Affinage

ASS1

Argininosuccinate synthase · UniProt P00966

Length
412 aa
Mass
46.5 kDa
Annotated
2026-06-09
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASS1 is a cytosolic urea-cycle enzyme whose control over aspartate and arginine flux makes it a metabolic checkpoint with broad effects on proliferation, redox balance, and cell death (PMID:26560030, PMID:34861885). Loss of ASS1 raises cytosolic aspartate, which activates the CAD complex through mTOR/S6K1-driven CAD phosphorylation to fuel de novo pyrimidine synthesis and tumor proliferation, and re-expression of ASS1 with ASL suppresses tumor growth in an enzymatic-activity-dependent manner by diverting aspartate away from nucleotide synthesis (PMID:26560030, PMID:34861885). Beyond canonical catalysis, ASS1 acts as a tumor suppressor by directly binding PHGDH and driving its ubiquitination-mediated degradation to restrain serine synthesis (PMID:38710705). ASS1 activity is gated post-translationally: CLOCK acetylates ASS1 at K165/K176 to inactivate it, imposing a circadian rhythm on arginine biosynthesis and ureagenesis (PMID:28985504). Following DNA damage, ASS1 accumulates in both compartments — in the nucleus it cooperates with ASL to generate fumarate that succinates SMARCC1 and destabilizes the SMARCC1–SNF5 chromatin-remodeling complex, repressing p53-regulated cell-cycle genes, while in the cytosol it restrains nucleotide synthesis to pause the cell cycle (PMID:38858597). ASS1 transcription is governed by opposing regulators, with HIF-1α repressing and c-MYC activating expression under control of DEC1 and p300/HDAC2-dependent histone acetylation at the promoter (PMID:27765932, PMID:28883660). Through its enzymatic generation of AMP, ASS1 activates AMPK to drive fatty acid oxidation and govern hepatic and tumor lipid homeostasis (PMID:35655095, PMID:38914306). ASS1 mutations associated with citrullinemia type I disrupt its interaction with PRMT7, linking the enzyme to the molecular pathogenesis of that disease (PMID:28587924).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2009 Low

    Before molecular characterization, the genomic position of ASS1 was unknown; mapping it provided the physical anchor for later genetic and disease studies.

    Evidence Somatic cell hybrid mapping using balanced reciprocal translocations of chromosome 9

    PMID:219990

    Open questions at the time
    • Provides genomic localization only, no molecular mechanism
    • Does not address enzymatic or regulatory function
  2. 2014 Medium

    It was unclear how arginine starvation kills ASS1-deficient cancers; this work established mitochondrial damage as the upstream trigger of autophagic cell death.

    Evidence ADI-PEG20 treatment of ASS1-deficient breast cancer cells with mitochondrial assays and autophagy-deficient lines, in vitro and in vivo

    PMID:24692592

    Open questions at the time
    • Molecular link between mitochondrial ROS and autophagy initiation not defined
    • Single tumor type
  3. 2015 High

    The metabolic consequence of ASS1 loss in cancer was unresolved; this study showed aspartate accumulation activates CAD via mTOR/S6K1 to drive pyrimidine synthesis and proliferation.

    Evidence Metabolic flux analysis, citrullinemia patient studies, mTOR/S6K1 inhibition, and CAD assays in ASS1-deficient cancer cells

    PMID:26560030

    Open questions at the time
    • Does not address non-metabolic ASS1 functions
    • Mechanism of aspartate-driven CAD phosphorylation not structurally resolved
  4. 2017 High

    How ASS1 activity is tuned over time was unknown; CLOCK-mediated acetylation at K165/K176 was shown to inactivate ASS1 and impose circadian control on ureagenesis.

    Evidence In vitro acetylation assay, MS site mapping, K165/K176 mutagenesis, Co-IP, and oscillation profiling in human cells and mouse liver

    PMID:28985504

    Open questions at the time
    • Deacetylase that reverses the modification not identified
    • Whether acetylation alters localization is unaddressed
  5. 2017 Medium

    The transcriptional logic of ASS1 silencing in cancer was unclear; DEC1 was identified as a master regulator coordinating HIF-1α repression and c-MYC activation at the ASS1 promoter.

    Evidence ChIP, knockdown/overexpression of HIF-1α/c-MYC/DEC1, proteasome inhibitors, and demethylation treatment

    PMID:27765932

    Open questions at the time
    • DNA-methylation-independent mechanism not fully resolved
    • No structural validation of promoter complexes
  6. 2017 Medium

    The chromatin basis of HIF-1α-mediated ASS1 silencing was undefined; p300/HDAC2/Sin3A control of H3K14ac/H3K27ac was shown to gate in situ HIF-1α degradation and ASS1 de-repression upon arginine starvation.

    Evidence ChIP for histone marks and factors, knockdown/overexpression of p300/HDAC2/Sin3A/PHD2, antioxidant assays

    PMID:28883660

    Open questions at the time
    • Generality across tumor types unknown
    • Connection to DEC1 axis not integrated
  7. 2017 Medium

    Whether ASS1 has protein partners relevant to disease was unknown; PRMT7 was identified as a direct interactor disrupted by citrullinemia mutations.

