Affinage

BIRC6

Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6 · UniProt Q9NR09

Length
4857 aa
Mass
530.3 kDa
Annotated
2026-06-09
100 papers in source corpus 31 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BIRC6 (BRUCE/Apollon) is a megadalton, trans-Golgi-associated protein that integrates apoptosis control, ubiquitin signaling, and autophagy through a single chimeric architecture combining a BIR domain with a ubiquitin-conjugating (UBC/E2) module (PMID:15200957, PMID:15507451). As an inhibitor of apoptosis, it binds pro-apoptotic clients including caspase-9, SMAC/DIABLO, and HtrA2, restrains caspase activity, and targets clients such as SMAC for proteasomal degradation, with apoptotic signals in turn dismantling BIRC6 via caspase/HtrA2 cleavage and proteasomal turnover (PMID:15200957, PMID:15507451, PMID:22788920). Cryo-EM structures resolve BIRC6 as an antiparallel U-shaped homodimer enclosing a central cavity that houses receptor sites for caspase-9, HtrA2, SMAC, and LC3B; it directly restricts executioner caspases-3/-7 and ubiquitinates caspases-3/-7/-9 exclusively through the noncanonical E1 UBA6, while SMAC binds at multiple subnanomolar sites to competitively displace clients and relieve their inhibition (PMID:36758105, PMID:36758104, PMID:36758106, PMID:38291026). BIRC6 is a UBA6-exclusive E2 that wins priority over other UBA6-competent E2 enzymes via a high-affinity interaction with the UBA6 ubiquitin-fold domain and a thioester-switch mechanism that disengages it upon ubiquitin loading (PMID:41350950). Beyond apoptosis, BIRC6 governs cytokinetic abscission by relocating from Golgi/vesicular compartments to the midbody ring (PMID:18329369), supports DNA double-strand break repair by scaffolding USP8-mediated deubiquitination of BRIT1 and activating ATR signaling at stalled forks (PMID:25733871, PMID:26683461, PMID:30693543), and is required for meiotic homologous recombination in the male germline (PMID:32139899). It bidirectionally regulates autophagy: it promotes autophagosome-lysosome fusion through ubiquitin-independent interactions with GABARAP/GABARAPL1 and Syntaxin 17 (PMID:29426817), yet with UBA6 monoubiquitinates LC3B to drive its proteasomal degradation and negatively regulate autophagy (PMID:31692446, PMID:38291026). BIRC6 abundance is itself tightly controlled by Nrdp1-mediated ubiquitination and by autophagic clearance (PMID:14765125, PMID:31213539). Genetically, loss of BIRC6 function causes embryonic/perinatal lethality with placental defects in mice (PMID:15640352, PMID:15485903), and liver-specific deletion impairs ATR activation and promotes hepatocellular carcinoma (PMID:30693543).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2004 High

    Established the core dual identity of BIRC6 as both an IAP and a ubiquitin ligase, answering what kind of molecule BRUCE is and how it suppresses cell death.

    Evidence Wild-type/mutant constructs, in vitro ubiquitination, Co-IP, apoptosis assays, and subcellular fractionation defining BIR-dependent caspase inhibition, Smac/HtrA2/caspase antagonism, and trans-Golgi localization

    PMID:15200957 PMID:15507451

    Open questions at the time
    • Did not resolve which caspases are inhibited directly versus via ubiquitination
    • E1 enzyme partner not identified at this stage
  2. 2004 High

    Identified how BIRC6 levels are set, showing the RING E3 Nrdp1 ubiquitinates BRUCE for proteasomal degradation to license apoptosis.

    Evidence Co-IP, in vitro ubiquitination with purified proteins and UbcH5c, RNAi knockdown, and proteasome inhibition

    PMID:14765125

    Open questions at the time
    • Did not define stimuli triggering Nrdp1 engagement
    • Ubiquitin chain linkage on BRUCE not characterized
  3. 2005 High

    Defined the in vivo developmental requirement and downstream apoptotic pathway, showing C-terminal/UBC-domain loss triggers p53-dependent mitochondrial apoptosis and embryonic lethality.

    Evidence Conditional knockout mouse plus p53 RNAi rescue in H460 cells with caspase and mitochondrial readouts

    PMID:15485903 PMID:15640352

    Open questions at the time
    • Apparent discrepancy between apoptosis-driven lethality and apoptosis-independent placental differentiation defect not reconciled
    • Direct p53 ubiquitination by BIRC6 not shown here
  4. 2008 High

    Extended BIRC6 function beyond apoptosis to cell division, showing it relocates to the midbody ring to drive cytokinetic abscission and ubiquitin redistribution.

    Evidence RNAi depletion, live-cell imaging, immunofluorescence, and electron microscopy

    PMID:18329369

    Open questions at the time
    • Ubiquitination substrates at the midbody ring not identified
    • Whether E2/E3 activity is required for abscission not resolved
  5. 2015 High

    Revealed a nuclear DNA-repair scaffold role, showing BIRC6 bridges USP8 and BRIT1 to enable BRIT1 deubiquitination and DSB recruitment via its UBC domain.

