Affinage

NOL3

Nucleolar protein 3 · UniProt O60936

Round 2 corrected Audit flag: wrong gene
Length
208 aa
Mass
22.6 kDa
Annotated
2026-04-29
130 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOL3 (ARC) is a CARD-domain-containing inhibitor of programmed cell death that protects terminally differentiated cells—particularly cardiomyocytes, skeletal myocytes, and neurons—from apoptotic and necrotic stimuli. Its N-terminal CARD engages in nonhomotypic interactions with the death domains of Fas, FADD, TNFR1, and the pro-apoptotic effector Bax, thereby blocking both extrinsic DISC assembly and intrinsic mitochondrial cytochrome c release, as well as TNFα-induced necrosis by preventing RIP1 recruitment to TNFR1 (PMID:15383280, PMID:24440909). CK2-mediated phosphorylation at Thr149 targets ARC to mitochondria and is required for caspase-8 binding, while MDM2-dependent ubiquitin-proteasomal degradation and Ras-MEK/ERK-driven transcriptional and post-translational stabilization set its steady-state levels (PMID:12191471, PMID:17142834, PMID:20392691). In cancer cells ARC accumulates in the nucleus where it binds the p53 tetramerization domain, triggering Crm1-dependent p53 nuclear export and functional inactivation, promoting tumor growth, chemoresistance, and metastasis (PMID:18087040, PMID:22037876).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Identification of ARC as a tissue-restricted, CARD-containing caspase inhibitor established that a dedicated anti-apoptotic protein exists in skeletal and cardiac muscle to block death-receptor signaling.

    Evidence Co-immunoprecipitation and caspase activity assays in 293T cells with death receptor stimulation

    PMID:9560245

    Open questions at the time
    • Endogenous loss-of-function not yet tested
    • Mechanism of selective caspase recognition unknown
    • Intrinsic pathway role not addressed
  2. 1999 Medium

    Discovery of alternative splicing producing a nuclear/nucleolar Nop30 isoform that modulates pre-mRNA splicing revealed that NOL3 has functions beyond apoptosis inhibition.

    Evidence Yeast two-hybrid, Co-IP with splicing factor SRp30c, and alternative splicing reporter assays

    PMID:10196175

    Open questions at the time
    • Physiological relevance of Nop30-mediated splicing regulation not established in vivo
    • Relationship between nucleolar and cytoplasmic isoform functions unclear
  3. 2002 High

    Demonstration that CK2 phosphorylation at Thr149 directs ARC to mitochondria and is required for caspase-8 binding resolved how a cytoplasmic protein gains access to its target.

    Evidence In vitro kinase assay, T149A mutagenesis, subcellular fractionation, and Co-IP

    PMID:12191471

    Open questions at the time
    • Upstream signals controlling CK2-ARC axis not defined
    • Whether dephosphorylation reverses mitochondrial targeting unknown
  4. 2004 High

    Mapping of ARC's nonhomotypic CARD interactions with Fas/FADD death domains and Bax C-terminus unified its roles in extrinsic and intrinsic apoptosis under a single structural mechanism.

    Evidence Reciprocal Co-IP, DISC assembly assays, Bax activation/translocation assays, siRNA knockdown and overexpression

    PMID:15004034 PMID:15383280

    Open questions at the time
    • No atomic-resolution structure of CARD-DD or CARD-Bax complexes
    • Stoichiometry and competition between targets unresolved
  5. 2004 Medium

    Identification of ARC as a calcium-binding protein whose P/E-rich domain binds Ca²⁺ and modulates caspase-8 interaction linked calcium homeostasis to death-pathway regulation.

    Evidence Ca²⁺ overlay assay, Stains-all, Co-IP under varying Ca²⁺, thapsigargin treatment

    PMID:15509781

    Open questions at the time
    • Ca²⁺ binding affinity and kinetics not quantified
    • Structural basis for Ca²⁺-regulated interaction unknown
  6. 2006 High

    ARC knockout mice revealed that endogenous ARC is dispensable for development but essential for cardioprotection under ischemic and biomechanical stress, validating the in vitro anti-apoptotic function in vivo.

    Evidence ARC-null mice subjected to aortic banding and ischemia/reperfusion, plus human failing heart tissue analysis

    PMID:16505176

    Open questions at the time
    • Neuronal phenotypes in ARC-null mice not characterized
    • Redundancy with other anti-apoptotic CARD proteins not explored
  7. 2006 High

    Discovery that MDM2 ubiquitinates ARC for proteasomal degradation, and that ubiquitin-site mutants stabilize ARC and enhance cytoprotection, established post-translational turnover as a key regulatory axis.