    Evidence Yeast two-hybrid, pull-down assays, and mutagenesis of citrullinemia-associated residues

    PMID:28587924

    Open questions at the time
    • Functional consequence of PRMT7 binding on ASS1 activity not defined
    • No methylation of ASS1 demonstrated
  8. 2017 Medium

    The metabolic rewiring underlying arginine-deprivation therapy was unclear; arginine deprivation was shown to suppress the Warburg effect and create synthetic lethality with glutaminase inhibition in ASS1-deficient tumors.

    Evidence Metabolite profiling, PKM2/PHGDH Westerns, ADI-PEG20 plus glutaminase inhibitor combinations in vitro and in vivo

    PMID:28122247

    Open questions at the time
    • Durability of synthetic lethality not assessed
    • Single therapeutic combination
  9. 2018 Medium

    How hypoxia further suppresses ASS1 and benefits cancer cells was unknown; HIF-1α-induced miR-224-5p was shown to downregulate ASS1, conferring pH and redox advantages.

    Evidence miR-224-5p gain/loss-of-function, intracellular pH, glutamine-dependence, and glutathione assays under hypoxia/acidosis

    PMID:30573518

    Open questions at the time
    • Direct miR-224-5p:ASS1 target site not validated in this entry
    • Causal link between pH and growth not isolated
  10. 2019 Medium

    Mechanisms of ASS1 repression beyond transcription factors were unclear; AR was shown to drive the ASS1P3 pseudogene as a ceRNA decoy sequestering miR-34a-5p to suppress ASS1 in renal carcinoma.

    Evidence RIP, AGO2 assay, miR-34a-5p 3'UTR luciferase reporter, and genetic manipulation with xenografts

    PMID:31000693

    Open questions at the time
    • Specificity of ASS1P3 ceRNA activity in other tissues unknown
    • Quantitative contribution versus other regulators not defined
  11. 2019 Medium

    How arginine starvation sensitizes tumors to chemotherapy was unclear; c-MYC nuclear translocation was shown to upregulate hENT1 and confer gemcitabine susceptibility.

    Evidence Western blot, c-MYC assays, hENT1 surface immunofluorescence, FITC-cytosine uptake, and c-MYC inhibitor rescue in vivo

    PMID:31113844

    Open questions at the time
    • Direct transcriptional control of hENT1 by c-MYC not shown here
    • Restricted to ASS1-negative context
  12. 2020 Medium

    ASS1's role under nutrient stress was unknown; c-MYC-induced ASS1 was shown to drive nitric-oxide-dependent S-nitrosylation of gluconeogenic enzymes to support purine synthesis during glucose deprivation.

    Evidence ASS1 manipulation under glucose deprivation, c-MYC ChIP, S-nitrosylation assays, and metabolic flux analysis

    PMID:35121952

    Open questions at the time
    • Source/regulation of NO production by ASS1 not detailed
    • Generality beyond glucose-deprived state unknown
  13. 2021 Medium

    Whether ASS1 is degradation-controlled in cancer was unknown; a LOC113230 scaffold recruiting LRPPRC/TRAF2 was shown to ubiquitinate ASS1, an axis Snail represses via TGF-β to stabilize ASS1 and promote metastasis.

    Evidence Co-IP of LRPPRC/TRAF2/ASS1, ubiquitination assays, Snail ChIP at LOC113230 E-boxes, and xenograft metastasis models

    PMID:34184805

    Open questions at the time
    • Direct E3 ubiquitin transfer by TRAF2 to ASS1 not structurally shown
    • Single cancer type
  14. 2021 Medium

    The therapeutic value of restoring urea-cycle enzymes in renal cancer was untested; ASS1/ASL re-expression was shown to suppress tumor growth dependent on enzymatic activity.

    Evidence Genetic re-expression with catalytically inactive controls, 2D/3D and xenograft growth assays, and metabolomics in ccRCC

    PMID:34861885

    Open questions at the time
    • Relative contributions of aspartate conservation versus NO regulation not separated
    • Limited to ccRCC lines
  15. 2021 Medium

    An extra-metabolic role for ASS1 in fibrosis was unknown; ASS1 loss in IPF fibroblasts was shown to activate Met–Src–STAT3 signaling driving fibroblast proliferation and invasion.

    Evidence ASS1 knockdown/overexpression, proliferation/migration/invasion assays, Met/Src/STAT3 Westerns, and bleomycin mouse model

    PMID:33508432

    Open questions at the time
    • Mechanism linking ASS1 metabolism to Met activation undefined
    • Whether enzymatic activity is required not tested
  16. 2021 Medium

    A non-metabolic immune function was unsuspected; secreted ASS1 was shown to bind LPS, inhibit bacterial growth, and protect against endotoxemia.

    Evidence Gel-shift LPS binding, bacterial growth inhibition, macrophage cytotoxicity, and rodent endotoxemia models with recombinant ASS

    PMID:21481813

    Open questions at the time
    • Structural basis of LPS binding unknown
    • Mechanism of hepatic ASS1 release into circulation undefined
  17. 2022 Medium

    How ASS1 connects to lipid metabolism was unclear; the MANF–ASS1–AMPK axis was shown to operate through ASS1-derived AMP generation regulating hepatic lipid homeostasis.