    Evidence Co-IP complex reconstitution, in vitro deubiquitination, HR repair assay, foci imaging, domain mutants, and mouse genetics

    PMID:25733871 PMID:26683461

    Open questions at the time
    • How an E2/E3 domain promotes a deubiquitination reaction mechanistically remains unclear
    • Direct enzymatic substrate of BIRC6 in this complex not defined
  6. 2018 High

    Showed a ubiquitin-independent autophagy function, with BIRC6 promoting autophagosome-lysosome fusion via GABARAP/GABARAPL1 and STX17 interactions.

    Evidence RNAi screen, reciprocal Co-IP, tandem-fluorescent LC3 flux assays, LAMP2 co-localization, and non-catalytic N-terminal rescue

    PMID:29426817

    Open questions at the time
    • Structural basis of STX17/GABARAP binding not defined here
    • Reconciliation with later negative regulation of autophagy not addressed
  7. 2019 High

    Defined an opposing, catalytic autophagy-suppressing role, showing UBA6-BIRC6 monoubiquitinates LC3B for degradation and that BIRC6 also acts through PA28γ, AMPK-ULK1 energy sensing, and ATR activation.

    Evidence Whole-genome CRISPR screen, IP, flux assays, AMP/ATP measurements, DNA fiber assays, and liver-specific knockout carcinogenesis model

    PMID:30693543 PMID:31091257 PMID:31213539 PMID:31692446

    Open questions at the time
    • How the pro-fusion and anti-LC3 functions are balanced in cells is unresolved
    • No direct BIRC6-AMPK interaction demonstrated
  8. 2023 High

    Provided the structural mechanism, resolving BIRC6 as an antiparallel homodimer whose central cavity houses client receptor sites and showing SMAC competitively displaces caspases at subnanomolar affinity.

    Evidence Three convergent cryo-EM studies with in vitro ubiquitination and binding competition assays

    PMID:36758104 PMID:36758105 PMID:36758106

    Open questions at the time
    • In vivo regulation of cavity occupancy not addressed
    • Dynamics of client exchange in cells not measured
  9. 2024 High

    Refined the structural model and substrate logic, identifying a ubiquitin-like domain and an LC3-interacting region, and showing differential SMAC competition and autophagic degradation of BIRC6 and caspase-9.

    Evidence Cryo-EM, binding competition, site-directed mutagenesis of the LC3 ubiquitylation site, and autophagy flux assays

    PMID:38291026

    Open questions at the time
    • Physiological trigger for switching between LC3 ubiquitination and BIRC6 autophagic clearance not defined
  10. 2024 High

    Expanded the substrate repertoire beyond apoptosis, showing BIRC6 selectively ubiquitinates KRAS4A at the Golgi to support its GTP loading and growth signaling.

    Evidence BioID proximity labeling, Co-IP, in vitro ubiquitination with site mapping, RNAi, and GTP-loading assay

    PMID:39705142

    Open questions at the time
    • Whether KRAS4A ubiquitination is UBA6-dependent not stated
    • Generality across cell types not established
  11. 2025 High

    Explained how BIRC6 monopolizes ubiquitin charging, demonstrating it is a UBA6-exclusive E2 that outcompetes rival E2s and uses a thioester switch to avoid inhibiting the E1.

    Evidence Multi-state structural capture of the BIRC6-UBA6 complex, ubiquitin transfer assays, UBA6 Cys-Cap loop mutagenesis, and E2 competition assays

    PMID:41350950

    Open questions at the time
    • How E1-E2 priority is regulated across cellular states not addressed
    • Consequences for non-apoptotic substrates not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BIRC6's competing roles—anti-apoptotic IAP, bidirectional autophagy regulator, cytokinesis and DNA-repair scaffold, and KRAS4A/Axin/p53 ubiquitin ligase—are coordinated and prioritized within a single cell remains unresolved.
  • No unified model integrating ubiquitin-dependent and ubiquitin-independent functions
  • Tissue- and stimulus-specific substrate selection mechanisms undefined
  • Several cancer-context substrates (Axin, p53, HECTD1 regulation) lack in vitro reconstitution

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005794 Golgi apparatus 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005764 lysosome 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-73894 DNA Repair 4 R-HSA-9612973 Autophagy 4 R-HSA-392499 Metabolism of proteins 2 R-HSA-1640170 Cell Cycle 1
Partners
BRIT1CASPASE-9GABARAPNRDP1SMAC/DIABLOSTX17UBA6USP8