    Evidence Pulse-chase, ubiquitin acceptor mutagenesis, MDM2 RING mutant, MDM2-null cell rescue

    PMID:17142452 PMID:17142834

    Open questions at the time
    • Additional E3 ligases not excluded
    • Deubiquitinase for ARC not identified
  8. 2007 High

    Finding that nuclear ARC binds the p53 tetramerization domain and triggers Crm1-dependent p53 export revealed a pro-oncogenic function distinct from its canonical anti-apoptotic role.

    Evidence Co-IP, nuclear/cytoplasmic fractionation, leptomycin B treatment, ARC siRNA in breast cancer cells

    PMID:18087040

    Open questions at the time
    • How ARC gains nuclear entry in cancer cells not resolved
    • Structural interface between ARC CARD and p53 tetramerization domain unmapped
  9. 2010 High

    Demonstration that Ras-MEK/ERK signaling transcriptionally and post-translationally upregulates ARC connected oncogenic signaling to ARC-mediated survival and cell-cycle progression.

    Evidence Activated Ras overexpression, MEK inhibitor, promoter reporter, ubiquitination assay, transgenic mouse

    PMID:20392691

    Open questions at the time
    • Direct transcription factor binding NOL3 promoter not identified
    • Whether other oncogenic pathways converge on ARC unclear
  10. 2012 Medium

    Identification of a NOL3 mutation cosegregating with familial cortical myoclonus linked ARC dysfunction to a Mendelian neurological disorder, extending its physiological relevance beyond the heart.

    Evidence Linkage mapping, targeted sequencing, Sanger validation, in vitro PTM assay in a 4-generation family

    PMID:22926851

    Open questions at the time
    • Precise functional consequence of the mutation on ARC activity in neurons not defined
    • No animal model recapitulating the myoclonus phenotype
  11. 2014 High

    Proof that ARC blocks TNFα-induced necrosis via its CARD domain by disrupting RIP1 recruitment to TNFR1 expanded its role from an apoptosis inhibitor to a general cell death suppressor.

    Evidence ARC overexpression/knockdown, CARD mutagenesis, TNFR1-RIP1 Co-IP, in vivo vaccinia virus model

    PMID:24440909

    Open questions at the time
    • Whether ARC modulates MLKL-dependent necroptosis downstream of RIPK3 not tested
    • Relative contribution of anti-necrotic vs anti-apoptotic activity in vivo unknown
  12. 2015 High

    Characterization of ARC-null skeletal muscle revealed caspase-independent, AIF-mediated apoptosis and mitochondrial calcium vulnerability, showing ARC protects against non-canonical apoptotic pathways.

    Evidence ARC knockout mice, muscle contractility, TUNEL, subcellular fractionation for AIF, isolated mitochondrial calcium stress

    PMID:25596718

    Open questions at the time
    • Direct ARC-AIF interaction not demonstrated
    • Whether fiber-type shift is cell-autonomous not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Structural basis of ARC's nonhomotypic CARD interactions with death domains, Bax, and p53, the mechanism of its nuclear import in cancer cells, and the identity of transcription factors directly driving NOL3 expression downstream of Ras-ERK remain unresolved.
  • No crystal or cryo-EM structure of ARC or its complexes
  • Nuclear import signal or carrier for ARC in cancer not identified
  • Transcription factor occupancy at NOL3 promoter not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-5357801 Programmed Cell Death 6 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2
Partners
BAXCASP8FADDFASMDM2RIPK1TNFR1TP53