    Evidence Co-IP/MS, hepatocyte MANF knockout/overexpression, ASS1 activity assays, urea-cycle metabolite profiling, and AMPK phosphorylation

    PMID:35655095

    Open questions at the time
    • Whether MANF directly binds ASS1 not resolved
    • Mechanism by which MANF modulates ASS1 activity unknown
  18. 2022 Medium

    Additional upstream repressors of ASS1 were sought; PGAM1 was shown to suppress ASS1 via a cAMP/AMPK/CEBPB axis, with ASS1 induction required for the anti-proliferative effect of PGAM1 loss.

    Evidence RNA-seq after PGAM1 knockdown, CEBPB pathway analysis, double-knockdown epistasis, and in vivo tumor assays

    PMID:35674458

    Open questions at the time
    • Direct CEBPB binding to ASS1 promoter not shown
    • Single tumor type
  19. 2022 Low

    Whether ASS1 protects hepatocytes was unclear; FXR was shown to promote ASS1 transcription, enhancing arginine synthesis and reducing apoptosis in acute liver injury.

    Evidence FXR agonist/antagonist, ASS1 reporter assays, scRNA-seq, apoptosis markers, and TAA liver-injury model

    PMID:35477090

    Open questions at the time
    • Direct FXR–ASS1 promoter binding not clearly demonstrated
    • Causal role of ASS1 in apoptosis reduction not isolated
  20. 2023 Medium

    How ASS1 affects ferroptosis was unknown; ASS1 was shown to drive glutamine reductive carboxylation and an mTORC1–SREBP1–SCD5 axis producing monounsaturated fatty acids to resist ferroptosis.

    Evidence Glutamine isotope metabolomics, ASS1 loss-of-function, transcriptomics, and erastin ferroptosis assays in NSCLC, in vivo

    PMID:36892426

    Open questions at the time
    • Direct effect of ASS1 enzymatic products on SREBP1 not defined
    • Context-dependence versus tumor-suppressive role unresolved
  21. 2024 Medium

    A direct tumor-suppressive partner of ASS1 was unknown; ASS1 was shown to bind PHGDH and promote its ubiquitination, restraining serine synthesis as the basis of its anti-proliferative activity in TNBC.

    Evidence Co-IP, ubiquitination assays, PHGDH knockout epistasis, serine/glycine rescue, and in vitro/in vivo tumor models

    PMID:38710705

    Open questions at the time
    • E3 ligase mediating PHGDH ubiquitination not identified
    • Whether ASS1 catalytic activity is required not defined
  22. 2024 High

    A moonlighting nuclear function in the DNA-damage response was unknown; ASS1 with ASL was shown to generate fumarate that succinates SMARCC1, remodeling chromatin and pausing the cell cycle alongside cytosolic nucleotide restraint.

    Evidence Subcellular fractionation, isotope-tracing metabolomics, succination assays, SMARCC1–SNF5 disruption analysis in colon cancer cells and citrullinemia fibroblasts

    PMID:38858597

    Open questions at the time
    • Mechanism of ASS1 nuclear import not defined
    • Selectivity of SMARCC1 succination over other targets unclear
  23. 2024 Medium

    How ASS1 supports tumor survival under detachment was unclear; ASS1 was shown to activate AMPK/CPT1A to enhance fatty acid oxidation and anoikis resistance in ovarian cancer.

    Evidence ASS1 overexpression/knockdown, CPT1A inhibition, AMP/ATP ratio and FAO assays, AMPK phosphorylation, and anoikis assays

    PMID:38914306

    Open questions at the time
    • Reconciliation with tumor-suppressive ASS1 roles not addressed
    • Direct AMP supply mechanism not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ASS1's opposing context-dependent roles — tumor suppressor via PHGDH degradation and aspartate conservation versus tumor promoter via AMPK/FAO and ferroptosis resistance — are determined within a given cell.
  • No unifying model reconciling pro- and anti-tumor functions
  • Determinants of nuclear versus cytosolic ASS1 partitioning unknown
  • How post-translational acetylation integrates with degradation control undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 2 GO:0008289 lipid binding 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 2 GO:0005576 extracellular region 1 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 1 R-HSA-4839726 Chromatin organization 1 R-HSA-9909396 Circadian clock 1
Partners
ASLCLOCKLRPPRCMANFPHGDHPRMT7SMARCC1TRAF2