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 BIRC6/BRUCE functions as a chimeric E2/E3 ubiquitin ligase and IAP: it inhibits caspase activity and apoptosis via its BIR domain, is antagonized by Smac binding, by HtrA2 protease cleavage, and by caspase-mediated cleavage, and ubiquitinates Smac as a substrate. BRUCE localizes to the trans-Golgi network as a peripheral membrane protein. Wild-type and mutant BRUCE constructs, Co-IP, in vitro ubiquitination assay, apoptosis assays, subcellular fractionation/localization Molecular cell High 15200957
2004 BRUCE/Apollon associates with both precursor and mature forms of Smac and caspase-9 (binding regions beyond the IAP-binding motif), promotes proteasomal degradation of Smac, and inhibits caspase-9 activity but not caspase-3 activity. Upon apoptotic stimuli, BRUCE is degraded by proteasomes and/or cleaved by caspases or HtrA2 depending on stimulus and cell type. Co-immunoprecipitation, in vitro caspase activity assays, proteasome inhibitor experiments, cell-based apoptosis assays The Journal of biological chemistry High 15507451
2004 Nrdp1/FLRF, a RING-finger E3 ubiquitin ligase, associates with BRUCE and, in the presence of exogenous E2 UbcH5c, catalyzes BRUCE ubiquitination in vitro. Nrdp1 overexpression promotes BRUCE ubiquitination and proteasomal degradation in vivo; RNAi knockdown of Nrdp1 reduces apoptosis-induced BRUCE loss. Thus Nrdp1 is a writer that targets BRUCE for degradation to promote apoptosis. Co-immunoprecipitation, in vitro ubiquitination assay with purified proteins, RNAi knockdown, proteasome inhibitor experiments The EMBO journal High 14765125
2005 Deletion of the C-terminal half of BRUCE (including the UBC domain) in mice activates caspases and apoptosis in placenta/yolk sac causing embryonic lethality, associated with p53 nuclear localization, upregulation of Bax, Bak, Pidd, mitochondrial translocation of Bax and caspase-2, cytochrome c and AIF release, and caspase-9/-3 activation. p53 RNAi rescue in human H460 cells confirms p53 is a downstream effector of BRUCE in the mitochondrial apoptosis pathway. Conditional knockout mouse, RNAi rescue in cell lines, Western blot, immunofluorescence, caspase activity assays Proceedings of the National Academy of Sciences of the United States of America High 15640352
2004 BRUCE-deficient mice die perinatally with growth retardation linked to impaired placental labyrinth maturation and spongiotrophoblast reduction; no elevated apoptosis was detected in knockout tissues or fibroblasts, suggesting a role in placental/trophoblast differentiation distinct from anti-apoptotic function. Gene targeting/knockout mouse, histology, TUNEL apoptosis assay Molecular and cellular biology High 15485903
2008 BRUCE is a major regulator of cytokinesis abscission: during cytokinesis it relocates from vesicular/trans-Golgi network compartments to the midbody ring, serving as a platform for membrane delivery machinery and mitotic regulators. BRUCE depletion causes defective abscission, cytokinesis-associated apoptosis, blocked vesicular targeting, and defective midbody ring formation. Ubiquitin relocalizes from midbody microtubules to the midbody ring during cytokinesis, and BRUCE depletion disrupts this ubiquitin relocalization. RNAi depletion in cell culture, live-cell imaging, immunofluorescence, electron microscopy, co-localization studies Cell High 18329369
2015 BRUCE acts as a scaffold bridging USP8 and BRIT1 in a nuclear complex; it promotes USP8-catalyzed deubiquitination of K63-ubiquitinated BRIT1, which is a prerequisite for BRIT1 recruitment to DNA double-strand breaks (DSBs) via γ-H2AX. Loss of BRUCE impairs BRIT1 deubiquitination, BRIT1-γH2AX binding, BRIT1 DSB foci, chromatin relaxation, and homologous recombination repair. BRUCE-mutant mice show genomic instability. Co-immunoprecipitation, in vitro deubiquitination assay, RNAi knockdown, immunofluorescence foci assays, HR repair assay, mouse genetics Proceedings of the National Academy of Sciences of the United States of America High 25733871
2015 The UBC (E2) domain of BRUCE, but not its BIR domain, is required for BRIT1 deubiquitination and recruitment to DSBs: UBC domain mutation or deletion does not disrupt the BRUCE-USP8-BRIT1 complex but impairs downstream deubiquitination and DSB repair, implicating BRUCE's E3 ligase activity in facilitating USP8-mediated deubiquitination. Domain deletion/point mutation analysis, Co-IP, γ-H2AX/BRIT1 foci assays, HR repair assay PloS one Medium 26683461
2018 BIRC6/BRUCE positively regulates autophagosome-lysosome fusion: BRUCE depletion leads to defective autophagosome-lysosome fusion. BRUCE selectively interacts with ATG8 family members GABARAP and GABARAPL1, and with Syntaxin 17 (STX17), all critical regulators of autophagosome-lysosome fusion. BRUCE co-localizes with LAMP2 (lysosomal marker). A non-catalytic N-terminal fragment lacking the UBC domain rescues autolysosome formation in Bruce-/- cells, indicating this role is independent of ubiquitin-conjugating activity. RNAi screen, Co-immunoprecipitation, autophagy flux assays (tandem fluorescent LC3), immunofluorescence co-localization, domain deletion rescue experiments Nature communications High 29426817
