Affinage

RELA

Transcription factor p65 · UniProt Q04206

Length
551 aa
Mass
60.2 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RELA/RelA (p65) is the principal transcriptional effector of canonical NF-κB signaling, held inactive in the cytoplasm and released to drive inflammatory, metabolic, and cell-fate gene programs upon stimulus (PMID:9831247, PMID:22842493). Its activity is governed by a dense post-translational code: IKK- or MSK1/PKA-dependent phosphorylation at Ser536 and Ser276 licenses assembly with the coactivators CBP/p300, which acetylate RelA at K221 (enhancing DNA binding and impairing IκBα reassembly) and K310 (required for full transcriptional activity) (PMID:12456660, PMID:16135789, PMID:24019758). Structurally, the RelA transactivation domain (TA2) folds upon binding the TAZ1 domain of CBP/p300 while its DNA-binding domain engages the KIX domain in a Ser276-phosphorylation-dependent manner, coordinating activation of large gene sets and the IκBα-mediated negative feedback loop (PMID:24019758). This activating code is opposed by dephosphorylation (PP2A, PPM1A) and by PRMT1-mediated arginine dimethylation at R30 in the DNA-binding loop, which blocks DNA binding (PMID:11591705, PMID:23812431, PMID:27051065), while TIP60 sustains acetyl-K310 levels and MIIP shields RelA from HDAC6 deacetylation (PMID:22249179, PMID:29038521). Beyond canonical inflammation, deamidation by CAD reprograms RelA toward glycolytic gene expression, and RelA represses or activates target promoters governing autophagy (BECN1), metabolism (PDE3B, PRKN, ZBTB7A), regulatory T cell identity (FOXP3), and senescence-associated programs (PMID:32325032, PMID:19289499, PMID:26038580, PMID:21268019, PMID:38409852, PMID:31271899, PMID:33459422). RelA also acts non-transcriptionally: stress drives COMMD1-dependent ubiquitination and nucleolar translocation that triggers NPM/BAX-dependent apoptosis, and it sits upstream of both apoptotic and necroptotic cell-death pathways via A20/RIPK3 control (PMID:20048074, PMID:21660047, PMID:29167229, PMID:33314666). Oncogenic C11orf95/ZFTA-RELA fusions enter the nucleus constitutively to activate NF-κB and neoplastic transcriptional programs in ependymoma, while dominant-negative truncating RELA mutations cause an autoinflammatory type I interferonopathy through impaired NF-κB and enhanced TLR7-driven interferon production (PMID:24553141, PMID:33741710, PMID:37273177).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 Medium

    Established that RelA engages in mutually repressive crosstalk with nuclear hormone receptors, defining an early mechanism for integrating inflammatory and endocrine signaling.

    Evidence In vitro protein interaction and reporter assays with progesterone and androgen receptors

    PMID:8626413 PMID:8798655

    Open questions at the time
    • Interaction with AR is weak
    • Structural basis of mutual repression undefined
    • Not tied to specific endogenous target genes
  2. 1998 Medium

    Showed RelA cooperates combinatorially with other transcription factors on composite promoter elements, explaining cell-type-specific target gene selection.

    Evidence EMSA with recombinant proteins and reporter assays on the ICAM-1 promoter NF-κB/C/EBP element

    PMID:9831247

    Open questions at the time
    • Basis of cell-type specificity not resolved
    • No structure of the cooperative complex
  3. 2002 High

    Resolved that site-specific acetylation by p300/CBP encodes distinct functional outputs, transforming RelA from a binary switch into a tunable transcription factor.

    Evidence In vitro acetylation, K-to-R mutagenesis, and dominant-negative p300 in cells

    PMID:12456660

    Open questions at the time
    • Deacetylase counterparts not identified here
    • In vivo stoichiometry of modifications unknown
  4. 2005 High

    Linked upstream phosphorylation to downstream acetylation, establishing an ordered modification cascade controlling RelA activation.

    Evidence Phospho-specific antibodies, catalytically inactive IKK/PKA mutants, RelA-/- MEF reconstitution, ChIP

    PMID:15923614 PMID:16135789

    Open questions at the time
    • Quantitative kinetics of the cascade undefined
    • Stoichiometric coupling in vivo not measured
  5. 2001 High

    Identified phosphatases as direct negative regulators, showing RelA phosphorylation is reversible and actively opposed.

    Evidence Co-IP with domain mapping and in vitro dephosphorylation with purified PP2A; later in vitro PPM1A phosphatase assays

    PMID:11591705 PMID:23812431

    Open questions at the time
    • Site specificity of PP2A on RelA not fully resolved
    • Physiological triggers of dephosphorylation undefined
  6. 2009 Medium

    Demonstrated RelA's transcriptional reach beyond inflammation into autophagy and senescence, and its requirement for genomic stability.