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 NOL3/ARC was identified as a novel apoptosis inhibitor containing an N-terminal CARD domain fused to a C-terminal proline/glutamic acid-rich region, expressed predominantly in skeletal muscle and cardiac tissue. Immunoprecipitation showed ARC interacts selectively with caspase-2, caspase-8, and C. elegans CED-3, but not caspase-1, -3, or -9. ARC inhibited caspase-8 enzymatic activity and blocked apoptosis induced by FADD, TRADD, and death receptors CD95/Fas, TNF-R1, and TRAMP/DR3. Immunoprecipitation, caspase activity assays, overexpression in 293T cells, death receptor stimulation assays Proceedings of the National Academy of Sciences of the United States of America High 9560245
1999 Alternative splicing of the NOL3/NOP gene produces two isoforms with different C-terminal ends and distinct subcellular localizations: Nop30 (nuclear/nucleolar) and a cytosolic isoform with a proline/glutamic acid-rich C-terminus. Nop30 multimerizes and binds the RS domain of splicing factor SRp30c but not other splicing factors tested. Overexpression of Nop30 alters alternative exon usage in preprotachykinin and SRp20 reporter genes. Yeast two-hybrid screen, in vitro protein interaction assays, co-immunoprecipitation, overexpression reporter assays, immunofluorescence localization The Journal of biological chemistry Medium 10196175
2002 ARC function is regulated by protein kinase CK2, which phosphorylates ARC at threonine 149. This phosphorylation targets ARC to mitochondria. ARC can only bind caspase-8 when localized to mitochondria, not in the cytoplasm, establishing phosphorylation-dependent subcellular localization as a prerequisite for caspase inhibition. In vitro kinase assay, site-directed mutagenesis, subcellular fractionation, co-immunoprecipitation, overexpression Molecular cell High 12191471
2003 ARC expression is reduced in the CA1 hippocampal region following transient global ischemia, coinciding with TUNEL-positive cell death. Forced expression of ARC in hippocampal neurons or B103 neuronal cells significantly reduced hypoxia-induced cell death, with the C-terminal P/E-rich region being effective in attenuating hypoxic insults. Western blotting, immunohistochemistry, TUNEL assay, forced expression in primary neuronal cultures and neuronal cell lines FEBS letters Medium 12753927
2003 ARC inhibits cardiomyocyte apoptosis in part by reducing K+ efflux through voltage-gated K+ (Kv) channels. Overexpression of ARC in H9c2 cells significantly decreased Kv currents, and suppressed the staurosporine-induced increase in Kv currents and subsequent apoptosis. Whole-cell patch clamp electrophysiology, overexpression in H9c2 cells, staurosporine-induced apoptosis assay American journal of physiology. Cell physiology Medium 12734105
2004 ARC inhibits both extrinsic and intrinsic apoptosis pathways through nonhomotypic death-fold interactions. ARC's CARD domain engages heterotypic interactions with the death domains (DDs) of Fas and FADD, blocking Fas-FADD binding and DISC assembly. ARC also binds Bax via its CARD domain interacting with the Bax C-terminus, inhibiting Bax activation and mitochondrial translocation. Knockdown of endogenous ARC facilitates DISC assembly and triggers spontaneous Bax activation. Co-immunoprecipitation, DISC assembly assays, Bax activation assays, siRNA knockdown, overexpression Molecular cell High 15383280
2004 ARC co-immunoprecipitates with Bax and prevents Bax activation and cytochrome c release in hydrogen peroxide-treated H9c2 cells. The CARD domain of ARC (L31F mutant defective) is required for this interaction. Recombinant ARC protein abrogated Bax-induced cytochrome c release from isolated mitochondria. TAT-ARC transduction blocked cytochrome c release after ischemia/reperfusion. Co-immunoprecipitation, TAT-fusion protein transduction, isolated mitochondria assay, cytochrome c release assay, in vivo ischemia/reperfusion model The Journal of biological chemistry High 15004034
2004 ARC is a Ca2+-dependent regulator of caspase-8 and cell death. ARC protein binds Ca2+ through its C-terminal proline/glutamic acid-rich (P/E-rich) domain as shown by Ca2+ overlay and Stains-all assays. ARC expression reduces cytosolic Ca2+ transients and protects against Ca2+-mediated cytotoxicity. The protein-protein interaction between ARC and caspase-8 is decreased by elevated Ca2+ concentration in vitro and by thapsigargin treatment in vivo, linking calcium binding to regulation of caspase-8 inhibition. Ca2+ overlay assay, Stains-all staining, co-immunoprecipitation, siRNA knockdown, cell death assays with Ca2+ ionophores/thapsigargin Molecular and cellular biology Medium 15509781
