p8 (NUPR1) shows cell growth-dependent subcellular localization: nuclear in actively dividing sub-confluent cells, nucleo-cytoplasmic in G0/G1-arrested cells. A conserved bipartite NLS (including Lys65, 69, 76, 77) is required for nuclear import. Nuclear localization is energy-dependent and is regulated by acetylation (trichostatin A causes cytoplasmic accumulation). Nuclear export does not involve CRM1. Immunocytochemistry, GFP-fusion protein localization, NLS mutagenesis, pharmacological inhibitors (sodium azide/2-DG, leptomycin B, trichostatin A), live-cell imaging Journal of cellular biochemistry High 16294328
2017 NUPR1 binds to the C-terminal region of Polycomb protein RING1B with ~10 µM affinity; the binding region on NUPR1 is a hydrophobic patch at the '30s region' (around Ala33); Ala33Gln and Thr68Gln mutations reduce this binding. The interaction is inhibited by trifluoperazine. Interaction was confirmed in cellulo by protein ligation assay. NMR, site-directed mutagenesis, isothermal titration calorimetry, molecular docking, protein ligation assay in cellulo Proceedings of the National Academy of Sciences of the United States of America High 28720707
2019 ZZW-115 (a trifluoperazine-derived compound) binds NUPR1 through the region around Thr68, which is located in the NLS region; ZZW-115 inhibits nuclear translocation of NUPR1 by competing with importins, induces tumor regression in xenografted mice, and causes cell death primarily by necroptosis. Biophysical binding assays (ITC, fluorescence), molecular modeling, cell viability assays, mouse xenograft model, nuclear translocation assay The Journal of clinical investigation High 30920390
2019 NUPR1 binds to several importin proteins (establishing its nuclear translocation mechanism); ZZW-115 competes with importins for binding to the NLS region of NUPR1, inhibiting nuclear translocation; NUPR1 directly stimulates the SUMOylation machinery in a cell-free system, and ZZW-115 reduces SUMOylation of DDR proteins, sensitizing cancer cells to genotoxic agents. Interactome/mass spectrometry proteomics, nuclear translocation assay, cell-free SUMOylation assay with recombinant NUPR1, co-immunoprecipitation, genotoxicity assays JCI insight High 32780723
2020 Phosphorylation of Thr68 in the NLS of NUPR1 hampers its binding to importin α3 (Impα3); the phosphorylated peptide adopts a turn-like conformation (confirmed by 2D NMR NOE), while the unphosphorylated peptide is random coil; removal of Lys65 or Lys69 also reduces binding, indicating importance of positive charges. NMR spectroscopy (2D 1H-NMR, NOE), isothermal titration calorimetry, molecular docking, fluorescence spectroscopy, peptide phospho-mimetic mutagenesis Biomolecules High 32933064
2021 NUPR1 drives ferroptosis resistance by transcriptionally activating LCN2 expression, which reduces intracellular iron accumulation and subsequent oxidative damage; LCN2 depletion mimics NUPR1 deficiency for ferroptosis induction, and re-expression of LCN2 restores resistance in NUPR1-deficient cells. NanoString technology, shRNA knockdown, LCN2 overexpression rescue, pancreas-specific Lcn2 conditional knockout mice, erastin treatment, pancreatitis mouse models Nature communications High 33510144
2022 NUPR1 binds PARP1 in the nucleus and inhibits PARP1 activity in vitro; NUPR1 inactivation (by ZZW-115 or genetic knockout) leads to hyperPARylation, mitochondrial catastrophe (membrane potential loss, superoxide production, ROS increase, Ca2+ elevation), and cell death through a non-canonical Parthanatos (AIF does not translocate from mitochondria); this cell death is rescued by the PARP inhibitor olaparib or NAD+ precursor NMN. Co-immunoprecipitation (NUPR1–PARP1), in vitro PARP1 activity assay with recombinant NUPR1, NUPR1 mutants (Ala33, Thr68), ZZW-115 treatment, NAD+/NADH measurement, mitochondrial membrane potential, superoxide/ROS assays, olaparib/PARG inhibitor rescue Communications biology High 35869257
