Affinage

BCL2

Apoptosis regulator Bcl-2 · UniProt P10415

Round 2 corrected
Length
239 aa
Mass
26.3 kDa
Annotated
2026-04-28
130 papers in source corpus 45 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BCL-2 is a master anti-apoptotic regulator that governs cell survival by integrating mitochondrial membrane permeabilization, calcium signaling, and autophagy. It resides on the outer mitochondrial membrane, endoplasmic reticulum, and nuclear envelope, where it sequesters pro-apoptotic BH3-only proteins (BIM, BID, BAD, PUMA) through its hydrophobic BH1–BH3 groove, thereby preventing BAX/BAK oligomerization, cytochrome c release, and caspase activation (PMID:8358790, PMID:9027314, PMID:11583631, PMID:15694340). BCL-2 also forms ion-conductive channels via its α5/α6 helices (PMID:9144199), inhibits Beclin 1-dependent autophagy through direct binding that is relieved by JNK1-mediated phosphorylation at T69/S70/S87 (PMID:16179260, PMID:18570871), and modulates ER and ryanodine receptor-mediated Ca²⁺ release via its BH4 domain (PMID:24762814, PMID:12543100). Its activity is terminated by caspase-3 cleavage at Asp34 — converting it into a pro-apoptotic BAX-like fragment — and by XIAP/ARTS-directed ubiquitination at Lys17, while its expression is repressed by p53 at the P2 promoter and post-transcriptionally by miR-15a/miR-16-1 (PMID:9395403, PMID:29020630, PMID:11313951, PMID:16166262).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1985 High

    The identification of bcl-2 at the t(14;18) breakpoint established a new oncogene locus juxtaposed to the immunoglobulin heavy-chain enhancer, raising the question of how this translocation drives lymphomagenesis.

    Evidence Chromosomal breakpoint cloning and Southern blotting in follicular lymphomas and cell lines

    PMID:3924412

    Open questions at the time
    • No protein product yet characterized
    • Mechanism of oncogenesis unknown
  2. 1986 High

    Cloning of bcl-2 cDNA revealed two alternatively spliced isoforms and showed that the t(14;18) translocation preserves normal BCL-2 protein, implying oncogenesis through deregulated expression rather than a mutant product.

    Evidence cDNA cloning and nucleotide sequencing from lymphoma-derived libraries

    PMID:2875799 PMID:3523487

    Open questions at the time
    • Function of BCL-2 protein entirely unknown
    • No structural information
  3. 1988 High

    Gene-transfer experiments showed BCL-2 promotes oncogenesis by blocking programmed cell death rather than stimulating proliferation, defining a fundamentally new category of oncogene.

    Evidence BCL-2 overexpression in cell lines with proliferation and survival assays

    PMID:2848196

    Open questions at the time
    • Subcellular site of action unknown
    • Molecular mechanism of death inhibition unresolved
  4. 1990 High

    Subcellular fractionation and transgenic mouse models placed BCL-2 at mitochondrial membranes and demonstrated that it extends B-cell survival in vivo without increasing cycling, confirming a pure survival function.

    Evidence Immunolocalization, subcellular fractionation, Eμ-bcl-2 transgenic mice

    PMID:1908951 PMID:2250705

    Open questions at the time
    • Binding partners unknown
    • Whether inner or outer mitochondrial membrane uncertain
  5. 1992 High

    Ultrastructural immunoelectron microscopy resolved BCL-2 to the outer mitochondrial membrane (correcting earlier inner-membrane assignment) and additionally to the perinuclear membrane and ER, defining its multi-compartment topology.

    Evidence Three independent ultrastructural preparation methods with concordant results in lymphoma and carcinoma cells

    PMID:1453000 PMID:8402648

    Open questions at the time
    • Functional significance of ER/nuclear envelope pools unknown
    • Membrane insertion mechanism uncharacterized
  6. 1993 High

    Discovery of BCL-2/BAX heterodimerization and structure–function mapping of BH1/BH2 domains established that the BCL-2:BAX ratio governs cell fate, providing the first molecular mechanism for BCL-2's anti-apoptotic activity.

    Evidence Yeast two-hybrid, reciprocal co-IP, mutagenesis of BH1 (G145) and BH2 (W188), apoptosis assays

    PMID:8183370 PMID:8358790

    Open questions at the time
    • No structural model of the BCL-2/BAX interface
    • Whether BCL-2 acts solely by sequestering BAX or has additional mechanisms
  7. 1995 High

    Identification of BAD as a BH3-only protein that displaces BAX from BCL-2/BCL-XL introduced the competing-dimerization model and revealed that BH3-only proteins act as sentinels that neutralize anti-apoptotic family members.