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 ASS1 deficiency in cancer increases cytosolic aspartate levels, which activates the CAD complex (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase) by upregulating substrate availability and increasing CAD phosphorylation by S6K1 through the mTOR pathway, thereby facilitating de novo pyrimidine synthesis and supporting proliferation. Metabolic flux analysis, citrullinemia patient studies, mTOR/S6K1 pathway inhibition experiments, CAD activity assays in ASS1-deficient cancer cells Nature High 26560030
2017 CLOCK directly acetylates ASS1 at lysine residues K165 and K176 (facilitated by BMAL1) to inactivate ASS1, and this acetylation exhibits circadian oscillation in human cells and mouse liver, driven by rhythmic CLOCK–ASS1 interaction, thereby imposing circadian regulation on arginine biosynthesis and ureagenesis. In vitro acetylation assay, mass spectrometry identification of acetylation sites, site-directed mutagenesis of K165 and K176, co-immunoprecipitation of CLOCK–ASS1 complex, circadian oscillation profiling in cells and mouse liver Molecular cell High 28985504
2017 HIF-1α and c-MYC act as reciprocal negative and positive transcriptional regulators of ASS1 expression by binding to the ASS1 promoter; DEC1 functions as the master regulator controlling both HIF-1α and c-MYC levels to regulate ASS1 transcription independently of ASS1 promoter DNA methylation. Promoter binding assays (ChIP), overexpression and knockdown of HIF-1α, c-MYC, and DEC1, use of proteasomal inhibitors (bortezomib, carfilzomib) to modulate HIF-1α, cisplatin and 5-aza-dC treatment to alter ASS1 expression Oncotarget Medium 27765932
2017 At the ASS1 promoter, the histone acetyltransferase p300 maintains H3K14ac and H3K27ac marks that support HIF-1α-mediated ASS1 silencing; arginine starvation induces p300 dissociation, allowing HDAC2 and Sin3A to deacetylate these histone marks, which facilitates PHD2-driven proteasomal degradation of HIF-1α in situ, leading to ASS1 de-repression. Chromatin immunoprecipitation (ChIP) for histone marks and transcription factor binding, knockdown/overexpression of p300, HDAC2, Sin3A, PHD2, antioxidant sensitivity assays Scientific reports Medium 28883660
2014 Prolonged arginine starvation (via ADI-PEG20) in ASS1-deficient breast cancer cells induces mitochondrial oxidative stress, impairs mitochondrial bioenergetics and integrity, and triggers cytotoxic autophagy; cell death requires autophagy competence, placing mitochondrial damage upstream of autophagic cell death in the arginine starvation pathway. ADI-PEG20 treatment of ASS1-deficient breast cancer cells in vitro and in vivo, mitochondrial ROS/bioenergetics assays, autophagy-deficient cell lines, genetic suppression of autophagy Science signaling Medium 24692592
2017 PRMT7 directly interacts with ASS1 (confirmed by yeast two-hybrid and pull-down assays), and ASS1 mutations associated with citrullinemia type I disrupt the PRMT7–ASS1 interaction, implicating loss of this interaction in the molecular pathogenesis of the disease. Yeast two-hybrid screening, pull-down assay, site-directed mutagenesis of ASS1 citrullinemia-associated residues, computational interface mapping Journal of molecular biology Medium 28587924
2021 Snail prevents LOC113230-mediated ubiquitination and degradation of ASS1: LOC113230 acts as a scaffold to recruit LRPPRC and the TRAF2 E3 ubiquitin ligase to ASS1, resulting in ASS1 ubiquitination and degradation; Snail represses LOC113230 transcription (via E-box binding) in response to TGF-β, thereby stabilizing ASS1 and promoting arginine synthesis for colorectal cancer migration. Co-immunoprecipitation identifying LRPPRC/TRAF2/ASS1 complex, ubiquitination assays, LOC113230 overexpression/knockdown, Snail ChIP at E-boxes in LOC113230 promoter, xenograft metastasis experiments EMBO reports Medium 34184805
2024 ASS1 directly binds to PHGDH and promotes its ubiquitination-mediated proteasomal degradation, thereby inhibiting de novo serine synthesis; the tumor-suppressive effect of ASS1 in triple-negative breast cancer is strongly dependent on this mechanism, as PHGDH knockout abrogates ASS1's anti-proliferative activity. Co-immunoprecipitation identifying ASS1–PHGDH interaction, ubiquitination assays, PHGDH knockout epistasis experiments, serine/glycine rescue experiments, in vitro and in vivo tumor models Cell death & disease Medium 38710705
2024 Following DNA damage, ASS1 expression is elevated in both cytosol and nucleus (partly p53-dependent); in the nucleus, ASS1 and ASL generate fumarate that succينates SMARCC1, destabilizing the SMARCC1–SNF5 chromatin-remodeling complex and decreasing transcription of a subset of p53-regulated cell cycle genes; in the cytosol, ASS1 restrains nucleotide synthesis to pause cell cycle progression. Subcellular fractionation, metabolomics with isotope tracing, succination assays, SMARCC1–SNF5 complex disruption analysis, doxorubicin-induced DNA damage in colon cancer cells and citrullinemia fibroblasts Nature metabolism High 38858597
2023 ASS1 promotes reductive carboxylation of cytosolic glutamine, reducing mitochondrial-derived lipid ROS; additionally, ASS1 activates the mTORC1–SREBP1–SCD5 axis to promote de novo monounsaturated fatty acid synthesis using acetyl-CoA derived from the glutamine reductive pathway, conferring resistance to ferroptosis in non-small cell lung cancer cells. Stable isotope-labeled glutamine metabolomics, ASS1 loss-of-function (knockdown/knockout), transcriptome sequencing, erastin-induced ferroptosis assays in vitro and in vivo xenograft models Cancer research Medium 36892426
2020 Under glucose deprivation, ASS1 expression is induced by c-MYC, and ASS1 increases nitric oxide synthesis and activates gluconeogenic enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase via S-nitrosylation, enhancing flux through gluconeogenesis to support serine, glycine, and subsequent purine synthesis. ASS1 overexpression/knockdown under glucose deprivation, c-MYC ChIP and expression manipulation, S-nitrosylation assays of gluconeogenic enzymes, metabolic flux analysis Nature cancer Medium 35121952
2018 In hypoxia, ASS1 expression is further downregulated via HIF-1α-mediated induction of miR-224-5p; ASS1-depleted cancer cells maintain higher intracellular pH, depend less on extracellular glutamine, and display higher glutathione levels, indicating that ASS1 regulation under acidic/hypoxic conditions provides a redox and pH advantage to cancer cells. miR-224-5p gain/loss-of-function, intracellular pH measurements, glutamine dependence assays, glutathione quantification, ASS1 knockdown/overexpression under hypoxic and acidic conditions Cancer research Medium 30573518