2018 Inactivation of NUPR1 in pancreatic cancer cells causes mitochondrial failure (loss of membrane potential, ROS increase, decreased OXPHOS/ATP), relocation of mitochondria near ER, and ER-stress-coupled necrotic cell death that is reversed by necrostatin-1 (necroptosis inhibitor) but not by Z-VAD-FMK (caspase inhibitor). NUPR1 expression protects acinar cells from necrosis in vivo. NUPR1 shRNA/siRNA knockdown, transcriptomic analysis, mitochondrial membrane potential assay, ROS assay, ATP measurement, necrostatin-1/Z-VAD-FMK rescue, thapsigargin/brefeldin A/tunicamycin ER stress induction, acute pancreatitis mouse model Scientific reports High 30451898
2015 Nupr1 acts as a gene modifier of Kras(G12D)-induced senescence by regulating Dnmt1 expression and genome-wide DNA methylation levels; Nupr1 deficiency in Kras(G12D) mice increases β-galactosidase-positive (senescent) cells and activates the FoxO3a-Skp2-p27Kip1-pRb-E2F senescence pathway in vivo and in vitro. Nupr1-/- × Kras(G12D) mouse genetics, β-galactosidase staining, DNA methylation analysis, RNAi in human pancreatic cancer cells, Dnmt1 expression analysis, FoxO3a/Skp2/p27 pathway analysis Scientific reports High 26617245
2014 Nupr1 cooperates with oncogenic Kras(G12D) to bypass senescence and promote PanIN formation; genetic inactivation of Nupr1 impairs Kras-induced PanIN in mice, increasing senescent (β-galactosidase-positive) cells and activating the FoxO3a-Skp2-p27Kip1-pRb-E2F pathway. Pdx1-cre;LSL-KrasG12D;Nupr1-/- mouse model, β-galactosidase staining, gene expression profiling, RNAi in pancreatic cancer cells, pathway analysis Cell death and differentiation High 24902898
2012 NUPR1 confers chemoresistance in p53-deficient inflammatory breast cancer cells by causing Akt-mediated phosphorylation of p21 and its cytoplasmic re-localization, as well as activation of anti-apoptotic Bcl-xL; this defines a NUPR1-PI3K/Akt-phospho-p21 axis. NUPR1 overexpression/knockdown, Akt inhibitor treatment, Western blot for phospho-p21 and cytoplasmic/nuclear fractionation, Bcl-xL measurement, chemoresistance assays FEBS letters Medium 22858377
2002 p8 expression is required for tumor formation: transformed p8-/- MEFs cannot form colonies in soft agar or tumors in nude mice, while restoration of p8 expression in p8-/- MEFs restores tumor-forming ability. p8-/- MEF transformation with rasV12/E1A, soft agar colony assay, subcutaneous and intraperitoneal tumor formation in nude mice, p8 rescue by re-expression EMBO reports High 11818333
2015 NUPR1 knockdown suppresses liver cancer cell invasion in a Ca2+-signaling-dependent manner; granulin was identified as a key downstream transcriptional effector of NUPR1 via promoter binding assay; the NUPR1-granulin pathway is associated with mitochondrial defect-derived glycolytic activation. NUPR1 knockdown, invasion assay with Ca2+ signaling inhibitors, promoter binding (ChIP-like) assay, gene expression profiling Hepatology Medium 26173068
2022 NUPR1 interacts with aryl hydrocarbon receptor (AhR) and promotes AhR degradation via the autophagy-lysosome pathway and decreased nuclear AhR translocation, thereby reducing CYP enzyme transcription, lowering ROS generation after ionizing radiation, and conferring radioresistance in hepatocellular carcinoma. Co-immunoprecipitation (NUPR1-AhR), RNA sequencing, ROS/lipid peroxidation assays, colony formation assay, xenograft tumor model, AhR activator rescue BMC medicine Medium 36258210
2022 NUPR1 promotes cancer cell proliferation and metastasis by directly increasing TFE3 transcriptional activity, which maintains autophagic flux and lysosomal function; NUPR1 knockdown suppresses TFE3-dependent autophagy. NUPR1 stable knockdown, label-free quantitative proteomics, tandem mass tag proteomics, TFE3 activity assay, autophagy flux assay, in vitro and in vivo tumor models Signal transduction and targeted therapy Medium 35462576