    Evidence ChIP/EMSA at the BECN1 promoter and RelA-/- fibroblast senescence and DNA-repair assays

    PMID:19289499 PMID:19779484

    Open questions at the time
    • Mechanism linking RelA loss to DNA repair defects unresolved
    • Direct repair targets not identified
  7. 2010 High

    Revealed a non-canonical stress pathway in which COMMD1-dependent ubiquitination drives RelA into the nucleolus, decoupling RelA localization from transcription.

    Evidence Co-IP, gain/loss-of-function, NoLS mutagenesis, and fluorescence microscopy; followed by NoLS-RelA fusion epistasis with NPM knockdown

    PMID:20048074 PMID:21660047

    Open questions at the time
    • Identity of the full ubiquitin ligase complex incomplete
    • Physiological stress signals targeting RelA to nucleolus undefined
  8. 2013 High

    Provided the structural basis for RelA-coactivator engagement, explaining how phosphorylation gates coactivator recruitment genome-wide.

    Evidence NMR structure of RelA-TA2:TAZ1, ITC, point mutants, and genome-wide expression/ChIP analysis

    PMID:24019758

    Open questions at the time
    • Full ternary architecture with DNA not resolved
    • Dynamics of KIX vs TAZ1 occupancy in vivo unclear
  9. 2014 High

    Identified an oncogenic gain-of-function in which a fusion protein constitutively activates the canonical RelA program to drive ependymoma.

    Evidence C11orf95-RELA fusion expression, neural stem cell transformation, and mouse tumor models

    PMID:24553141

    Open questions at the time
    • Contribution of the C11orf95 moiety to genomic targeting not yet defined here
  10. 2016 High

    Added arginine methylation as a repressive mark directly inhibiting RelA DNA binding, broadening the modification code beyond phospho/acetyl.

    Evidence Co-IP, in vitro PRMT1 methylation, MD simulation, mutagenesis, and ChIP

    PMID:27051065

    Open questions at the time
    • Demethylase counterpart not identified
    • Crosstalk with acetylation at neighboring residues unexplored
  11. 2020 High

    Showed deamidation reprograms RelA target selectivity toward glycolysis, connecting NF-κB modification to cancer metabolism.

    Evidence In vitro CAD deamidation, mass spectrometry, RELA mutants, and glycolytic gene profiling across cancer lines

    PMID:32325032

    Open questions at the time
    • Reversal of deamidation not addressed
    • Structural impact on DNA-binding specificity undefined
  12. 2021 High

    Defined how RelA fusion proteins seize non-canonical genomic sites and coactivators, and how RelA dynamics dictate cell-death decisions.

    Evidence Multi-omics of ZFTA-RELA with coactivator pharmacology and mouse models; live-cell imaging and modeling of A20/RIPK3 feedforward circuit

    PMID:33314666 PMID:33459422 PMID:33741710

    Open questions at the time
    • Determinants of PLAGL-motif targeting by the fusion unresolved
    • Single-cell heterogeneity in death decisions incompletely mapped
  13. 2023 High

    Established that loss-of-function dominant-negative RELA mutations cause autoinflammatory disease through impaired NF-κB and excess type I interferon.

    Evidence Patient cell functional studies, TLR7 stimulation, and dominant-negative RelA expression in RelA-/- MEFs across families

    PMID:37273177

    Open questions at the time
    • Mechanistic link between NF-κB loss and IFN gain not fully dissected
    • Genotype-phenotype correlation across mutation positions incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the combinatorial post-translational code (phospho/acetyl/methyl/deamidation/PARylation), coactivator choice, and subcellular trafficking are integrated to select among RelA's divergent inflammatory, metabolic, autophagic, and cell-death gene programs in a given cell remains unresolved.
  • No unified model linking modification state to genome-wide target selection
  • Quantitative crosstalk between competing modifications undefined
  • Cell-type determinants of canonical vs non-canonical RelA fate unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 3 GO:0005730 nucleolus 2 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 2
Partners
CEBPBCOMMD1CREBBP/EP300FOXO3KAT5PPM1APPP2R1APRMT1
Complex memberships
NF-κB (canonical RelA/p50)