2019 UBA6 and BIRC6 cooperate to monoubiquitinate LC3B, targeting it for proteasomal degradation, thereby negatively regulating autophagy. Knockout of UBA6 or BIRC6 increases autophagic flux under nutrient deprivation or protein synthesis inhibition, decreases aggresome-like structures and α-synuclein aggregates. Whole-genome CRISPR/Cas9 knockout screen, genetic rescue, autophagic flux assays (tandem GFP-mCherry-LC3B), immunoprecipitation, proteasome inhibitor experiments eLife High 31692446
2019 BRUCE together with proteasome activator PA28γ promotes proteasomal degradation of LC3-I, inhibiting autophagy initiation. SIP/CacyBP inhibits Nrdp1-mediated ubiquitination of BRUCE under normal conditions, thereby protecting BRUCE. Upon starvation, SIP together with Rab8 promotes translocation of BRUCE into recycling endosomes and autophagic degradation of BRUCE by optineurin-mediated autophagy, thus relieving BRUCE-dependent LC3-I degradation. Co-immunoprecipitation, in vitro ubiquitination assay, autophagy flux assays, confocal microscopy, RNAi knockdown, cell fractionation Proceedings of the National Academy of Sciences of the United States of America High 31213539
2019 BRUCE is required for ATR activation during replication stress: BRUCE is recruited to DNA damage sites, and BRUCE depletion impairs ATR activation, phosphorylation of CHK1 and RPA, and monoubiquitination of FANCD2, resulting in stalled replication forks and increased replication origin firing. Liver-specific Bruce knockout in mice impairs ATR activation and promotes hepatocellular carcinoma development. RNAi depletion, immunofluorescence, Western blot for ATR-pathway markers, DNA fiber assay, liver-specific conditional knockout mouse, diethylnitrosamine carcinogenesis model Hepatology (Baltimore, Md.) High 30693543
2019 BRUCE depletion lowers cellular ATP/AMP ratio, activating AMPK (pThr-172) and downstream ULK1 (pSer-555), which induces autophagy independently of starvation. This energy-sensing pathway establishes a BRUCE-AMPK-ULK1 axis in autophagy regulation. RNAi knockdown, AMP/ATP ratio measurement, Western blot for AMPK and ULK1 phosphorylation, LC3 puncta quantification, autophagy flux assays PloS one Medium 31091257
2011 Drosophila BRUCE (dBruce) physically interacts with the IAP-antagonist Reaper via Reaper's IBM and GH3 motifs and promotes Reaper ubiquitination on unconventional non-lysine acceptor sites (as demonstrated with lysine-deficient Reaper mutants). Loss of dBruce elevates Reaper protein levels, indicating BRUCE inhibits apoptosis by targeting IAP-antagonists for ubiquitination. Co-immunoprecipitation, in vitro ubiquitination assay with lysine-deficient substrates, genetic loss-of-function (dBruce-/- background), RNAi knockdown Cell death and differentiation High 21886178
2008 Prostaglandin F2alpha (PGF2alpha) increases BRUCE expression in skeletal myoblasts via the NFAT2 transcription factor pathway, and PGF2alpha-mediated reduction of muscle cell death during myogenesis is dependent on BRUCE. Overexpression of BRUCE alone is sufficient to promote muscle cell survival and myotube growth. In vitro myogenesis, siRNA knockdown, BRUCE overexpression, NFAT2 inhibitor experiments, in vivo muscle injury model Cell death and differentiation Medium 18566603
2023 Cryo-EM structures of full-length human BIRC6 reveal it forms an antiparallel homodimer arranged in a megadalton crescent shape with a central cavity containing receptor sites for client proteins (caspase-9, HTRA2, SMAC, LC3B). BIRC6 directly restricts executioner caspases-3 and -7, ubiquitinates caspases-3, -7, and -9 exclusively via the noncanonical E1 UBA6. SMAC binds BIRC6 at multiple sites with subnanomolar affinity, competitively displacing caspases and thus antagonizing BIRC6 anti-caspase function. SMAC binding to BIRC6 obstructs client binding, impeding ubiquitination of both apoptotic and autophagic substrates. Cryo-electron microscopy structure determination, in vitro ubiquitination assays, binding competition assays, structure-function mutagenesis Science (New York, N.Y.) High 36758104 36758105 36758106
2024 BIRC6 forms an anti-parallel U-shaped dimer with multiple previously unannotated domains including a ubiquitin-like domain. Smac/DIABLO outcompetes effector caspase-3 and HtrA2 but not procaspase-9 for binding to the BIRC6 central cavity. BIRC6 binds LC3 through an LC3-interacting region (LIR), and mutation of the LC3 ubiquitylation site promotes autophagy and autophagic degradation of BIRC6. Induction of autophagy promotes autophagic degradation of BIRC6 and caspase-9 but not other effector caspases. Cryo-EM structure, in vitro binding competition assays, site-directed mutagenesis, autophagy flux assays, Co-immunoprecipitation Nature communications High 38291026
2025 BIRC6 is a UBA6-exclusive E2 enzyme that gains priority over all other UBA6-competent E2s through an exceptionally high-affinity interaction driven by BIRC6 engagement with the UBA6 ubiquitin fold domain (modulated by the UBA6 Cys-Cap loop). BIRC6 uses a bespoke thioester switch mechanism to disengage from UBA6 upon receiving ubiquitin, preventing UBA6 inhibition. This E1-E2 priority underpins BIRC6's functional importance in regulating cell death, embryogenesis, and autophagy. Structural capture of BIRC6-UBA6 complex in multiple states (cryo-EM/crystallography), in vitro ubiquitin transfer assays, mutagenesis of UBA6 Cys-Cap loop, E2 competition assays Nature structural & molecular biology High 41350950