2016 NUPR1 silencing in HCC cells influences expression of RELB and IER3 genes; NUPR1 regulates RUNX2 expression; these together define a NUPR1/RELB/IER3/RUNX2 pathway regulating NF-κB and ERK signaling in HCC. Stable NUPR1 knockdown, gene expression profiling, network analysis, RUNX2/RELB/IER3 siRNA, cell viability/migration assays, sorafenib sensitivity assays Cell death & disease Medium 27336713
2016 NUPR1 is downregulated in highly malignant tumor-repopulating cells (TRCs) grown in soft fibrin matrices; this downregulation is mediated by YAP nuclear translocation (controlled by Cdc42-mediated F-actin and Lats1); Nupr1 negatively regulates Nestin and Tert expression and suppresses TRC growth. Soft fibrin matrix TRC culture, YAP ChIP at Nupr1 promoter, Nupr1 siRNA/overexpression, Cdc42/Lats1 pathway inhibition, in vivo tumor formation in immune-competent mice Oncogenesis Medium 27089143
2011 Amino acid starvation induces p8 expression via the GCN2/ATF4 pathway; an Amino Acid Response Element (AARE) in the p8 promoter mediates this regulation; evidence provided in vitro and in vivo. p8 promoter AARE mutagenesis, reporter assay, ATF4 knockdown, GCN2-/- mouse studies, amino acid deprivation experiments Biochemical and biophysical research communications Medium 21867687
2017 Nupr1 mediates METH-induced neuronal apoptosis and autophagy through the CHOP-Trib3 endoplasmic reticulum stress signaling pathway; silencing Nupr1 reduces METH-induced apoptosis and autophagy both in vitro (neurons, PC12 cells) and in vivo (rat striatum via lentivirus-mediated shRNA). shRNA/siRNA knockdown of Nupr1, CHOP, Trib3 in primary neurons and PC12 cells; lentiviral striatum injection in rats; Western blot for ER stress, apoptosis, autophagy markers Frontiers in molecular neuroscience Medium 28694771
2021 Nupr1 mediates TGF-β-induced myofibroblast activation and EMT via the Smad3 signaling pathway; Nupr1-/- mice are protected from UUO-induced renal fibrosis; the NUPR1 inhibitor trifluoperazine (TFP) alleviates renal fibrosis in vivo. Nupr1-/- mouse UUO model, TGF-β treatment of fibroblasts/epithelial cells, α-SMA/collagen expression, Smad3 phosphorylation analysis, TFP pharmacological inhibition FASEB journal High 33617091
2022 Nupr1 regulates HSC quiescence by inhibiting p53 expression; Nupr1 deletion activates quiescent HSCs and confers competitive engraftment advantage; restoration of p53 in Nupr1-/- HSCs offsets the engraftment advantage. Nupr1-/- mouse model, competitive transplantation assay, serial transplantation, p53 rescue experiment, in vitro expansion protocol Haematologica Medium 33299232
2013 Nupr1 suppresses β-cell proliferation by inhibiting Ccna2 and Tcf19 promoter activities; Nupr1-/- mice have increased β-cell mass due to enhanced islet cell proliferation and are protected from HFD-induced glucose intolerance. Nupr1-/- mouse model, BrdU incorporation (β-cell proliferation), luciferase reporter for Ccna2 and Tcf19 promoters, gene arrays, HFD challenge Diabetologia High 23900510
2025 Tumor-derived lactate upregulates NUPR1 expression in tumor-associated macrophages via histone lactylation; NUPR1 then inhibits ERK and JNK signaling, promotes M2 macrophage polarization and PD-L1/SIRPA expression, leading to CD8+ T cell exhaustion and immune suppression. scRNA-seq analysis, functional in vitro and in vivo assays, histone lactylation assay, ERK/JNK pathway analysis, pharmacological NUPR1 inhibition, PD-1 blockade combination experiments Advanced science Medium 40305758
2023 WTAP promotes NUPR1 expression via m6A modification in an eIF3A-mediated manner (m6A-EIF3A mechanism), which stabilizes NUPR1 mRNA; NUPR1 in turn positively regulates LCN2 transcription to suppress ferroptosis in triple-negative breast cancer cells. m6A dot blot assay, RNA immunoprecipitation (RIP), RNA degradation assay, WTAP/NUPR1/LCN2 siRNA, iron/GSH measurements Biochemical genetics Medium 37477758