2005 ARC is expressed at high levels in various non-myogenic and non-neurogenic human and rat cancer cell lines. In cancer cells, ARC localizes almost exclusively to the nucleus, unlike its cytoplasmic localization in non-cancer cells. Nuclear ARC in cancer cells does not co-localize with the Nop30 isoform (nucleolar). Immunofluorescence, subcellular fractionation, Western blotting in multiple cancer cell lines FEBS letters Medium 15848180
2006 ARC-deficient mice develop normally but show accelerated cardiomyopathy under biomechanical stress (aortic banding) and markedly increased myocardial infarct sizes after ischemia/reperfusion. Increased apoptotic cardiomyocytes were observed in ARC-deficient mice under both stress conditions. ARC protein levels are markedly reduced in failing human hearts. ARC had no effect on hypertrophic cardiomyocyte growth responses. ARC knockout mouse generation, aortic banding model, ischemia/reperfusion model, cardiac function measurements, apoptosis assays, human heart tissue analysis Circulation High 16505176
2006 ARC protein degradation is mediated by the ubiquitin-proteasomal pathway in response to death stimuli. Mutation of ARC ubiquitin acceptor residues stabilizes ARC protein, preserves its steady-state levels during apoptosis, and improves cytoprotection. Decreases in ARC protein levels during apoptosis are post-translational (not transcriptional) and constitute a trigger rather than a consequence of cell death. Pulse-chase experiments, ubiquitin acceptor site mutagenesis, proteasome inhibitor treatment, apoptosis assays The Journal of biological chemistry High 17142452
2006 MDM2 is a critical regulator of ARC protein levels in cardiomyocytes. Oxidative stress reduces ARC levels while upregulating MDM2. MDM2 directly accelerates ARC protein turnover via ubiquitination and proteasomal degradation, requiring a functioning MDM2 RING finger domain (C464A mutant cannot direct ARC degradation). MDM2 knockout fibroblasts show defective ARC degradation rescued by MDM2 reconstitution. MDM2 overexpression and knockdown, MDM2 C464A mutant, MDM2 knockout cells, ubiquitination assay, proteasome inhibitor rescue, Western blotting The Journal of biological chemistry High 17142834
2007 p53 transcriptionally represses ARC at both the mRNA and protein levels in response to reactive oxygen species and anoxia. p53-induced ARC repression is transcription-dependent. ARC can interact with proapoptotic proteins PUMA and Bad via its N-terminus, displacing their association with Bcl-2. p53-mediated ARC repression prevents ARC from counteracting PUMA/Bad proapoptotic activity. p53 knockdown (siRNA), quantitative RT-PCR, Western blotting, co-immunoprecipitation, domain mapping Molecular and cellular biology Medium 17998337
2007 ARC directly binds the p53 tetramerization domain in the nucleus, inhibiting p53 tetramerization. This exposes a nuclear export signal in p53 and triggers Crm1-dependent relocalization of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells results in spontaneous p53 tetramerization, nuclear p53 accumulation, and activation of p53 target genes. Co-immunoprecipitation, nuclear/cytoplasmic fractionation, CRM1 inhibitor (leptomycin B), ARC siRNA knockdown, p53 target gene reporter assays Proceedings of the National Academy of Sciences of the United States of America High 18087040
2008 ARC is the only caspase-8 inhibiting regulator with consistently elevated expression across all stages of renal cell carcinomas. The ratio of ARC to caspase-8 mRNA is significantly increased during RCC carcinogenesis and tumor progression, suggesting ARC's inhibition of caspase-8 contributes to RCC chemoresistance. Quantitative RT-PCR in primary human RCC tissues and non-neoplastic renal tissue across tumor stages Apoptosis : an international journal on programmed cell death Low 18516683
2010 Ras induces ARC expression through effects on both transcription and protein stability. Overexpression of activated N-Ras or H-Ras increases ARC mRNA and protein. Ras activates the NOL3 promoter in a MEK/ERK-dependent manner. Ras also stabilizes ARC protein by suppressing its polyubiquitination and proteasomal degradation. ARC mediates Ras-induced cell survival and cell cycle progression. Activated Ras overexpression, N-Ras siRNA knockdown, promoter reporter assay, MEK inhibitor treatment, ubiquitination assay, transgenic mouse model The Journal of biological chemistry High 20392691