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 p300 and CBP acetyltransferases acetylate RelA principally at lysines 218, 221, and 310. Acetylation at K221 enhances DNA binding and impairs IκBα assembly, while acetylation at K310 is required for full transcriptional activity without affecting DNA binding or IκBα assembly. In vitro acetylation assay, lysine-to-arginine mutagenesis, dominant-negative p300 co-expression, co-immunoprecipitation The EMBO journal High 12456660
2005 Phosphorylation of RelA at serine 276 (by MSK1/PKA) or serine 536 (by IKK1/IKK2) promotes assembly of phospho-RelA with p300, thereby enhancing p300-mediated acetylation of RelA at lysine 310, which increases transcriptional activity. Catalytically inactive IKK or PKA mutants blocked K310 acetylation. Anti-acetyl-K310 RelA antibody, in vitro p300 acetylation assay, catalytically inactive kinase mutants, RelA-deficient MEF reconstitution, chromatin immunoprecipitation (E-selectin promoter) Molecular and cellular biology High 16135789
2001 Protein phosphatase 2A (PP2A) physically associates with RelA via its PR65 (subunit A) subunit through both the N- and C-terminal regions of RelA, and the purified PP2A core enzyme directly dephosphorylates RelA in a concentration-dependent manner. Co-immunoprecipitation, in vitro dephosphorylation assay with purified PP2A, okadaic acid inhibitor studies The Journal of biological chemistry High 11591705
2013 The DNA-binding domain of RelA interacts with the KIX domain of CBP/p300, and the transcriptional activation domain (TA2) of RelA binds the TAZ1 domain of CBP/p300. NMR structure of RelA-TA2:TAZ1 complex shows RelA-TA2 folds upon binding through conserved hydrophobic sites. Ser276 phosphorylation is prerequisite for the KIX interaction. Both interactions together control a large set of RelA-activated genes and regulate the NF-κB negative feedback loop through IκBα. NMR structure determination, isothermal calorimetry, RelA point mutants, genome-wide gene expression analysis, chromatin immunoprecipitation, mathematical modeling PLoS biology High 24019758
2009 RSV infection activates cytoplasmic MSK1 in a reactive-oxygen-species-dependent manner; MSK1 phosphorylates RelA at Ser276, which is required for RSV-induced NF-κB-dependent gene expression. A RelA S276A mutation in RelA−/− MEFs failed to support RSV-induced cytokine gene expression. Site-directed mutagenesis (S276A), siRNA knockdown of MSK1, ROS inhibition, reconstitution of RelA−/− MEFs, NF-κB reporter assays Journal of virology High 19706715
2013 PPM1A (a PP2C family phosphatase) directly dephosphorylates RelA at S536 and S276 in vitro and in cells, selectively inhibiting NF-κB transcriptional activity and decreasing expression of MCP-1/CCL2 and IL-6. PPM1A depletion enhanced NF-κB-dependent cell invasion. In vitro phosphatase assay, immunoblotting with phospho-specific antibodies, siRNA knockdown, invasion assays, mouse metastasis model Oncogene High 23812431
2016 PRMT1 (type I protein arginine methyltransferase 1) directly interacts with the Rel homology domain of RelA and asymmetrically dimethylates RelA at R30, a residue in the DNA-binding L1 loop, inhibiting RelA binding to DNA and repressing NF-κB target genes in response to TNFα. Co-immunoprecipitation, in vitro methylation assay, molecular dynamics simulation, mutagenesis, chromatin immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 27051065
2012 TIP60 histone acetyltransferase interacts with RelA/p65 via its HAT domain and maintains acetylated K310 RelA levels in the TNFα-dependent NF-κB signaling pathway, facilitating sequential recruitment of acetyl-K310 RelA to IL-6, IL-8, c-IAP1, and XIAP promoters with concomitant H3/H4 acetylation. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, western blotting The Journal of biological chemistry Medium 22249179
2010 Stress-induced nucleolar translocation of RelA is preceded by ubiquitination of RelA. COMMD1 binds RelA in response to stress and acts as a rate-limiting component of the RelA ubiquitin ligase complex; COMMD1 overexpression promotes nucleolar targeting of RelA while knockdown blocks it, retaining RelA in the nucleoplasm. The nucleolar localization signal (amino acids 27–30) is critical for ubiquitination. Co-immunoprecipitation, siRNA knockdown, overexpression, fluorescence microscopy, domain mutagenesis Cancer research Medium 20048074
2011 Direct targeting of RelA to the nucleolus (via a viral NoLS-RelA fusion) induces apoptosis independently of NF-κB transcriptional activity. This requires nucleophosmin (NPM/B23.1): nucleolar RelA causes NPM relocalization from the nucleolus to the cytoplasm, and cytoplasmic NPM facilitates mitochondrial accumulation of BAX to mediate apoptosis. Viral NoLS-RelA fusion construct, siRNA knockdown of NPM, subcellular fractionation, live-cell imaging, TUNEL assay, BAX mitochondrial accumulation assay Cell death and differentiation High 21660047
2014 C11orf95-RELA fusion proteins (arising from chromothripsis of chromosome 11q13.1) translocate spontaneously to the nucleus to activate NF-κB target genes and transform neural stem cells to form ependymomas in mice, establishing the fusion as an oncogenic driver of canonical NF-κB signaling. Fusion protein expression, nuclear translocation assay, neural stem cell transformation, mouse tumor model, gene expression analysis Nature High 24553141