2024 NUPR1 promotes FTH1 transcription in HCC cells, enhancing iron storage and conferring resistance to ferroptosis; this is driven upstream by circPIAS1 sponging miR-455-3p to increase NUPR1 levels. ChIP confirmed NUPR1 binding to the FTH1 promoter. RNA immunoprecipitation, luciferase reporter, RNA pulldown, FISH, ChIP (NUPR1 at FTH1 promoter), NUPR1 knockdown/overexpression, ZZW-115 treatment, xenograft mouse model Molecular cancer High 38802795

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 NUPR1 is a critical repressor of ferroptosis. Nature communications 227 33510144
1997 Isolation of COM1, a new gene required to complete meiotic double-strand break-induced recombination in Saccharomyces cerevisiae. Genetics 188 9215887
2001 Fidelity of mitotic double-strand-break repair in Saccharomyces cerevisiae: a role for SAE2/COM1. Genetics 124 11333222
2006 Regulation of apoptosis by the p8/prothymosin alpha complex. Proceedings of the National Academy of Sciences of the United States of America 108 16478804
2000 Human p8 is a HMG-I/Y-like protein with DNA binding activity enhanced by phosphorylation. The Journal of biological chemistry 108 11056169
2010 A novel protein Com1 is required for normal conidium morphology and full virulence in Magnaporthe oryzae. Molecular plant-microbe interactions : MPMI 107 19958144
2013 Effect of oral consumption of probiotic Lactobacillus planatarum P-8 on fecal microbiota, SIgA, SCFAs, and TBAs of adults of different ages. Nutrition (Burbank, Los Angeles County, Calif.) 105 24984992
2009 Emerging role of nuclear protein 1 (NUPR1) in cancer biology. Cancer metastasis reviews 105 19153668
2022 NUPR1 promotes the proliferation and metastasis of oral squamous cell carcinoma cells by activating TFE3-dependent autophagy. Signal transduction and targeted therapy 99 35462576
2016 NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance. Cell death & disease 94 27336713
2009 Stress-inducible protein p8 is involved in several physiological and pathological processes. The Journal of biological chemistry 89 19926786
2019 Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis. The Journal of clinical investigation 84 30920390
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2019 Influence of Lactobacillus plantarum P-8 on Fermented Milk Flavor and Storage Stability. Frontiers in microbiology 68 30687239
2007 A conserved function for a Caenorhabditis elegans Com1/Sae2/CtIP protein homolog in meiotic recombination. The EMBO journal 67 18007596
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1977 Identification of the mammalian DNA-binding protein P8 as glyceraldehyde-3-phosphate dehydrogenase. European journal of biochemistry 66 413714
2024 CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis. Molecular cancer 59 38802795
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2012 Cytoplasmic translocation of p21 mediates NUPR1-induced chemoresistance: NUPR1 and p21 in chemoresistance. FEBS letters 52 22858377
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2000 Expression of a novel factor, com1, is regulated by 1,25-dihydroxyvitamin D3 in breast cancer cells. Cancer research 47 11034106
2012 Lentivirus-mediated RNAi knockdown of NUPR1 inhibits human nonsmall cell lung cancer growth in vitro and in vivo. Anatomical record (Hoboken, N.J. : 2007) 46 22961798
2017 Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B. Proceedings of the National Academy of Sciences of the United States of America 44 28720707
2012 Recombinogenic properties of Pyrococcus furiosus strain COM1 enable rapid selection of targeted mutants. Applied and environmental microbiology 44 22544252
2006 Helix-loop-helix protein p8, a transcriptional regulator required for cardiomyocyte hypertrophy and cardiac fibroblast matrix metalloprotease induction. Molecular and cellular biology 44 17116693
2019 Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma. Cells 43 31744261
2014 Co-dependence of HTLV-1 p12 and p8 functions in virus persistence. PLoS pathogens 43 25375128