2014 BIRC6 interacts with p53 and facilitates its ubiquitin-proteasome-mediated degradation in hepatocellular carcinoma cells. BIRC6 knockdown stabilizes p53, and RNA interference targeting p53 partially reverses the pro-apoptotic effects of BIRC6 depletion. Co-immunoprecipitation, Western blot, siRNA knockdown, lentiviral shRNA, in vivo xenograft International journal of cancer Medium 25196217
2017 BIRC6 stability is regulated by the Src-family kinase Lyn: RNAi knockdown or pharmacological inhibition of Lyn reduces BIRC6 protein stability and increases formation of an N-terminal BIRC6 cleavage fragment, coinciding with reduced BIRC6 phosphopeptide (S480/S482/S486), suggesting Lyn-dependent phosphorylation stabilizes BIRC6. Phosphoproteomic mass spectrometry, RNAi knockdown, kinase inhibitors (dasatinib/ponatinib), Western blot PloS one Medium 28520795
2021 BIRC6 stability is increased by EGF-JNK signaling, which prevents BIRC6 ubiquitination and degradation mediated by the E3 ubiquitin ligase HECTD1. BIRC6 in turn decreases SMAC expression by inducing the ubiquitin-proteasome pathway in TNBC cells. Co-immunoprecipitation, Western blot, siRNA knockdown, EGF/JNK pathway inhibitors, in vivo xenograft Molecular therapy. Nucleic acids Medium 34729249
2021 In hepatocytes, BRUCE co-localizes and interacts with PKA in the cytoplasm, suppressing PKA activity and thereby reducing PKA-dependent phosphorylation (Ser-675) and nuclear accumulation of β-catenin. BRUCE deficiency elevates PKA activity and pSer-675-β-catenin, establishing a BRUCE-PKA-β-catenin signaling axis in liver disease progression. Liver-specific conditional knockout mouse, Co-immunoprecipitation, kinase activity assay, Western blot, immunofluorescence World journal of hepatology Medium 33815677
2024 BIRC6 interacts with KRAS4A (but not KRAS4B) on the Golgi apparatus and mono- and di-ubiquitinates KRAS4A at lysines 128 and 147. BIRC6 silencing diminishes GTP loading of KRAS4A and growth stimulation by KRAS4A but not KRAS4B. Proximity labeling (BioID), Co-immunoprecipitation, in vitro ubiquitination assay, mass spectrometry identification of ubiquitination sites, RNAi knockdown, GTP-loading assay Cell reports High 39705142
2020 In Bruce-/- male germline (conditional knockout), spermatogonia maintenance is impaired and meiotic spermatocytes show persistent DNA breaks, defective homologous synapsis, non-homologous chromosomal associations, and absent ATM/ATR signaling at unsynapsed regions, establishing BRUCE as essential for meiotic homologous recombination and genomic stability in the male germline. Conditional germline-specific knockout mouse, immunofluorescence with synapsis markers (SYCP1/3), γ-H2AX/RAD51 foci, ATM/ATR staining, chromosome spread analysis Cell death and differentiation High 32139899
2002 Drosophila BRUCE (dBruce) inhibits cell death induced by Reaper and Grim but not Hid using gain-of-function and loss-of-function alleles. The BIR domain alone is insufficient; the E2 domain is required. dBruce does not promote direct degradation of Rpr or Grim, but its activity requires their N-terminal IAP-binding motifs. dBruce does not block Dronc caspase or Debcl/dBorg. Drosophila gain-of-function transgenes, loss-of-function deletion alleles, genetic epistasis, in vivo cell death assays Current biology : CB High 12121627
2012 BIRC6 binds and degrades the cytoplasmic fraction of the pro-apoptotic protein DIABLO/Smac in neuroblastoma cells: BIRC6 silencing by shRNA increases DIABLO protein levels and induces apoptosis; Co-immunoprecipitation confirmed direct BIRC6-DIABLO interaction. Lentiviral shRNA knockdown, Co-immunoprecipitation, immunofluorescence, MTT apoptosis assay BMC cancer Medium 22788920
2008 Drosophila Bruce and the effector caspase Dcp-1 regulate starvation-induced autophagy during oogenesis in two nutrient checkpoints (germarium and mid-oogenesis), demonstrating that Bruce functions at the intersection of autophagy and apoptosis regulation in vivo. Systematic RNAi screen of cell death genes, genetic loss-of-function alleles, autophagy marker assays (ATG mutants), DNA fragmentation assay, oogenesis in vivo model The Journal of cell biology Medium 18794330
2009 Dexamethasone (acting via glucocorticoid receptor) decreases BRUCE expression in neural progenitor cells (NPCs) and reduces NPC proliferation; BRUCE overexpression counteracts dexamethasone-induced reduction. Dex also elevates Usp8/Ubpy which via Nrdp1 decreases BRUCE, suggesting a glucocorticoid-Nrdp1-BRUCE axis regulating NPC cell division. Glucocorticoid receptor antagonist (RU486), RNAi silencing, BRUCE overexpression, cell proliferation assay FEBS letters Medium 19527720
2080 BIRC6 modulates Axin protein stability via ubiquitination: BIRC6 interacts with Axin by co-immunoprecipitation, co-localizes with Axin in the cytoplasm, overexpression promotes Axin ubiquitination and degradation, and knockdown suppresses Axin ubiquitination, leading to β-catenin pathway activation in renal cancer cells. Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, siRNA knockdown, lentiviral overexpression, Western blot, in vivo xenograft with Wnt inhibitor ACS omega Medium 38405482