2011 ARC promotes breast carcinogenesis by driving primary tumor growth, invasion, and metastasis, and by conferring chemoresistance. In the PyMT transgenic model, deletion of the ARC-encoding gene nol3 decreased primary tumor burden and markedly reduced lung metastases. Ectopic ARC overexpression in metastatic breast cancer cells increased invasion in vitro and lung metastasis in vivo. RNAi-mediated knockdown of ARC in human MDA-MB-231-LM2 cells reduced tumor volume, local invasion, and lung metastases. ARC knockout in PyMT transgenic mice, ARC overexpression in metastatic cell line, RNAi knockdown in humanized orthotopic model, in vitro invasion assay Cancer research High 22037876
2012 A mutation in NOL3 (identified by targeted sequencing and linkage to chromosome 16q21-22.1) cosegregates with familial cortical myoclonus in a 4-generation Canadian Mennonite family. This mutation was found to alter post-translational modification of NOL3 protein in vitro, suggesting altered NOL3 function underlies neuronal membrane hyperexcitability and myoclonus. SNP mapping, microsatellite linkage, targeted massively parallel sequencing, Sanger sequencing, in vitro post-translational modification assay Annals of neurology Medium 22926851
2014 ARC blocks TNFα-induced regulated necrosis in addition to apoptosis. TNFα-induced necrosis was abrogated by wild-type ARC overexpression but not by a CARD-domain mutant. ARC knockdown exacerbated TNFα-induced necrosis rescued by wild-type but not CARD-defective ARC. The mechanism involves ARC interaction with TNF receptor 1 (TNFR1), interfering with RIP1 recruitment to TNFR1, a critical step in TNFα-induced necrosis. ARC overexpression and siRNA knockdown, CARD domain mutagenesis, co-immunoprecipitation with TNFR1, RIP1 recruitment assay, in vivo vaccinia virus infection model Cell death and differentiation High 24440909
2015 ARC deficiency in skeletal muscle leads to lower maximum tetanic force, fiber type shift toward type II fibers, reduced fiber cross-sectional area, increased DNA fragmentation, and elevated apoptosis-inducing factor (AIF) in cytosolic fractions. Mitochondria from ARC KO red muscle are more susceptible to calcium stress. These effects occur independent of caspase or calpain activation, indicating caspase-independent mitochondrial apoptotic signaling. ARC knockout mice, muscle contractility measurements, fiber typing, TUNEL assay, subcellular fractionation, AIF Western blot, isolated mitochondrial calcium stress assay Apoptosis : an international journal on programmed cell death High 25596718
2016 Tat-fused NOL3 protein transduces into HT22 hippocampal cells and inhibits H2O2-induced reactive oxygen species production, DNA fragmentation, and mitochondrial membrane potential loss. Tat-NOL3 prevents neuronal cell death by regulating apoptotic signaling including Bax, Bcl-2, caspase-2, -3, -8, PARP, and p53. In a forebrain ischemia model, Tat-NOL3 transduced into brain tissue and protected CA1 hippocampal neurons by regulating microglial and astrocyte activation. TAT-fusion protein transduction, ROS measurement, mitochondrial membrane potential assay, Western blotting of apoptotic markers, in vivo ischemia model with immunohistochemistry International journal of molecular medicine Medium 27221790
2019 ARC regulates leukemia-microenvironment interactions through an ARC/IL1β/Cox-2/PGE2/β-catenin/ARC circuit. AML-MSC cocultures increase Cox-2 expression in MSCs and PGE2 production in an ARC/IL1β-dependent manner. PGE2 induces β-catenin expression in AML cells, which in turn regulates ARC levels. β-catenin inhibition decreases ARC and sensitizes AML cells to chemotherapy. ARC-knockdown AML cells in mice show lower IL1β/PGE2 levels and increased chemosensitivity. AML-MSC co-culture, ARC knockdown, β-catenin inhibition, ELISA for IL1β and PGE2, xenograft mouse model with ARC-knockdown cells Cancer research Medium 30674535
2021 NOL3/ARC inhibits both intrinsic (mitochondrial) and extrinsic (death receptor) apoptosis pathways, as well as necrosis, through its CARD domain. ARC interacts with Bax, Bcl-2, caspase-2, caspase-8, FADD, Fas, and TNFR1. ARC also modulates ER stress responses, oxidative stress, and Ca2+ homeostasis in cardiomyocytes. CK2-mediated phosphorylation at Thr149 governs ARC's mitochondrial localization and caspase inhibitory function. Review synthesizing co-immunoprecipitation, mutagenesis, knockout mouse data, and in vitro/in vivo functional studies from multiple prior publications Apoptosis : an international journal on programmed cell death Medium 33604728