2021 ZFTA-RELA (ZRfus) fusion activates NF-κB target genes and binds thousands of unique genomic sites enriched with PLAGL transcription factor motifs beyond canonical κB sites. ZRfus recruits transcriptional coactivators BRD4, EP300, CBP, and Pol2 to activate neoplastic transcriptional programs involving MAPK, focal adhesion, and gene imprinting networks. CUT&RUN, ChIP-seq, ATAC-seq, RNA-seq, pharmacological inhibition of BRD4/EP300/CBP, autochthonous mouse tumor model via in utero electroporation Cancer discovery High 33741710
2021 In senescent cells, DNA double-strand breaks activate two mechanistically distinct phases of NF-κB: an early IKK/proteasome-dependent phase controlling anti-apoptotic genes, and a late IKK- and proteasome-independent phase driven by altered phosphorylation of RelA/p65 (in part via GSK3β) that silences NFKBIA transcription to constitutively activate NF-κB for SASP gene expression. RNA-sequencing, genetic KO (NFKBIA), pharmacological inhibition (IKK, proteasome, GSK3β), phospho-specific immunoblotting, in vitro and in vivo senescence models The EMBO journal High 33459422
2020 The enzyme CAD deamidates the RelA subunit of NF-κB in cancer cells; this post-translational modification switches RelA function from NF-κB-responsive inflammatory gene expression to glycolytic enzyme expression, promoting aerobic glycolysis and cell proliferation. In vitro deamidation assay, mass spectrometry, RELA mutant expression, glycolytic enzyme expression profiling, cancer cell line survey, glycolytic enzyme inhibition Cell metabolism High 32325032
2012 LPS stimulation in macrophages promotes PARP-1 binding to RelA/p65 and poly(ADP-ribosyl)ation of RelA, which upregulates NF-κB transcriptional activity and proinflammatory cytokine expression. ERK-dependent phosphorylation of PARP-1 mediates this PARP-1–RelA interaction. Co-immunoprecipitation, signal pathway inhibitors (ERK inhibitor), reporter assays, cytokine mRNA quantification Human immunology Medium 22391342
2017 EGF stimulation induces PKCε-dependent phosphorylation of MIIP at Ser303; phospho-MIIP interacts with nuclear RelA, preventing HDAC6-mediated deacetylation of RelA and thereby enhancing RelA transcriptional activity and colorectal cancer metastasis. PP1 mediates MIIP-S303 dephosphorylation to oppose this process. Co-immunoprecipitation, phospho-specific antibodies, siRNA knockdown, kinase assay, HDAC6 deacetylation assay, metastasis assays Nature communications High 29038521
2009 p65/RelA directly binds a conserved κB site in the BECN1 (Atg6) promoter both in vitro and in living cells (ChIP in PMA-ionomycin–stimulated Jurkat cells), upregulating BECN1 mRNA and protein and increasing autophagy. EMSA, chromatin immunoprecipitation, luciferase reporter, siRNA knockdown, autophagy assays Molecular and cellular biology Medium 19289499
2009 RelA/p65 is required for cellular senescence maintenance: RelA/p65−/− primary fibroblasts immortalize faster than wild-type cells, accompanied by genomic instability (increased DNA mutations, gene deletions, chromosomal translocations) linked to compromised DNA repair. RelA/p65 knockout fibroblasts, senescence assays, comet assay, chromosomal analysis, DNA repair functional assays EMBO reports Medium 19779484
1996 RelA (p65) and the progesterone receptor (PR) physically interact in vitro, and this interaction mediates mutual transcriptional repression: RelA represses PR-activated transcription and PR represses TNFα-induced NF-κB/RelA activity. In vitro protein–protein interaction assay, transient transfection reporter assays, TNFα stimulation The Journal of biological chemistry Medium 8626413
1996 RelA (p65) and androgen receptor (AR) mutually repress each other's transcriptional activity; a weak AR–RelA protein–protein interaction was detected. RelA-mediated repression involves the AR N-terminal region (residue 297 to DNA-binding domain). The repression is not mediated through IκBα upregulation or reciprocal reduction of protein levels, nor through significant mutual inhibition of DNA binding. Transient transfection reporter assays, EMSA, immunoblotting, in vitro protein–protein interaction The Journal of biological chemistry Medium 8798655
2005 RelA/p65 stabilizes IκBβ protein from 26S proteasome-mediated degradation, a process mediated largely through the RelA C-terminal domain. In RelA/p65−/− fibroblasts, IκBβ is profoundly reduced (more than IκBα). A proteolysis-resistant form of IκBβ but not IκBα causes severe growth defect and apoptosis in RelA/p65−/− fibroblasts. RelA/p65 KO fibroblasts, reconstitution with RelA C-terminal truncations, proteasome inhibitor studies, apoptosis assays Molecular and cellular biology High 15923614
1998 RelA and C/EBPβ form a cooperative DNA-binding complex on a composite NF-κB/C/EBP element in the ICAM-1 promoter. Complex formation requires intact C/EBP and NF-κB binding sites, depends on nuclear translocation of RelA, was demonstrated with recombinant proteins, and is cell-type specific (present in A549/HeLa/EVC304 but not Jurkat/Raji cells). This complex synergistically activates ICAM-1 promoter in response to TNFα. EMSA with recombinant proteins, co-immunoprecipitation from nuclear extracts, reporter assays, TNFα stimulation Cell growth & differentiation Medium 9831247
2014 RIP3 kinase-dead mutant expression induces caspase-dependent cleavage of RelA/p65 (at least partially by caspase-6), and a non-cleavable RelA D361E mutant rescues cells from apoptosis, establishing that caspase-mediated cleavage of RelA is required for RIP3-KD–induced apoptosis in leukemia cells. RIP3-KD overexpression, caspase inhibitor assays, non-cleavable RelA D361E mutant rescue, immunoblotting Cell death & disease Medium 25144719