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture. Cancer research 529 10606224
1995 Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture. Cancer research 282 7850785
2004 Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase. Molecular cell 183 15200957
2008 Effector caspase Dcp-1 and IAP protein Bruce regulate starvation-induced autophagy during Drosophila melanogaster oogenesis. The Journal of cell biology 157 18794330
2008 Final stages of cytokinesis and midbody ring formation are controlled by BRUCE. Cell 150 18329369
2005 The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development. Proceedings of the National Academy of Sciences of the United States of America 129 15640352
2004 Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis. The EMBO journal 120 14765125
1996 Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment--fifteenth Bruce F. Cain Memorial Award Lecture. Cancer research 98 8971150
2013 Epstein-Barr virus-encoded microRNA BART15-3p promotes cell apoptosis partially by targeting BRUCE. Journal of virology 97 23678170
2020 Anti-apoptotic proteins in the autophagic world: an update on functions of XIAP, Survivin, and BRUCE. Journal of biomedical science 86 32019552
2019 Negative regulation of autophagy by UBA6-BIRC6-mediated ubiquitination of LC3. eLife 85 31692446
2018 The IAP family member BRUCE regulates autophagosome-lysosome fusion. Nature communications 85 29426817
2011 Comparative proteomics of colon cancer stem cells and differentiated tumor cells identifies BIRC6 as a potential therapeutic target. Molecular & cellular proteomics : MCP 78 21788403
2004 The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9. The Journal of biological chemistry 78 15507451
2002 Drosophila Bruce can potently suppress Rpr- and Grim-dependent but not Hid-dependent cell death. Current biology : CB 71 12121627
2009 Die hard: are cancer stem cells the Bruce Willises of tumor biology? Cytometry. Part A : the journal of the International Society for Analytical Cytology 69 19051297
2004 BRUCE, a giant E2/E3 ubiquitin ligase and inhibitor of apoptosis protein of the trans-Golgi network, is required for normal placenta development and mouse survival. Molecular and cellular biology 61 15485903
2007 Inactivation of the oxytocin and the vasopressin (Avp) 1b receptor genes, but not the Avp 1a receptor gene, differentially impairs the Bruce effect in laboratory mice (Mus musculus). Endocrinology 56 17947352
2019 circ-BIRC6, a circular RNA, promotes hepatocellular carcinoma progression by targeting the miR-3918/Bcl2 axis. Cell cycle (Georgetown, Tex.) 54 30931701
2023 Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science (New York, N.Y.) 52 36758105
2019 SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation. Proceedings of the National Academy of Sciences of the United States of America 50 31213539
2020 CircRNA BIRC6 promotes non-small cell lung cancer cell progression by sponging microRNA-145. Cellular oncology (Dordrecht, Netherlands) 44 32297303
2013 Elevated expression of BIRC6 protein in non-small-cell lung cancers is associated with cancer recurrence and chemoresistance. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 43 23287853
2020 MALAT1 knockdown inhibits prostate cancer progression by regulating miR-140/BIRC6 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 42 31935634
2015 BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1. Proceedings of the National Academy of Sciences of the United States of America 41 25733871
1995 Initiatives with platinum- and quinazoline-based antitumor molecules--Fourteenth Bruce F. Cain Memorial Award Lecture. Cancer research 41 7796401
2014 BIRC6 promotes hepatocellular carcinogenesis: interaction of BIRC6 with p53 facilitating p53 degradation. International journal of cancer 40 25196217
2023 Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6. Science (New York, N.Y.) 37 36758106
2022 Circular RNA BIRC6 depletion promotes osteogenic differentiation of periodontal ligament stem cells via the miR-543/PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment. Stem cell research & therapy 37 35964136
1998 Translational research: walking the bridge between idea and cure--seventeenth Bruce F. Cain Memorial Award lecture. Cancer research 36 9766639
2013 BIRC6 protein, an inhibitor of apoptosis: role in survival of human prostate cancer cells. PloS one 35 23409057
2023 Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases. Science (New York, N.Y.) 34 36758104
2016 miR-30e Blocks Autophagy and Acts Synergistically with Proanthocyanidin for Inhibition of AVEN and BIRC6 to Increase Apoptosis in Glioblastoma Stem Cells and Glioblastoma SNB19 Cells. PloS one 30 27388765
2014 The BIRC6 gene as a novel target for therapy of prostate cancer: dual targeting of inhibitors of apoptosis. Oncotarget 30 25071009
2016 BIRC6 Targeting as Potential Therapy for Advanced, Enzalutamide-Resistant Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 29 27663589
2002 BRUCE: a program for the detection of transfer-messenger RNA genes in nucleotide sequences. Nucleic acids research 29 12140330