2017 Arginine deprivation in ASS1-deficient cancer cells inhibits the Warburg effect by reducing aerobic glycolysis with decreased PKM2 expression and phosphorylation, while increasing serine biosynthesis (via PHGDH upregulation), glutamine anaplerosis, and oxidative phosphorylation; concurrent arginine deprivation and glutaminase inhibition is synthetic lethal across ASS1-deficient tumor lines. Metabolite profiling, Western blotting for PKM2/PHGDH, arginine starvation (ADI-PEG20), glutaminase inhibitor combination studies in vitro and in vivo xenograft models Cell reports Medium 28122247
2021 Recombinant ASS1 physically binds to bacterial lipopolysaccharide (LPS) as shown by gel-shift assay and suppresses E. coli growth in culture; endogenous hepatic ASS1 is released into circulation within 1 hour of LPS challenge, acting as a component of the innate immune response to reduce LPS cytotoxicity, suppress TNF-α production, and increase survival in rodent endotoxemia models. Gel-shift assay for LPS binding, bacterial growth inhibition assay, mouse macrophage cytotoxicity assays, in vivo LPS endotoxemia model with recombinant ASS injection International immunopharmacology Medium 21481813
2022 MANF (mesencephalic astrocyte-derived neurotrophic factor) resides in the same immunoprecipitated complex as ASS1; MANF knockout decreases ASS1 activity while MANF overexpression enhances ASS1 activity; ASS1 activates AMPK by generating an intracellular pool of AMP from the urea cycle, and this MANF–ASS1–AMPK axis regulates hepatic lipid homeostasis. Immunoprecipitation-coupled mass spectrometry proteomics, hepatocyte-specific MANF knockout and overexpression, ASS1 enzymatic activity assays, urea cycle metabolite profiling, AMPK phosphorylation assays Acta pharmacologica Sinica Medium 35655095
2024 ASS1 overexpression activates AMPK and its downstream effector CPT1A by disrupting the AMP/ATP balance, enhancing fatty acid oxidation (FAO) and ATP generation in ovarian cancer cells; CPT1A inhibition reverses ASS1-induced FAO and disrupts AMPK activation, placing CPT1A downstream of the ASS1/AMPK axis in anoikis resistance. ASS1 overexpression/knockdown, CPT1A inhibition, AMP/ATP ratio measurements, FAO assays, AMPK phosphorylation analysis, anoikis resistance assays Cancer letters Medium 38914306
2021 Re-expression of both ASS1 and ASL in ccRCC cell lines suppresses tumor growth in 2D, 3D, and in vivo xenograft models in an enzymatic-activity-dependent manner; the growth suppression involves conservation of cellular aspartate (diverting it away from pyrimidine synthesis), regulation of nitric oxide synthesis, and altered pyrimidine production. Genetic re-expression of ASS1 and ASL in ccRCC cell lines, catalytically inactive mutant controls, 2D/3D growth assays, xenograft models, metabolomics Cancer & metabolism Medium 34861885
2022 PGAM1 negatively regulates ASS1 expression through the cAMP/AMPK/CEBPB transcriptional axis; PGAM1 knockdown markedly upregulates ASS1 expression, and ASS1 upregulation is required for the anti-proliferative effect of PGAM1 depletion in breast cancer cells. RNA sequencing after PGAM1 knockdown, CEBPB transcription factor pathway analysis, ASS1 knockdown epistasis experiments, in vivo tumor growth assays Molecular oncology Medium 35674458
2019 Androgen receptor (AR) decreases ASS1 protein expression to promote renal cell carcinoma proliferation via the pseudogene ASS1P3: AR binds ASS1P3, which acts as a competing endogenous RNA (ceRNA) decoy for miR-34a-5p; miR-34a-5p binds the 3'UTR of ASS1 to suppress ASS1 protein expression, and AR-driven ASS1P3 upregulation sequesters miR-34a-5p to reduce ASS1. RIP assay demonstrating AR binding to ASS1P3, AGO2 assay, luciferase reporter for miR-34a-5p targeting ASS1 3'UTR, AR/ASS1P3/miR-34a-5p knockdown/overexpression, in vivo xenograft experiments Cell death & disease Medium 31000693
2022 FXR (Farnesoid X receptor) directly promotes ASS1 transcription; FXR agonist obeticholic acid (OCA) upregulates ASS1 expression and enhances arginine synthesis, reducing hepatocyte apoptosis (decreased Cyt C, PARP, and Caspase 3 levels) in TAA-induced acute liver injury. FXR agonist/antagonist treatment, ASS1 transcriptional reporter assays, single-cell RNA-seq data analysis, apoptosis marker measurement, in vivo TAA liver injury model Biochemical and biophysical research communications Low 35477090
2019 Arginine starvation with ADI-PEG20 combined with docetaxel stabilizes c-MYC and causes its nuclear translocation in ASS1-negative tumor cells, which increases hENT1 cell-surface expression and renders cells susceptible to gemcitabine; c-MYC inhibition blocks hENT1 upregulation, placing c-MYC as a required mediator between arginine starvation and gemcitabine sensitization. Protein expression analysis (Western blot), c-MYC activity assays, live-cell immunofluorescence for hENT1 surface localization, FITC-cytosine uptake assay, c-MYC inhibitor rescue experiments, in vivo tumor growth studies Clinical cancer research Medium 31113844
2009 ASS1 was chromosomally localized to the distal long arm of chromosome 9, region 9q34–9qter, by somatic cell hybrid mapping using human cells carrying balanced reciprocal translocations involving chromosome 9. Somatic cell hybrid mapping with balanced reciprocal translocations, subchromosomal assignment Cytogenetics and cell genetics Low 219990
2021 ASS1 loss in fibroblastic foci of IPF-patient lung fibroblasts promotes fibroblast proliferation, migration, and invasion; mechanistically, ASS1 knockdown activates the hepatocyte growth factor receptor Met and its downstream Src–STAT3 signaling axis. ASS1 knockdown/overexpression, proliferation/migration/invasion assays, Western blot for Met, Src, STAT3 activation, bleomycin mouse model Molecular therapy Medium 33508432
2024 β-sitosterol selectively targets ASS1 (identified by network pharmacology and validated in vitro); inhibition of ASS1 by β-sitosterol enhances the interaction between Nrf2 and Keap1, promoting ubiquitin-dependent degradation of Nrf2, which decreases transcription of antioxidant genes HO-1 and NQO1, causing ROS accumulation that upregulates PTEN and suppresses AKT phosphorylation in ovarian cancer cells. Network pharmacology target prediction, ASS1 overexpression/knockdown, Nrf2–Keap1 co-immunoprecipitation, ubiquitination assays, ROS measurement, PTEN/AKT pathway analysis, in vitro and in vivo tumor models Free radical biology & medicine Medium 38364944