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Genome-scale RNAi screen for host factors required for HIV replication. Cell host & microbe 627 18976975
2006 Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 624 17088211
2010 The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 511 20211139
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2011 New views of Arc, a master regulator of synaptic plasticity. Nature neuroscience 398 21278731
2018 The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer. Cell 381 29328916
2009 The Arc of synaptic memory. Experimental brain research 369 19690847
1999 Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 363 10235267
1998 ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. Proceedings of the National Academy of Sciences of the United States of America 301 9560245
2011 Arc in synaptic plasticity: from gene to behavior. Trends in neurosciences 300 21963089
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2009 The geometry of leptin action in the brain: more complicated than a simple ARC. Cell metabolism 231 19187770
2016 A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nature neuroscience 213 27869800
2010 Arc regulates spine morphology and maintains network stability in vivo. Proceedings of the National Academy of Sciences of the United States of America 212 20921410
2005 Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus. Proceedings of the National Academy of Sciences of the United States of America 205 16020527
2010 Age-related changes in Arc transcription and DNA methylation within the hippocampus. Neurobiology of aging 167 20189687
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2004 Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions. Molecular cell 147 15383280
2004 Apoptosis repressor with caspase recruitment domain protects against cell death by interfering with Bax activation. The Journal of biological chemistry 142 15004034
2017 Arc protein: a flexible hub for synaptic plasticity and cognition. Seminars in cell & developmental biology 138 28890419
2002 Phosphorylation by protein kinase CK2: a signaling switch for the caspase-inhibiting protein ARC. Molecular cell 137 12191471
2015 Structural basis of arc binding to synaptic proteins: implications for cognitive disease. Neuron 135 25864631
2002 A component of the ARC/Mediator complex required for TGF beta/Nodal signalling. Nature 135 12167862
2013 Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity. Nature neuroscience 121 23749147
2015 Motor Learning Consolidates Arc-Expressing Neuronal Ensembles in Secondary Motor Cortex. Neuron 118 26051420
2017 Mammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism. Nature communications 99 28986522
2010 Time-dependent expression of Arc and zif268 after acquisition of fear conditioning. Neural plasticity 97 20592749
2006 Apoptosis repressor with caspase recruitment domain is required for cardioprotection in response to biomechanical and ischemic stress. Circulation 97 16505176
2014 Triad3A regulates synaptic strength by ubiquitination of Arc. Neuron 96 24945773
2010 Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells. Molecular & cellular proteomics : MCP 93 21044950
2022 The genetic history of the Southern Arc: A bridge between West Asia and Europe. Science (New York, N.Y.) 91 36007055
2007 p53 initiates apoptosis by transcriptionally targeting the antiapoptotic protein ARC. Molecular and cellular biology 90 17998337
2007 Regulation of p53 tetramerization and nuclear export by ARC. Proceedings of the National Academy of Sciences of the United States of America 88 18087040
2008 UV-enhanced bioactivity and cell response of micro-arc oxidized titania coatings. Acta biomaterialia 87 18430620
2006 Clinical and molecular genetic features of ARC syndrome. Human genetics 86 16896922
2012 MicroRNA regulation of the synaptic plasticity-related gene Arc. PloS one 81 22844515
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2014 MicroRNA-185 regulates chemotherapeutic sensitivity in gastric cancer by targeting apoptosis repressor with caspase recruitment domain. Cell death & disease 79 24763054
2015 Localization and local translation of Arc/Arg3.1 mRNA at synapses: some observations and paradoxes. Frontiers in molecular neuroscience 76 25628532
2009 Arachidonic acid, ARC channels, and Orai proteins. Cell calcium 76 19278724
2018 Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake. PLoS biology 74 29689050
2018 The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility. Neuron 74 29861284
1985 The bacteriophage P22 arc and mnt repressors. Overproduction, purification, and properties. The Journal of biological chemistry 74 2995361
2006 Ubiquitination and degradation of the anti-apoptotic protein ARC by MDM2. The Journal of biological chemistry 72 17142834
2004 ARC channels: a novel pathway for receptor-activated calcium entry. Physiology (Bethesda, Md.) 70 15546853
2019 Adolescent Alcohol Exposure Epigenetically Suppresses Amygdala Arc Enhancer RNA Expression to Confer Adult Anxiety Susceptibility. Biological psychiatry 67 30827484