2015 FOXO3 binds NF-κB RelA in the cytosol, preventing FOXO3 degradation and preventing RelA nuclear translocation. The interaction site was mapped near the FOXO3 transactivation domain; deletion of the FOXO3 DNA-binding domain sequence restored RelA activation. Co-immunoprecipitation, subcellular fractionation, domain deletion constructs, NF-κB reporter assays in tumor-associated dendritic cells Journal of immunology Medium 26561547
2015 Hepatic NF-κB/RelA inhibits PDE3B transcription through three DNA-binding sites in the PDE3B gene promoter in response to TNFα, thereby maintaining elevated intracellular cAMP; deletion of liver p65 in mice increases PDE3B expression and improves hepatic insulin sensitivity on a high-fat diet. Liver-specific p65 knockout mice (Alb-cre × floxed-p65), ChIP, promoter reporter assay, metabolic phenotyping Diabetes High 26038580
2012 Proline-rich tyrosine kinase 2 (Pyk2) promotes RelA/p65 phosphorylation at Ser536 (via IKK) and facilitates nuclear translocation of RelA in thrombin-stimulated endothelial cells; Pyk2 knockdown blocked RelA nuclear translocation even when IκBα degradation still occurred. siRNA knockdown of Pyk2, IKKα/β, phospho-specific immunoblotting, nuclear translocation assay, NF-κB reporter, VCAM-1/MCP-1 expression American journal of respiratory cell and molecular biology Medium 22842493
2012 In hypoxia, only the RelA NF-κB subunit and IκBα localize to mitochondria (specifically the mitoplast containing mtDNA); p50 is found in the ER. Hypoxia-induced mitochondrial RelA and IκBα accumulation requires ROS and STAT3 but not HIF1α or intracellular Ca2+ release. STAT3 inhibition blocks RelA mitochondrial localization. Mitochondrial fractionation, protease protection (mitoplast isolation), hypoxia treatment, STAT3 inhibitor, ROS scavenger, immunoblotting Bioscience reports Medium 31484794
2013 ASPP2 enhances nuclear RelA/p65 activity by binding IκB, and nuclear RelA/p65 mediates transcriptional repression of ΔNp63 expression in keratinocytes, thereby suppressing squamous cell carcinoma development. Co-immunoprecipitation (ASPP2-IκB), reporter assays, genetic epistasis (ASPP2 haploinsufficiency + p63 heterozygosity mouse model), NF-κB activity assays Proceedings of the National Academy of Sciences of the United States of America Medium 24127607
2011 CD28-induced NF-κB signals mediate FOXP3 transcription in human CD4+ T cells via nuclear translocation of RelA (not c-Rel). RelA dimers occupy novel κB-binding sites on the FOXP3 gene, correlating with histone acetylation and Pol II recruitment; RelA knockdown significantly reduces CD28-costimulated FOXP3 expression. ChIP, EMSA, siRNA knockdown, flow cytometry, reporter assays, primary T cell stimulation European journal of immunology Medium 21268019
2023 Heterozygous dominant-negative truncating RELA mutations (in the 3' segment) produce truncated RelA proteins lacking full transactivation domains; these exert a dominant-negative effect and lead to enhanced TLR7-driven type I/III IFN secretion and interferon-stimulated gene expression in patient pDCs and myeloid cells, establishing a type I interferonopathy mechanism. Patient cell functional studies, TLR7 stimulation assays, mRNA expression (TLR7, MYD88), cytokine secretion assays, dominant-negative RelA expression in RelA−/− MEFs The Journal of experimental medicine High 37273177
2017 Embryonic lethality of RelA-deficient mice is mediated by both apoptosis and necroptosis: deletion of Rip3 or Mlkl partially prevents it, while combined ablation of Fadd and Rip3/Mlkl or blocking RIP1 kinase activity fully rescues embryonic lethality, placing RelA upstream of both cell death pathways. Genetic epistasis using RelA/Rip3, RelA/Mlkl, RelA/Fadd/Rip3 triple-knockout mice; RIP1 kinase-dead knock-in (RIP1K45A) Journal of immunology High 29167229
2020 TNF-induced NFκB/RelA dynamics control necroptosis decisions via an incoherent feedforward loop: RelA-driven inducible expression of TNFAIP3/A20 interferes with the RIPK3-containing necrosome complex, protecting a fraction of cells from transient TNF exposure. Dysregulated NF-κB dynamics diminish TNF-induced necroptosis. Live-cell microscopy, mathematical modeling of death kinetics, A20 inducible expression, RIPK3 complex analysis Molecular systems biology Medium 33314666
2024 High glucose induces formation of a RELA/p65–HDAC8 complex that binds the PRKN (Parkin) promoter and represses PRKN expression, impairing mitophagy; sodium butyrate (NaB) blocks RELA nuclear translocation and directly inhibits nuclear HDAC8, restoring PRKN expression and mitophagy. ChIP assay (RELA-HDAC8 at PRKN promoter), co-immunoprecipitation (RELA-HDAC8 complex), HDAC8 overexpression, NaB treatment, mitophagy assays, diabetic mouse model Autophagy Medium 38409852
2015 ZBTB2 represses RelA/p65 gene transcription by inhibiting Sp1 binding to a GC-box (bp -31 to -21) in the RelA/p65 proximal promoter. Reduced RelA/p65 expression by ZBTB2 indirectly increases PDK4 expression (through relief of RelA-mediated PGC1α repression), reprogramming glucose metabolism toward glycolysis. Reporter assays with promoter deletions and mutations, EMSA, ChIP, siRNA knockdown, metabolic flux analysis Nucleic acids research Medium 25609694
2019 Under hypoxia, NF-κB (RelA/p65) represses ZBTB7A transcription by binding NF-κB-binding elements in the ZBTB7A 5'-upstream regulatory region, downregulating the transcriptional repressor FBI-1, which in turn derepresses SLC16A3 (MCT4) expression to increase lactate efflux and colon cancer cell growth. ChIP, transient transfection/reporter assays, oligonucleotide pulldowns, hypoxia cell treatments, mRNA/protein expression analysis Biochimica et biophysica acta. Gene regulatory mechanisms Medium 31271899