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. Nature 314 26560030
2013 The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology. PloS one 186 23951225
2022 Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nature communications 178 35013236
2014 Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells. Science signaling 169 24692592
1991 Antibodies to proliferating cell nuclear antigen as S-phase probes in flow cytometric cell cycle analysis. Cancer research 159 1678682
2017 Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers. Cell reports 129 28122247
1999 Neogenesis vs. apoptosis As main components of pancreatic beta cell ass changes in glucose-infused normal and mildly diabetic adult rats. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 110 10385610
2018 The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer's disease. Progress in neurobiology 81 29733887
2016 A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas. Cell death & disease 78 27735949
2009 Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene. Human mutation 78 19006241
2020 Targeting purine synthesis in ASS1-expressing tumors enhances the response to immune checkpoint inhibitors. Nature cancer 75 35121952
2017 mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia. Free radical biology & medicine 72 28807816
2017 Argininosuccinate synthase 1 (ASS1): A marker of unclassified hepatocellular adenoma and high bleeding risk. Hepatology (Baltimore, Md.) 71 28646562
1992 Use of ass' milk in multiple food allergy. Journal of pediatric gastroenterology and nutrition 71 1593372
2008 Intracellular Aß triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiology of aging 70 18771817
2018 Exercise training as S-Klotho protein stimulator in sedentary healthy adults: Rationale, design, and methodology. Contemporary clinical trials communications 63 30023455
2017 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis. Molecular cell 63 28985504
1998 Carbocyclic adenosine analogues as S-adenosylhomocysteine hydrolase inhibitors and antiviral agents: recent advances. Nucleosides & nucleotides 63 9708366
1979 Regional asssignments of the loci AK3, ACONS, and ASS on human chromosome 9. Cytogenetics and cell genetics 62 219990
2023 ASS1-Mediated Reductive Carboxylation of Cytosolic Glutamine Confers Ferroptosis Resistance in Cancer Cells. Cancer research 61 36892426
2015 Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta neuropathologica 61 26715565
2010 Ancient DNA from Nubian and Somali wild ass provides insights into donkey ancestry and domestication. Proceedings. Biological sciences 61 20667880
2021 Gut flora-targeted photobiomodulation therapy improves senile dementia in an Aß-induced Alzheimer's disease animal model. Journal of photochemistry and photobiology. B, Biology 55 33610085
2019 Arginine Starvation and Docetaxel Induce c-Myc-Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 55 31113844
2017 Serpentine endophytic bacterium Pseudomonas azotoformans ASS1 accelerates phytoremediation of soil metals under drought stress. Chemosphere 51 28686889
2017 Transcription Factor AsMYC2 Controls the Jasmonate-Responsive Expression of ASS1 Regulating Sesquiterpene Biosynthesis in Aquilaria sinensis (Lour.) Gilg. Plant & cell physiology 51 29016977
2007 Ass's milk in children with atopic dermatitis and cow's milk allergy: crossover comparison with goat's milk. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 48 18001430
2018 Acid-Induced Downregulation of ASS1 Contributes to the Maintenance of Intracellular pH in Cancer. Cancer research 46 30573518
2017 Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations. Human mutation 44 28111830
2021 Non-productive angiogenesis disassembles Aß plaque-associated blood vessels. Nature communications 43 34035282
2016 Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1α, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation. Oncotarget 43 27765932
2013 Oxysterols decrease apical-to-basolateral transport of Aß peptides via an ABCB1-mediated process in an in vitro Blood-brain barrier model constituted of bovine brain capillary endothelial cells. Brain research 41 23603412
2021 Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis. Molecular therapy : the journal of the American Society of Gene Therapy 38 33508432
2014 Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents. Acta neuropathologica communications 37 25540024
1995 Identification of a major hepatic copper binding protein as S-adenosylhomocysteine hydrolase. The Journal of biological chemistry 37 7657650
2016 Argininosuccinate synthetase 1 (ASS1) is a common metabolic marker of chemosensitivity for targeted arginine- and glutamine-starvation therapy. Cancer letters 36 27913198
2005 Synthesis, cytotoxicity, cellular uptake and influence on eicosanoid metabolism of cobalt-alkyne modified fructoses in comparison to auranofin and the cytotoxic COX inhibitor Co-ASS. Organic & biomolecular chemistry 34 16010362