    Evidence Yeast two-hybrid, co-IP, competition binding, apoptosis assays

    PMID:7834748

    Open questions at the time
    • Spectrum of BH3-only ligands for BCL-2 not yet defined
    • Quantitative affinities unknown
  8. 1997 High

    Three mechanistic breakthroughs converged: BCL-2 prevents cytochrome c efflux from mitochondria, forms ion-conductive channels via α5/α6 helices, and is cleaved by caspase-3 at Asp34 to generate a pro-apoptotic fragment — collectively defining both the protective and self-inactivating arms of BCL-2 action.

    Evidence Subcellular fractionation for cytochrome c, planar bilayer electrophysiology with Δα5/6 mutants, in vitro caspase-3 cleavage with D34A mutagenesis

    PMID:9027314 PMID:9144199 PMID:9395403

    Open questions at the time
    • Whether channel activity is required for anti-apoptotic function in intact cells
    • In vivo relevance of caspase-3 cleavage loop
  9. 1998 High

    Rapid identification of multiple BH3-only partners — BIM, BID, and Beclin 1 — expanded BCL-2's interactome and first linked it to autophagy regulation, while structure–function studies confirmed α5/α6 helices are essential for cytoprotection.

    Evidence Expression library screen (BIM), caspase-8 cleavage/mitochondrial fractionation (BID), yeast two-hybrid and FRET (Beclin 1), domain deletion in human cells and yeast (α5/α6)

    PMID:9430630 PMID:9727491 PMID:9765397 PMID:9812996

    Open questions at the time
    • BCL-2/Beclin 1 functional consequences on autophagy not yet demonstrated
    • BIM/BID affinity hierarchy for BCL-2 vs. other pro-survival members unknown
  10. 2000 High

    KSHV v-cyclin–CDK6-mediated phosphorylation of BCL-2 at S70/S87 was shown to inactivate its anti-apoptotic function, establishing the unstructured loop as a critical regulatory switch, while NOXA and PUMA were identified as p53-induced BH3-only proteins that neutralize BCL-2.

    Evidence In vitro kinase assays with mutagenesis (v-cyclin–CDK6), co-IP and antisense knockdown (NOXA, PUMA), cytochrome c release assays

    PMID:10807576 PMID:11056537 PMID:11463391 PMID:11463392

    Open questions at the time
    • Whether endogenous cellular CDKs similarly phosphorylate BCL-2 in non-viral contexts
    • Full phosphorylation site map in the loop not yet mapped
  11. 2001 High

    Multiple studies converged on transcriptional regulation and the sequestration model: p53 represses bcl-2 via TBP/HDAC1 at the P2 promoter, NF-κB2/BCL-3 activates it, and genetic epistasis with BAX/BAK double knockouts proved BCL-2 acts by sequestering BH3-only proteins upstream of BAX/BAK.

    Evidence Promoter mapping, co-IP of p53–TBP–HDAC1, NF-κB EMSA, BAX/BAK DKO cells, NMR structures with BH3 peptide binding

    PMID:11248023 PMID:11313951 PMID:11583631 PMID:12835724

    Open questions at the time
    • Chromatin-level regulation of bcl-2 locus incompletely mapped
    • Whether p53 direct mitochondrial interaction with BCL-2 is quantitatively relevant vs. transcriptional repression
  12. 2005 High

    Quantitative binding studies revealed that BH3 selectivity for BCL-2 varies >10,000-fold (high affinity for BAD, BIM, PUMA; negligible for NOXA), while functional studies demonstrated BCL-2 directly inhibits Beclin 1-dependent autophagy in cells and transgenic mouse hearts, establishing BCL-2 as a dual anti-apoptotic/anti-autophagic regulator.

    Evidence Fluorescence polarization and SPR binding measurements, co-IP with BCL-2 binding-defective mutants, cardiac autophagy in transgenic mice

    PMID:15694340 PMID:15901672 PMID:16166262 PMID:16179260

    Open questions at the time
    • How BCL-2 vs. BCL-XL selectivity for BH3-only proteins is determined structurally
    • Whether autophagy inhibition contributes to BCL-2-driven oncogenesis
  13. 2008 High

    JNK1 was identified as the kinase that phosphorylates BCL-2 at T69/S70/S87 during nutrient starvation, disrupting the BCL-2–Beclin 1 complex and activating autophagy; viral BCL-2 (lacking the phosphorylatable loop) constitutively suppresses autophagy, explaining a viral immune-evasion strategy.