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. The EMBO journal 697 12456660
2014 C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 509 24553141
2005 NF-kappaB RelA phosphorylation regulates RelA acetylation. Molecular and cellular biology 384 16135789
1996 Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor. The Journal of biological chemistry 297 8626413
2009 p65/RelA modulates BECN1 transcription and autophagy. Molecular and cellular biology 219 19289499
1996 Mutual transcriptional interference between RelA and androgen receptor. The Journal of biological chemistry 184 8798655
1995 RelA/p65 is a molecular target for the immunosuppressive action of protein kinase A. The EMBO journal 180 7744006
2013 Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription. PLoS biology 128 24019758
2014 RIP3 is downregulated in human myeloid leukemia cells and modulates apoptosis and caspase-mediated p65/RelA cleavage. Cell death & disease 113 25144719
2013 MicroRNA miR-324-3p induces promoter-mediated expression of RelA gene. PloS one 112 24265774
2011 Nucleolar NF-κB/RelA mediates apoptosis by causing cytoplasmic relocalization of nucleophosmin. Cell death and differentiation 112 21660047
2002 Listeria monocytogenes relA and hpt mutants are impaired in surface-attached growth and virulence. Journal of bacteriology 111 11790730
2001 Protein phosphatase 2A interacts with and directly dephosphorylates RelA. The Journal of biological chemistry 111 11591705
1988 The nucleotide sequence and characterization of the relA gene of Escherichia coli. The Journal of biological chemistry 105 2844820
2017 RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis. Cell death & disease 104 28358376
1996 Functional analysis of a relA/spoT gene homolog from Streptococcus equisimilis. Journal of bacteriology 101 8631718
2009 Respiratory syncytial virus infection induces a reactive oxygen species-MSK1-phospho-Ser-276 RelA pathway required for cytokine expression. Journal of virology 93 19706715
1999 Cloning and characterization of a bifunctional RelA/SpoT homologue from Mycobacterium tuberculosis. Gene 91 10375643
2007 Functions and regulation of NF-kappaB RelA during pneumococcal pneumonia. Journal of immunology (Baltimore, Md. : 1950) 88 17237440
2003 Mutation in the relA gene of Vibrio cholerae affects in vitro and in vivo expression of virulence factors. Journal of bacteriology 87 12896985
2015 Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway. Diabetes 86 26038580
2013 Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy. Kidney international 77 24067439
2018 Activation of the Stringent Response by Loading of RelA-tRNA Complexes at the Ribosomal A-Site. Molecular cell 76 29625042
2009 RelA/p65 functions to maintain cellular senescence by regulating genomic stability and DNA repair. EMBO reports 76 19779484
2016 Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response. Proceedings of the National Academy of Sciences of the United States of America 75 27051065
2017 RelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host. mBio 72 28049149
2016 microRNA-7-5p inhibits melanoma cell proliferation and metastasis by suppressing RelA/NF-κB. Oncotarget 69 27203220
2021 ZFTA-RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma. Cancer discovery 67 33741710
2018 Diagnostics of pediatric supratentorial RELA ependymomas: integration of information from histopathology, genetics, DNA methylation and imaging. Brain pathology (Zurich, Switzerland) 67 30325077
2016 miR-508-3p concordantly silences NFKB1 and RELA to inactivate canonical NF-κB signaling in gastric carcinogenesis. Molecular cancer 64 26801246
2021 Transcriptional repression of NFKBIA triggers constitutive IKK- and proteasome-independent p65/RelA activation in senescence. The EMBO journal 63 33459422
1997 Activation of multiple growth regulatory genes following inducible expression of IRF-1 or IRF/RelA fusion proteins. Oncogene 62 9333018
2010 Nucleolar targeting of RelA(p65) is regulated by COMMD1-dependent ubiquitination. Cancer research 58 20048074
2015 TLR9 signaling through NF-κB/RELA and STAT3 promotes tumor-propagating potential of prostate cancer cells. Oncotarget 57 26046794
2001 NF-kappaB/RelA transactivation is required for atypical protein kinase C iota-mediated cell survival. Oncogene 57 11521190
2012 New molecular bridge between RelA/p65 and NF-κB target genes via histone acetyltransferase TIP60 cofactor. The Journal of biological chemistry 56 22249179