2023 Downregulation of argininosuccinate synthase 1 (ASS1) is associated with hypoxia in placental development. Human cell 33 36995581
2019 Androgen receptor regulates ASS1P3/miR-34a-5p/ASS1 signaling to promote renal cell carcinoma cell growth. Cell death & disease 32 31000693
2015 Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities. Journal of medicinal chemistry 32 26010585
1998 Glucocorticoids induce G1 as well as S-phase lengthening in normal human stimulated lymphocytes: differential effects on cell cycle regulatory proteins. Experimental cell research 32 9596999
2024 β-Sitosterol targets ASS1 for Nrf2 ubiquitin-dependent degradation, inducing ROS-mediated apoptosis via the PTEN/PI3K/AKT signaling pathway in ovarian cancer. Free radical biology & medicine 31 38364944
2021 ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism. Cancer & metabolism 30 34861885
2020 WRKY44 represses expression of the wound-induced sesquiterpene biosynthetic gene ASS1 in Aquilaria sinensis. Journal of experimental botany 29 31639819
2015 Tailoring the antibody response to aggregated Aß using novel Alzheimer-vaccines. PloS one 29 25611858
2011 Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus. European journal of pharmacology 29 22200627
2020 lncRNA 00312 Attenuates Cell Proliferation and Invasion and Promotes Apoptosis in Renal Cell Carcinoma via miR-34a-5p/ASS1 Axis. Oxidative medicine and cellular longevity 28 32308805
2011 RP-HPLC-ESI-MS evidenced that salivary cystatin B is detectable in adult human whole saliva mostly as S-modified derivatives: S-Glutathionyl, S-cysteinyl and S-S 2-mer. Journal of proteomics 28 22057043
2024 ASS1 enhances anoikis resistance via AMPK/CPT1A-mediated fatty acid metabolism in ovarian cancer. Cancer letters 27 38914306
2015 Vitamin E: Curse or Benefit in Alzheimer's Disease? A Systematic Investigation of the Impact of α-, γ- and δ-Tocopherol on Aß Generation and Degradation in Neuroblastoma Cells. The journal of nutrition, health & aging 27 26054501
2024 ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response. Nature metabolism 25 38858597
2024 ASS1 inhibits triple-negative breast cancer by regulating PHGDH stability and de novo serine synthesis. Cell death & disease 24 38710705
2022 A Phase 1 study of ADI-PEG20 (pegargiminase) combined with cisplatin and pemetrexed in ASS1-negative metastatic uveal melanoma. Pigment cell & melanoma research 24 35466524
2017 Chromatin remodeling system p300-HDAC2-Sin3A is involved in Arginine Starvation-Induced HIF-1α Degradation at the ASS1 promoter for ASS1 Derepression. Scientific reports 24 28883660
2010 Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes. The American journal of pathology 24 20724589
2022 PGAM1 regulation of ASS1 contributes to the progression of breast cancer through the cAMP/AMPK/CEBPB pathway. Molecular oncology 23 35674458
2022 Aß Pathology and Neuron-Glia Interactions: A Synaptocentric View. Neurochemical research 23 35976488
2018 Aß Facilitates LTD at Schaffer Collateral Synapses Preferentially in the Left Hippocampus. Cell reports 23 29466733
2011 Induction of arginosuccinate synthetase (ASS) expression affects the antiproliferative activity of arginine deiminase (ADI) in melanoma cells. Oncology reports 22 21424129
2001 [Treatment of ASS-Associated Polyposis (ASSAP) with a cysteinyl leukotriene receptor antagonist - a prospective drug study on its antiinflammatory effects]. Laryngo- rhino- otologie 22 11602930
2021 Snail enhances arginine synthesis by inhibiting ubiquitination-mediated degradation of ASS1. EMBO reports 20 34184805
2020 Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans. Scientific reports 19 32678125
2019 Nocardioides yefusunii sp. nov., isolated from Equus kiang (Tibetan wild ass) faeces. International journal of systematic and evolutionary microbiology 19 31511125
2018 Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM. BMC cancer 19 29422017
2010 A highly sensitive peptide substrate for detecting two Aß-degrading enzymes: neprilysin and insulin-degrading enzyme. Journal of neuroscience methods 19 20435063
2021 Phase 1, pharmacogenomic, dose-expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1-deficient non-squamous non-small cell lung cancer. Cancer medicine 17 34382365
2014 Aggregation of Aß(25-35) on DOPC and DOPC/DHA bilayers: an atomic force microscopy study. PloS one 17 25551704
2011 Association of plasma Aß peptides with blood pressure in the elderly. PloS one 17 21525986
2022 Insulin-like growth factor 5 associates with human Aß plaques and promotes cognitive impairment. Acta neuropathologica communications 16 35513854
2015 Metagenomic sequence of saline desert microbiota from wild ass sanctuary, Little Rann of Kutch, Gujarat, India. Genomics data 15 26484162