2000 Serotonergic regulation of mRNA expression of Arc, an immediate early gene selectively localized at neuronal dendrites. Neuropharmacology 67 10698012
2015 Arc is a flexible modular protein capable of reversible self-oligomerization. The Biochemical journal 62 25748042
2005 Apoptosis repressor with caspase recruitment domain (ARC) is expressed in cancer cells and localizes to nuclei. FEBS letters 57 15848180
2005 ARC, an apoptosis suppressor limited to terminally differentiated cells, is induced in human breast cancer and confers chemo- and radiation-resistance. Cell death and differentiation 57 15861191
2004 Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. Genome research 57 15342556
2007 STIM1 and the noncapacitative ARC channels. Cell calcium 55 17391754
2005 Immediate early gene (ZENK, Arc) expression in the auditory forebrain of female canaries varies in response to male song quality. Journal of neurobiology 55 15898065
2019 An ARC-Regulated IL1β/Cox-2/PGE2/β-Catenin/ARC Circuit Controls Leukemia-Microenvironment Interactions and Confers Drug Resistance in AML. Cancer research 53 30674535
2014 Connecting ears to eye muscles: evolution of a 'simple' reflex arc. Brain, behavior and evolution 52 24776996
2011 Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance. Cancer research 51 22037876
2004 Calcium binding of ARC mediates regulation of caspase 8 and cell death. Molecular and cellular biology 51 15509781
2016 High-throughput analyses of hnRNP H1 dissects its multi-functional aspect. RNA biology 50 26760575
2008 ARC (apoptosis repressor with caspase recruitment domain) is a novel marker of human colon cancer. Cell cycle (Georgetown, Tex.) 48 18469522
2006 The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant. The Journal of biological chemistry 47 17142452
2003 Apoptosis repressor with caspase domain inhibits cardiomyocyte apoptosis by reducing K+ currents. American journal of physiology. Cell physiology 44 12734105
2015 Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk. PloS one 42 26474411
2018 Arc/Arg3.1 mediates a critical period for spatial learning and hippocampal networks. Proceedings of the National Academy of Sciences of the United States of America 41 30442670
2020 Arc silence aggravates traumatic neuronal injury via mGluR1-mediated ER stress and necroptosis. Cell death & disease 39 31919348
2014 Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features. Italian journal of pediatrics 38 25239142
2017 Regulation of spine structural plasticity by Arc/Arg3.1. Seminars in cell & developmental biology 37 28943393
2021 An mPOA-ARCAgRP pathway modulates cold-evoked eating behavior. Cell reports 36 34380037
2011 Neuroinflammation and the plasticity-related immediate-early gene Arc. Brain, behavior, and immunity 36 21320587
2015 Enhancement of dynamin polymerization and GTPase activity by Arc/Arg3.1. Biochimica et biophysica acta 35 25783003
1999 Alternative splicing determines the intracellular localization of the novel nuclear protein Nop30 and its interaction with the splicing factor SRp30c. The Journal of biological chemistry 35 10196175
2017 The mechanistic link between Arc/Arg3.1 expression and AMPA receptor endocytosis. Seminars in cell & developmental biology 32 28890421
2017 Transcriptional and post-translational regulation of Arc in synaptic plasticity. Seminars in cell & developmental biology 32 28890422
2015 The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection. Nucleic acids research 32 26612866
2008 Caspase-8 and its inhibitors in RCCs in vivo: the prominent role of ARC. Apoptosis : an international journal on programmed cell death 32 18516683
2018 Sleep loss disrupts Arc expression in dentate gyrus neurons. Neurobiology of learning and memory 31 29635031
2017 The Arc Gene Confers Genetic Susceptibility to Alzheimer's Disease in Han Chinese. Molecular neurobiology 31 28108859
2013 Involvement of hippocampal Arc in amnesia and its recovery by alcoholic extract of Ashwagandha leaves. Neurobiology of learning and memory 31 24012642
2010 Induction of the apoptosis inhibitor ARC by Ras in human cancers. The Journal of biological chemistry 30 20392691
2005 Regulation of activity-regulated cytoskeleton protein (Arc) mRNA after acute and chronic electroconvulsive stimulation in the rat. Brain research 30 16309632
2017 GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation. Frontiers in molecular neuroscience 29 28670266
2013 Differential activation of amygdala Arc expression by positive and negatively valenced emotional learning conditions. Frontiers in behavioral neuroscience 29 24367308
2022 Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer's Disease. Biomedicines 28 36009494
2019 Immune inflammation indicators in anal cancer patients treated with concurrent chemoradiation: training and validation cohort with online calculator (ARC: Anal Cancer Response Classifier). Cancer management and research 28 31118786
2017 Arc ubiquitination in synaptic plasticity. Seminars in cell & developmental biology 28 28890418
2016 ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination. Immunity 28 27496733