2012 Lipopolysaccharide activates ERK-PARP-1-RelA pathway and promotes nuclear factor-κB transcription in murine macrophages. Human immunology 56 22391342
1989 Protein sequences encoded by the relA and the spoT genes of Escherichia coli are interrelated. The Journal of biological chemistry 53 2542299
2001 Functional analysis of relA and rshA, two relA/spoT homologues of Streptomyces coelicolor A3(2). Journal of bacteriology 52 11344157
2021 Supratentorial ependymoma in childhood: more than just RELA or YAP. Acta neuropathologica 49 33481105
2019 Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression. mBio 49 31363026
2018 Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness. Oncogenesis 49 30467308
2015 ComGA-RelA interaction and persistence in the Bacillus subtilis K-state. Molecular microbiology 47 25899641
2001 relA over-expression reduces tumorigenicity and activates apoptosis in human cancer cells. British journal of cancer 47 11747334
1999 Overexpression of RelA causes G1 arrest and apoptosis in a pro-B cell line. The Journal of biological chemistry 46 10085110
2015 FOXO3-NF-κB RelA Protein Complexes Reduce Proinflammatory Cell Signaling and Function. Journal of immunology (Baltimore, Md. : 1950) 44 26561547
2013 PPM1A is a RelA phosphatase with tumor suppressor-like activity. Oncogene 43 23812431
2017 PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation. Nature communications 41 29038521
2013 ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63. Proceedings of the National Academy of Sciences of the United States of America 41 24127607
2012 N-α-acetyltransferase 10 protein inhibits apoptosis through RelA/p65-regulated MCL1 expression. Carcinogenesis 41 22496479
2011 Variants of the RELA gene are associated with schizophrenia and their startle responses. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 41 21593732
2020 Deamidation Shunts RelA from Mediating Inflammation to Aerobic Glycolysis. Cell metabolism 40 32325032
2015 NF-κB/RelA and Nrf2 cooperate to maintain hepatocyte integrity and to prevent development of hepatocellular adenoma. Journal of hepatology 39 26348541
1999 relA is required for actinomycin production in Streptomyces antibioticus. Journal of bacteriology 39 10368159
2019 Hypoxia-induced RelA/p65 derepresses SLC16A3 (MCT4) by downregulating ZBTB7A. Biochimica et biophysica acta. Gene regulatory mechanisms 36 31271899
2018 RELA/NEAT1/miR-302a-3p/RELA feedback loop modulates pancreatic ductal adenocarcinoma cell proliferation and migration. Journal of cellular physiology 36 30362505
2021 The RelA hydrolase domain acts as a molecular switch for (p)ppGpp synthesis. Communications biology 35 33790389
2019 LncRNA MATN1-AS1 prevents glioblastoma cell from proliferation and invasion via RELA regulation and MAPK signaling pathway. Annals of translational medicine 35 32042800
2014 Negative regulation of RelA phosphorylation: emerging players and their roles in cancer. Cytokine & growth factor reviews 35 25438737
2012 RelA protein stimulates the activity of RyhB small RNA by acting on RNA-binding protein Hfq. Proceedings of the National Academy of Sciences of the United States of America 35 22393021
2015 ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65. Nucleic acids research 34 25609694
2008 Role of NF-kappaB/RelA and MAPK pathways in keratinocytes in response to sulfur mustard. The Journal of investigative dermatology 34 18200059
2011 CD28 costimulation regulates FOXP3 in a RelA/NF-κB-dependent mechanism. European journal of immunology 33 21268019
2009 RelA regulates virulence and intracellular survival of Francisella novicida. Microbiology (Reading, England) 33 19762448
1978 Nonsense and insertion mutants in the relA gene of E. coli: cloning relA. Cell 32 365354
2012 Calcitriol decreases expression of importin α3 and attenuates RelA translocation in human bronchial smooth muscle cells. Journal of clinical immunology 31 22526597
2020 MicroRNA-3613-5p Promotes Lung Adenocarcinoma Cell Proliferation through a RELA and AKT/MAPK Positive Feedback Loop. Molecular therapy. Nucleic acids 30 33230458
2019 Fatty acid starvation activates RelA by depleting lysine precursor pyruvate. Molecular microbiology 30 31400173
2013 Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice. Journal of immunology (Baltimore, Md. : 1950) 30 23562811