1999 Intraspecies diversity of Coxiella burnetii as revealed by com1 and mucZ sequence comparison. FEMS microbiology letters 42 10547445
2014 Genetic inactivation of the pancreatitis-inducible gene Nupr1 impairs PanIN formation by modulating Kras(G12D)-induced senescence. Cell death and differentiation 41 24902898
2005 Com-1/P8 in oestrogen regulated growth of breast cancer cells, the ER-beta connection. Biochemical and biophysical research communications 41 15781258
2005 Inactivation of stress protein p8 increases murine carbon tetrachloride hepatotoxicity via preserved CYP2E1 activity. Hepatology (Baltimore, Md.) 41 15962327
2018 Long Noncoding RNA FEZF1-AS1 Promotes Osteosarcoma Progression by Regulating the miR-4443/NUPR1 Axis. Oncology research 40 29510778
2010 MRE11 and COM1/SAE2 are required for double-strand break repair and efficient chromosome pairing during meiosis of the protist Tetrahymena. Chromosoma 40 20422424
2006 Com-1/p8 acts as a putative tumour suppressor in prostate cancer. International journal of molecular medicine 40 17016631
1997 Differentiation of Coxiella burnetii by sequence analysis of the gene (com1) encoding a 27-kDa outer membrane protein. Microbiology and immunology 40 9444329
2022 NUPR1 contributes to radiation resistance by maintaining ROS homeostasis via AhR/CYP signal axis in hepatocellular carcinoma. BMC medicine 38 36258210
2020 ZZW-115-dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents. JCI insight 38 32780723
2016 Knockdown of NUPR1 inhibits the proliferation of glioblastoma cells via ERK1/2, p38 MAPK and caspase-3. Journal of neuro-oncology 38 28000106
2009 The small chromatin-binding protein p8 coordinates the association of anti-proliferative and pro-myogenic proteins at the myogenin promoter. Journal of cell science 38 19723804
2018 LncRNA FAL1 promotes carcinogenesis by regulation of miR-637/NUPR1 pathway in colorectal cancer. The international journal of biochemistry & cell biology 36 30267804
2016 Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices. Oncogenesis 36 27089143
2022 The role of NUPR1 in response to stress and cancer development. Toxicology and applied pharmacology 35 36116561
2018 A novel role for NUPR1 in the keratinocyte stress response to UV oxidized phospholipids. Redox biology 35 30466060
2013 Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis. Gut 34 24026351
2005 The age-related degeneration of oligodendrocytes in the hippocampus of the senescence-accelerated mouse (SAM) P8: a quantitative immunohistochemical study. Biological & pharmaceutical bulletin 34 15802797
2004 Nuclear protein p8 is associated with glucose-induced pancreatic beta-cell growth. Diabetes 33 14749270
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2021 Human Endogenous Retrovirus (HERV)-K env Gene Knockout Affects Tumorigenic Characteristics of nupr1 Gene in DLD-1 Colorectal Cancer Cells. International journal of molecular sciences 30 33920455
2023 WTAP Mediates NUPR1 Regulation of LCN2 Through m6A Modification to Influence Ferroptosis, Thereby Promoting Breast Cancer Proliferation, Migration and Invasion. Biochemical genetics 29 37477758
2020 NUPR1 Silencing Induces Autophagy-Mediated Apoptosis in Multiple Myeloma Cells Through the PI3K/AKT/mTOR Pathway. DNA and cell biology 29 31971825
2019 Autophagy represses fascaplysin-induced apoptosis and angiogenesis inhibition via ROS and p8 in vascular endothelia cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 29 30999113
2011 DsbA2 (27 kDa Com1-like protein) of Legionella pneumophila catalyses extracytoplasmic disulphide-bond formation in proteins including the Dot/Icm type IV secretion system. Molecular microbiology 29 21375592
2025 Lactylation-Driven NUPR1 Promotes Immunosuppression of Tumor-Infiltrating Macrophages in Hepatocellular Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 28 40305758