2008 Prostaglandin F2alpha promotes muscle cell survival and growth through upregulation of the inhibitor of apoptosis protein BRUCE. Cell death and differentiation 28 18566603
2020 Paclitaxel Suppresses Hepatocellular Carcinoma Tumorigenesis Through Regulating Circ-BIRC6/miR-877-5p/YWHAZ Axis. OncoTargets and therapy 27 33061425
2019 The BRUCE-ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development. Hepatology (Baltimore, Md.) 27 30693543
2012 Identification of BIRC6 as a novel intervention target for neuroblastoma therapy. BMC cancer 26 22788920
2011 Drosophila BRUCE inhibits apoptosis through non-lysine ubiquitination of the IAP-antagonist REAPER. Cell death and differentiation 26 21886178
2005 Progressive loss of the spongiotrophoblast layer of Birc6/Bruce mutants results in embryonic lethality. Genesis (New York, N.Y. : 2000) 26 15887267
2018 The anti-apoptotic ubiquitin conjugating enzyme BIRC6/BRUCE regulates autophagosome-lysosome fusion. Autophagy 23 29929453
2017 10H-3,6-Diazaphenothiazine induces G2/M phase cell cycle arrest and caspase-dependent apoptosis and inhibits cell invasion of A2780 ovarian carcinoma cells through the regulation of NF-κB and (BIRC6-XIAP) complexes. Drug design, development and therapy 23 29123378
2014 Expression and clinical significance of BIRC6 in human epithelial ovarian cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 23 24453032
2017 Exocrine Gland-Secreting Peptide 1 Is a Key Chemosensory Signal Responsible for the Bruce Effect in Mice. Current biology : CB 21 29033330
2010 Depletion of BIRC6 leads to retarded bovine early embryonic development and blastocyst formation in vitro. Reproduction, fertility, and development 21 20188030
2006 The contribution of Bruce Glick to the definition of the role played by the bursa of Fabricius in the development of the B cell lineage. Clinical and experimental immunology 21 16792666
2024 Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy. Nature communications 20 38291026
2019 Loss of BRUCE reduces cellular energy level and induces autophagy by driving activation of the AMPK-ULK1 autophagic initiating axis. PloS one 20 31091257
2017 BIRC6 mediates imatinib resistance independently of Mcl-1. PloS one 18 28520795
2011 Oestradiol treatment restores the capacity of castrated males to induce both the Vandenbergh and the Bruce effects in mice (Mus musculus). Reproduction (Cambridge, England) 18 22016382
2009 Dexamethasone regulates expression of BRUCE/Apollon and the proliferation of neural progenitor cells. FEBS letters 18 19527720
2018 MiR-204 acts as a potential therapeutic target in acute myeloid leukemia by increasing BIRC6-mediated apoptosis. BMB reports 17 29764561
2022 Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen. Neurobiology of stress 16 35655933
2022 Impact of stress on inhibitory neuronal circuits, our tribute to Bruce McEwen. Neurobiology of stress 16 35734023
2020 Long Non-Coding RNA DLEU1 Up-Regulates BIRC6 Expression by Competitively Sponging miR-381-3p to Promote Cisplatin Resistance in Nasopharyngeal Carcinoma. OncoTargets and therapy 16 32214823
2019 Analysis of the expression of BAX, BCL2, BIRC6, CASP3, CASP9 apoptosis genes during the first episode of schizophrenia. Psychiatria polska 16 32017818
2021 Overexpression of BIRC6 driven by EGF-JNK-HECTD1 signaling is a potential therapeutic target for triple-negative breast cancer. Molecular therapy. Nucleic acids 15 34729249
2021 BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer's disease. Translational psychiatry 13 34354038
2021 Silencing circ‑BIRC6 inhibits the proliferation, invasion, migration and epithelial‑mesenchymal transition of bladder cancer cells by targeting the miR‑495‑3p/XBP1 signaling axis. Molecular medicine reports 13 34542161
2020 Depletion of circ-BIRC6, a circular RNA, suppresses non-small cell lung cancer progression by targeting miR-4491. Bioscience trends 13 33177288
2005 Bruce/apollon promotes hippocampal neuron survival and is downregulated by kainic acid. Biochemical and biophysical research communications 13 16236253
2020 Bioactivity and cytotoxicity profiling of vincosamide and strictosamide, anthelmintic epimers from Sarcocephalus latifolius (Smith) Bruce leaf. Journal of ethnopharmacology 12 32697959
2015 The UBC Domain Is Required for BRUCE to Promote BRIT1/MCPH1 Function in DSB Signaling and Repair Post Formation of BRUCE-USP8-BRIT1 Complex. PloS one 12 26683461
2014 Association of a polymorphism in the BIRC6 gene with pseudoexfoliative glaucoma. PloS one 12 25118708
2013 Redescription and genetic characterization of Hysterothylacium thalassini Bruce, 1990 (Nematoda: Anisakidae) from marine fishes in the South China Sea. The Journal of parasitology 12 23343397
2016 Asymmetric hybridization between non-native winter moth, Operophtera brumata (Lepidoptera: Geometridae), and native Bruce spanworm, Operophtera bruceata, in the Northeastern United States, assessed with novel microsatellites and SNPs. Bulletin of entomological research 11 27876095
2015 Knockdown of the Inhibitor of Apoptosis BRUCE Sensitizes Resistant Breast Cancer Cells to Chemotherapeutic Agents. Journal of cancer science & therapy 11 26191375