2012 Role of RelA and SpoT in Burkholderia pseudomallei virulence and immunity. Infection and immunity 30 22778096
1998 Cooperative binding and synergistic activation by RelA and C/EBPbeta on the intercellular adhesion molecule-1 promoter. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 30 9831247
2023 Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity. The Journal of experimental medicine 29 37273177
2012 Regulation of Rela/p65 and endothelial cell inflammation by proline-rich tyrosine kinase 2. American journal of respiratory cell and molecular biology 29 22842493
2001 Involvement of stringent factor RelA in expression of the alkaline protease gene aprE in Bacillus subtilis. Journal of bacteriology 29 11443101
2023 Case report: Novel variants in RELA associated with familial Behcet's-like disease. Frontiers in immunology 27 36926348
2020 miR-7 Reduces Breast Cancer Stem Cell Metastasis via Inhibiting RELA to Decrease ESAM Expression. Molecular therapy oncolytics 27 32637582
2017 Embryonic Lethality and Host Immunity of RelA-Deficient Mice Are Mediated by Both Apoptosis and Necroptosis. Journal of immunology (Baltimore, Md. : 1950) 27 29167229
2009 Myeloid RelA regulates pulmonary host defense networks. The European respiratory journal 27 19679599
2021 A Novel RELA Truncating Mutation in a Familial Behçet's Disease-like Mucocutaneous Ulcerative Condition. Arthritis & rheumatology (Hoboken, N.J.) 26 32969189
2020 Characterization of RelA in Acinetobacter baumannii. Journal of bacteriology 26 32229531
2019 TLR4-RelA-miR-30a signal pathway regulates Th17 differentiation during experimental autoimmune encephalomyelitis development. Journal of neuroinflammation 26 31561751
2020 An incoherent feedforward loop interprets NFκB/RelA dynamics to determine TNF-induced necroptosis decisions. Molecular systems biology 25 33314666
2018 RelA driven co-expression of CXCL13 and CXCR5 is governed by a multifaceted transcriptional program regulating breast cancer progression. Biochimica et biophysica acta. Molecular basis of disease 25 30553016
2008 Differential RelA- and RelB-dependent gene transcription in LTbetaR-stimulated mouse embryonic fibroblasts. BMC genomics 25 19087315
2020 SRF Fusions Other Than With RELA Expand the Molecular Definition of SRF-fused Perivascular Tumors. The American journal of surgical pathology 23 33021523
2019 Sevoflurane exerts protective effects on liver ischemia/reperfusion injury by regulating NFKB3 expression via miR-9-5p. Experimental and therapeutic medicine 23 30906455
2014 RelA inhibits Bacillus subtilis motility and chaining. Journal of bacteriology 23 25331430
2005 RelA/p65 regulation of IkappaBbeta. Molecular and cellular biology 23 15923614
2003 Temperature-sensitive growth and decreased thermotolerance associated with relA mutations in Escherichia coli. Journal of bacteriology 23 13129947
2024 Sodium butyrate ameliorates high glucose-suppressed neuronal mitophagy by restoring PRKN expression via inhibiting the RELA-HDAC8 complex. Autophagy 22 38409852
2023 NF-κB/RelA controlled A20 limits TRAIL-induced apoptosis in pancreatic cancer. Cell death & disease 21 36596765
2018 Deubiquitinylase USP47 Promotes RelA Phosphorylation and Survival in Gastric Cancer Cells. Biomedicines 21 29786670
2020 Tranilast induces MiR-200c expression through blockade of RelA/p65 activity in leiomyoma smooth muscle cells. Fertility and sterility 20 32199621
2024 CRISPR-mediated Sox9 activation and RelA inhibition enhance cell therapy for osteoarthritis. Molecular therapy : the journal of the American Society of Gene Therapy 19 38879753
2020 MicroRNA-520c-3p targeting of RelA/p65 suppresses atherosclerotic plaque formation. The international journal of biochemistry & cell biology 19 33166679
2019 Hypoxia induces rapid, STAT3 and ROS dependent, mitochondrial translocation of RelA(p65) and IκBα. Bioscience reports 19 31484794
2015 RelA-Induced Interferon Response Negatively Regulates Proliferation. PloS one 19 26460486
2005 Expression of the GTP-binding protein (Galphas) is repressed by the nuclear factor kappaB RelA subunit in human myometrium. Endocrinology 19 16081638
2021 MicroRNA-138 improves LPS-induced trophoblast dysfunction through targeting RELA and NF-κB signaling. Cell cycle (Georgetown, Tex.) 18 33550900
2016 Targeting NF-κB RelA/p65 phosphorylation overcomes RITA resistance. Cancer letters 18 27721021

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