2021 Crowding Effects on the Structure and Dynamics of the Intrinsically Disordered Nuclear Chromatin Protein NUPR1. Frontiers in molecular biosciences 27 34291085
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2006 The SYT-SSX fusion protein down-regulates the cell proliferation regulator COM1 in t(x;18) synovial sarcoma. Molecular and cellular biology 27 17101797
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2021 Nupr1 mediates renal fibrosis via activating fibroblast and promoting epithelial-mesenchymal transition. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 33617091
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2015 Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation. Scientific reports 25 26617245
2005 Interaction of the stress protein p8 with Jab1 is required for Jab1-dependent p27 nuclear-to-cytoplasm translocation. Biochemical and biophysical research communications 25 16300740
2020 A Phosphorylation-Induced Switch in the Nuclear Localization Sequence of the Intrinsically Disordered NUPR1 Hampers Binding to Importin. Biomolecules 24 32933064
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2021 Design of Inhibitors of the Intrinsically Disordered Protein NUPR1: Balance between Drug Affinity and Target Function. Biomolecules 23 34680086
2020 Electroacupuncture Improves Cognitive Function in Senescence-Accelerated P8 (SAMP8) Mice via the NLRP3/Caspase-1 Pathway. Neural plasticity 23 33204250
2020 Quercetin induced NUPR1-dependent autophagic cell death by disturbing reactive oxygen species homeostasis in osteosarcoma cells. Journal of clinical biochemistry and nutrition 22 33041510
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2020 Trifluoperazine induces cellular apoptosis by inhibiting autophagy and targeting NUPR1 in multiple myeloma. FEBS open bio 21 32810364
2006 Upregulation of the stress-associated gene p8 in mouse models of demyelination and in multiple sclerosis tissues. Glia 21 16374777
2006 Glucose-dependent expansion of pancreatic beta-cells by the protein p8 in vitro and in vivo. American journal of physiology. Endocrinology and metabolism 21 16822955
2020 Evaluation of the Diagnostic Potential of Recombinant Coxiella burnetii Com1 in an ELISA for the Diagnosis of Q Fever in Sheep, Goats and Cattle. Microorganisms 20 32823774
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2016 Protective immunity induced by recombinant protein CPSIT_p8 of Chlamydia psittaci. Applied microbiology and biotechnology 18 27052378
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2012 Neuronal cell cycle re-entry markers are altered in the senescence accelerated mouse P8 (SAMP8). Journal of Alzheimer's disease : JAD 18 22451322
2012 Expression and roles of NUPR1 in cholangiocarcinoma cells. Anatomy & cell biology 18 22536548
2011 Amino acid deprivation regulates the stress-inducible gene p8 via the GCN2/ATF4 pathway. Biochemical and biophysical research communications 18 21867687
2006 Interaction of rice dwarf virus outer capsid P8 protein with rice glycolate oxidase mediates relocalization of P8. FEBS letters 18 17174956
2022 NUPR1 protects against hyperPARylation-dependent cell death. Communications biology 17 35869257
2019 Designing and repurposing drugs to target intrinsically disordered proteins for cancer treatment: using NUPR1 as a paradigm. Molecular & cellular oncology 17 31528692
2016 Stress Response Gene Nupr1 Alleviates Cyclosporin A Nephrotoxicity In Vivo. Journal of the American Society of Nephrology : JASN 17 27451286
2010 Proteomic changes associated with deletion of the Magnaporthe oryzae conidial morphology-regulating gene COM1. Biology direct 17 21040590
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2022 Loss of Nupr1 promotes engraftment by tuning the quiescence threshold of hematopoietic stem cell repository via regulating p53-checkpoint pathway. Haematologica 16 33299232
2022 NUPR1 imparts oncogenic potential in bladder cancer. Cancer medicine 15 36468653