2022 A new circular RNA-encoded protein BIRC6-236aa inhibits transmissible gastroenteritis virus (TGEV)-induced mitochondrial dysfunction. The Journal of biological chemistry 9 35863430
2020 BRUCE preserves genomic stability in the male germline of mice. Cell death and differentiation 9 32139899
2019 Circ_MDM2_000139, Circ_ATF2_001418, Circ_CDC25C_002079, and Circ_BIRC6_001271 Are Involved in the Functions of XAV939 in Non-Small Cell Lung Cancer. Canadian respiratory journal 9 31885751
2012 RNA interference-mediated validation of survivin and Apollon/BRUCE as new therapeutic targets for cancer therapy. Current topics in medicinal chemistry 9 22196277
2023 Evaluation of BIRC6 Expression in Oral Squamous Cell Carcinoma, Epithelial Dysplasia, Lichen Planus with and without Dysplasia, and Hyperkeratosis. Diagnostics (Basel, Switzerland) 8 38066801
2020 Reflections on Bruce S. McEwen's contributions to stress neurobiology and so much more. Stress (Amsterdam, Netherlands) 8 32851903
2017 BRUCE Protein, New Marker for Targeted Therapy of Gastric Carcinoma. Journal of gastrointestinal cancer 8 27614745
2012 BIRC6 (APOLLON) is down-regulated in acute myeloid leukemia and its knockdown attenuates neutrophil differentiation. Experimental hematology & oncology 8 23211188
2020 BIRC6 Is Associated with Vulnerability of Carotid Atherosclerotic Plaque. International journal of molecular sciences 7 33317170
2024 BIRC6 Modulates the Protein Stability of Axin to Regulate the Growth, Stemness, and Resistance of Renal Cancer Cells via the β-Catenin Pathway. ACS omega 6 38405482
2022 BIRC6 modifies risk of invasive bacterial infection in Kenyan children. eLife 6 35866869
2025 UBA6 specificity for ubiquitin E2 conjugating enzymes reveals a priority mechanism of BIRC6. Nature structural & molecular biology 5 41350950
2022 Oral Squamous Cell Carcinoma: The Role of BIRC6 Serum Level. BioMed research international 5 36033570
2016 Expression analysis of BRUCE protein in esophageal squamous cell carcinoma. Annals of diagnostic pathology 5 27649954
2024 The differential interactomes of the KRAS splice variants identify BIRC6 as a ubiquitin ligase for KRAS4A. Cell reports 4 39705142
2022 Exploring the Role of the Inhibitor of Apoptosis BIRC6 in Breast Cancer: A Database Analysis. JCO clinical cancer informatics 4 36455174
2020 Bruce Nathan Ames - Paradigm shifts inside the cancer research revolution. Mutation research. Reviews in mutation research 4 34083041
2019 A personally guided tour on some of our data with the Ames assay-A tribute to Professor Bruce Ames. Mutation research. Genetic toxicology and environmental mutagenesis 4 31585631
2019 Nrdp1 increases neuron apoptosis via downregulation of Bruce following intracerebral haemorrhage. Journal of inflammation (London, England) 4 31827407
2014 Apollon/Bruce is upregulated by Humanin. Molecular and cellular biochemistry 4 25138702
2008 Regulation of apoptosis and cytokinesis by the anti-apoptotic E2/E3 ubiquitin-ligase BRUCE. Ernst Schering Foundation symposium proceedings 4 19198067
2021 BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) regulation of β-catenin signaling in the progression of drug-induced hepatic fibrosis and carcinogenesis. World journal of hepatology 3 33815677
2018 Using the SSU, ITS, and Ribosomal DNA Operon Arrangement to Characterize Two Microsporidia Infecting Bruce Spanworm, Operophtera bruceata (Lepidoptera: Geometridae). The Journal of eukaryotic microbiology 3 30136341
2016 Nrdp1-mediated degradation of BRUCE decreases cell viability and induces apoptosis in human 786-O renal cell carcinoma cells. Experimental and therapeutic medicine 3 27446249
1988 The male-induced implantation failure (the Bruce effect) in laboratory mice: investigations on luteal failure in pregnancy-blocked females. Experimental and clinical endocrinology 3 3229446
1980 Evidence for the involvement of serotoninergic system in the male-induced ovo-implantation failure (Bruce effect) in mice. Annales d'endocrinologie 3 7235620
2023 The Media Coverage of Bruce Willis Reveals Unfamiliarity With Frontotemporal Degeneration. Innovation in aging 2 38046892
2020 [Effect of small interfering RNA-mediated BIRC6 silencing on apoptosis and autophagy of renal cancer 786-O cells]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 2 33243730
2020 A Wide Frequency Scanning Printed Bruce Array Antenna with Bowtie and Semi-Circular Elements. Sensors (Basel, Switzerland) 2 33261220
2010 Improved synthesis of (3E,6Z,9Z)-1,3,6,9-nonadecatetraene, attraction inhibitor of bruce spanworm, Operophtera bruceata, to pheromone traps for monitoring winter moth, Operophtera brumata. Journal of agricultural and food chemistry 2 20041659
1998 Volume 8, Number 2 (1997): Kyung-Eui Ro, Carl S. Keener, and Bruce A. McPheron, "Molecular Phylogenetic Study of the Ranunculaceae: Utility of the Nuclear 26S Ribosomal DNA in Inferring Intrafamilial Relationships," pp. 117-127: Molecular phylogenetics and evolution 2 9527909

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