2018 Position- and Time-Dependent Arc Expression Links Neuronal Activity to Synaptic Plasticity During Epileptogenesis. Frontiers in cellular neuroscience 27 30154698
2015 A Neuronal Activity-Dependent Dual Function Chromatin-Modifying Complex Regulates Arc Expression. eNeuro 27 26464965
2012 STIM and Orai proteins and the non-capacitative ARC channels. Frontiers in bioscience (Landmark edition) 27 22201777
2008 Basal and stress-induced modulation of activity-regulated cytoskeletal associated protein (Arc) in the rat brain following duloxetine treatment. Psychopharmacology 27 18704370
2003 Cleavage site of a major yolk protein (MYP) determined by cDNA isolation and amino acid sequencing in sea urchin, Hemicentrotus pulcherrimus. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 27 12781975
2021 Intercellular Arc Signaling Regulates Vasodilation. The Journal of neuroscience : the official journal of the Society for Neuroscience 26 34326146
2020 Loss of Arc attenuates the behavioral and molecular responses for sleep homeostasis in mice. Proceedings of the National Academy of Sciences of the United States of America 26 32350140
2022 Molecular physiology of Arc/Arg3.1: The oligomeric state hypothesis of synaptic plasticity. Acta physiologica (Oxford, England) 25 36073248
2021 Role of apoptosis repressor with caspase recruitment domain (ARC) in cell death and cardiovascular disease. Apoptosis : an international journal on programmed cell death 24 33604728
2013 Changes in the Egr1 and Arc expression in brain structures of pentylenetetrazole-kindled rats. Pharmacological reports : PR 24 23744421
2020 Activation of the ARCPOMC→MeA Projection Reduces Food Intake. Frontiers in neural circuits 23 33250721
2017 Arc - An endogenous neuronal retrovirus? Seminars in cell & developmental biology 23 28941877
2003 Down-regulation of ARC contributes to vulnerability of hippocampal neurons to ischemia/hypoxia. FEBS letters 23 12753927
2020 Effects of Ketamine on Learning and Memory in the Hippocampus of Rats through ERK, CREB, and Arc. Brain sciences 22 33383707
2011 Altered learning and Arc-regulated consolidation of learning in striatum by methamphetamine-induced neurotoxicity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 21 22071872
2009 Arc-repressor dimerization on DNA: folding rate enhancement by colocalization. Biophysical journal 21 19450491
2019 Secreted Amyloid Precursor Protein-Alpha Promotes Arc Protein Synthesis in Hippocampal Neurons. Frontiers in molecular neuroscience 20 31474829
2018 Effect of vanadium released from micro-arc oxidized porous Ti6Al4V on biocompatibility in orthopedic applications. Colloids and surfaces. B, Biointerfaces 20 29803152
2016 Rare mutations and hypermethylation of the ARC gene associated with schizophrenia. Schizophrenia research 20 27464451
2000 Activation of an effector immediate-early gene arc by methamphetamine. Annals of the New York Academy of Sciences 20 11085305
2020 The continuing arc toward phototropic enlightenment. Journal of experimental botany 19 31907539
2014 A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis. Cell death and differentiation 19 24440909
2012 Familial cortical myoclonus with a mutation in NOL3. Annals of neurology 18 22926851
2017 MSK1 regulates transcriptional induction of Arc/Arg3.1 in response to neurotrophins. FEBS open bio 17 28593137
2017 Community Structure of Lithotrophically-Driven Hydrothermal Microbial Mats from the Mariana Arc and Back-Arc. Frontiers in microbiology 17 28970817
2017 Chemogenomic analysis reveals key role for lysine acetylation in regulating Arc stability. Nature communications 17 29162813
2016 Tat-NOL3 protects against hippocampal neuronal cell death induced by oxidative stress through the regulation of apoptotic pathways. International journal of molecular medicine 17 27221790
2007 Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells. Oncogene 17 17724478
2023 NMDA Receptor-Arc Signaling Is Required for Memory Updating and Is Disrupted in Alzheimer's Disease. Biological psychiatry 16 36796600
2019 Membrane Morphologies Induced by Arc-Shaped Scaffolds Are Determined by Arc Angle and Coverage. Biophysical journal 16 30902368
2015 Functional, morphological, and apoptotic alterations in skeletal muscle of ARC deficient mice. Apoptosis : an international journal on programmed cell death 16 25596718
2013 ARC is highly expressed in nasopharyngeal carcinoma and confers X-radiation and cisplatin resistance. Oncology reports 16 23877130
2003 The activity-regulated cytoskeleton-associated (Arc) gene is a new light-inducible early gene in the mouse suprachiasmatic nucleus. Neuroscience 16 12617955
2022 Wired to Connect: The Autonomic Socioemotional Reflex Arc. Frontiers in psychology 15 35814106
2021 mRNA Trafficking in the Nervous System: A Key Mechanism of the Involvement of Activity-Regulated Cytoskeleton-Associated Protein (Arc) in Synaptic Plasticity. Neural plasticity 15 34603440
2007 mRNA expression of activity-regulated cytoskeleton-associated protein (arc) in the amygdala-kindled rats. Brain research 15 18062938