2014 Neuroprotective effects of electro acupuncture on hypoxic-ischemic encephalopathy in newborn rats Ass. Pakistan journal of pharmaceutical sciences 15 25410062
2011 Mitochondrial genome sequence of the Tibetan wild ass (Equus kiang). Mitochondrial DNA 15 21732718
2022 FXR/ASS1 axis attenuates the TAA-induced liver injury through arginine metabolism. Biochemical and biophysical research communications 14 35477090
2020 Down Regulation of SIRT2 Reduced ASS Induced NSCLC Apoptosis Through the Release of Autophagy Components via Exosomes. Frontiers in cell and developmental biology 14 33344455
2017 Taming the late Quaternary phylogeography of the Eurasiatic wild ass through ancient and modern DNA. PloS one 14 28422966
2002 Controlling Lewis basicity in polythioarsenate fluxes: stabilization of KSnAsS(5) and K(2)SnAs(2)S(6). Extended chains and slabs based on pyramidal beta-[AsS(4)](3-) and [AsS(3)](3-) units. Inorganic chemistry 14 12099862
2023 BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification. Molecular cancer research : MCR 13 36669126
2022 Hepatocyte-derived MANF mitigates ethanol-induced liver steatosis in mice via enhancing ASS1 activity and activating AMPK pathway. Acta pharmacologica Sinica 13 35655095
2014 Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors. Endocrine-related cancer 13 25121552
2018 Amino Acid Uptake Measured by [18F]AFETP Increases in Response to Arginine Starvation in ASS1-Deficient Sarcomas. Theranostics 12 29721066
2011 Inhibition of LPS toxicity by hepatic argininosuccinate synthase (ASS): novel roles for ASS in innate immune responses to bacterial infection. International immunopharmacology 12 21481813
2020 Use of Immunohistochemical Markers (HNF-1β, Napsin A, ER, CTH, and ASS1) to Distinguish Endometrial Clear Cell Carcinoma From Its Morphologic Mimics Including Arias-Stella Reaction. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 11 31094885
2017 PRMT7 Interacts with ASS1 and Citrullinemia Mutations Disrupt the Interaction. Journal of molecular biology 11 28587924
2016 Genomic variants in the ASS1 gene, involved in the nitric oxide biosynthesis and signaling pathway, predict hydroxyurea treatment efficacy in compound sickle cell disease/β-thalassemia patients. Pharmacogenomics 11 26895070
2014 Functional analysis of novel splicing and missense mutations identified in the ASS1 gene in classical citrullinemia patients. Clinica chimica acta; international journal of clinical chemistry 11 25179242
1998 Chromosomal rearrangements in a Somali wild ass pedigree, Equus africanus somaliensis (Perissodactyla, Equidae). Cytogenetics and cell genetics 11 9678344
2022 Asymptomatic ASS1 carriers with high blood citrulline levels. Molecular genetics & genomic medicine 10 35726796
2021 Intracellular arginine-dependent translation sensor reveals the dynamics of arginine starvation response and resistance in ASS1-negative cells. Cancer & metabolism 10 33478587
2019 Citrullinemia type I is associated with a novel splicing variant, c.773 + 4A > C, in ASS1: a case report and literature review. BMC medical genetics 10 31208364
2019 Pre-plaque Aß-Mediated Impairment of Synaptic Depotentiation in a Transgenic Rat Model of Alzheimer's Disease Amyloidosis. Frontiers in neuroscience 10 31474823
2018 Argininosuccinate Synthetase-1 (ASS1) Loss in High-Grade Neuroendocrine Carcinomas of the Urinary Bladder: Implications for Targeted Therapy with ADI-PEG 20. Endocrine pathology 10 29453600
2017 Chryseobacterium salipaludis sp. nov., isolated at a wild ass sanctuary. International journal of systematic and evolutionary microbiology 10 29256852
2014 Argininosuccinate synthetase (ASS) deficiency in high-grade pulmonary neuroendocrine carcinoma: an opportunity for personalized targeted therapy. Journal of cancer research and clinical oncology 10 25548129
2013 Prenatal diagnosis of citrullinemia type 1: a Chinese family with a novel mutation of the ASS1 gene. Brain & development 10 23611581
2009 Citrullinemia type I, classical variant. Identification of ASS-p~G390R (c.1168G>A) mutation in families of a limited geographic area of Argentina: a possible population cluster. Clinical biochemistry 10 19358837
2009 Gut immune balance is as easy as S-F-B. Immunity 10 19833084
2004 Early cirrhosis in a patient with type I citrullinaemia (CTLN1). Journal of inherited metabolic disease 10 15334737
2023 Polymorphic Variants of ASS1 Gene Related to Arginine Metabolism and the Risk of HCC. Protein and peptide letters 9 37254538
2022 ASS1 regulates immune microenvironment via CXCL8 signaling in ovarian cancer. Biochemical and biophysical research communications 9 36182868
2010 Reduced expression of ASS is closely related to clinicopathological features and post-resectional survival of hepatocellular carcinoma. Oncology letters 9 22966251

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