    Evidence JNK1/JNK2 siRNA, dominant-negative JNK1, phosphomimetic and non-phosphorylatable BCL-2 mutants, co-IP, autophagy assays

    PMID:18570871

    Open questions at the time
    • Phosphatase that reverses JNK1-mediated BCL-2 phosphorylation unknown
    • Whether loop phosphorylation also disrupts BH3-only protein binding
  14. 2014 High

    BCL-2 was found to directly inhibit ryanodine receptors via its BH4 domain, dampening intracellular Ca²⁺ release in neurons and HEK293 cells, extending BCL-2's functions beyond apoptosis and autophagy into calcium homeostasis.

    Evidence Endogenous co-IP from rat hippocampi, SPR with purified RyR domains, Ca²⁺ imaging in neurons

    PMID:24762814

    Open questions at the time
    • Physiological significance of BCL-2–RyR interaction in neurodegeneration models not tested
    • Whether BCL-2's Ca²⁺ effects at ER (IP3R) and RyR are independent or coordinated
  15. 2017 High

    XIAP was shown to ubiquitinate BCL-2 at Lys17 in a ternary complex assembled by the mitochondrial ARTS protein, providing a mechanism for apoptotic degradation of BCL-2 and explaining how cells dismantle anti-apoptotic protection once death signals pass a threshold.

    Evidence Co-IP, ubiquitination assays, K17A mutagenesis, XIAP and ARTS knockout MEFs, apoptosis assays

    PMID:29020630

    Open questions at the time
    • Whether other E3 ligases target BCL-2 for polyubiquitination and proteasomal degradation in non-apoptotic contexts
    • Structural basis of the ARTS-mediated ternary complex unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how BCL-2's channel activity relates to its anti-apoptotic function at physiological expression levels; the structural basis by which loop phosphorylation selectively disrupts Beclin 1 vs. BH3-only protein binding; whether BCL-2's ER Ca²⁺-modulatory and RyR-inhibitory functions are mechanistically linked or independent; and the full E3 ligase repertoire controlling BCL-2 turnover in healthy vs. malignant cells.
  • Channel activity relevance at endogenous expression levels
  • Structural basis of phosphorylation-dependent partner selectivity
  • Integration of Ca²⁺ regulatory functions across compartments

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0005215 transporter activity 2 GO:0008289 lipid binding 1
Localization
GO:0005739 mitochondrion 6 GO:0005635 nuclear envelope 3 GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-5357801 Programmed Cell Death 9 R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 3 R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
AMBRA1BADBAXBECN1BIDBIMRYRXIAP
Complex memberships
ARTS/XIAP/BCL-2 ternary complexBCL-2/BAX heterodimerBCL-2/Beclin 1 complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 The bcl-2 gene encodes two protein isoforms (bcl-2 alpha, 26 kDa, 239 aa; and bcl-2 beta, 22 kDa, 205 aa) produced by alternative splicing from at least two exons; t(14;18) chromosomal translocation juxtaposes bcl-2 with the immunoglobulin heavy-chain locus, producing hybrid transcripts that retain normal BCL-2 protein. cDNA cloning, nucleotide sequence analysis, hybrid transcript characterization Cell / PNAS High 2875799 3523487
1985 The t(14;18)(q32;q21) chromosomal breakpoints on chromosome 18 cluster within a 4.3 kb region near a new transcriptional unit (bcl-2), placing the Ig enhancer adjacent to bcl-2 and establishing this as a novel oncogene locus. Chromosomal breakpoint cloning, Southern blotting, cell-line and primary lymphoma analysis Cell High 3924412
1988 BCL-2 promotes oncogenesis via inhibition of programmed cell death rather than by stimulating cell proliferation, demonstrated by gene transfer into cells. Gene transfer / overexpression, functional cell death assays Nature High 2848196
1990 BCL-2 is an integral inner mitochondrial membrane protein (25 kDa) that blocks programmed cell death independently of promoting cell division; transgenic mice overexpressing bcl-2 show prolonged B-cell survival without increased cycling. Immunolocalization, subcellular fractionation, transgenic mouse model Nature High 2250705
1991 Bcl-2 overexpression in transgenic mice leads to long-term persistence of immunoglobulin-secreting cells and extended lifetime of memory B cells, demonstrating a role in B-cell memory maintenance. Transgenic mouse model, immunological assays Nature High 1908951
1992 Ultrastructural immunoelectron microscopy localized BCL-2 protein preferentially to the outer mitochondrial membrane (not the inner membrane or matrix), as well as to the perinuclear membrane, in lymphoma and breast carcinoma cells. Immunoelectron microscopy (progressive lowering of temperature, cryosectioning, freeze-substitution), confocal microscopy Journal of Histochemistry and Cytochemistry High 1453000
1993 BCL-2 protein resides primarily in the nuclear envelope, endoplasmic reticulum (smooth ER), and outer mitochondrial membrane; in vitro translation experiments showed transmembrane domain-dependent association with isolated mitochondria without import into a protease-resistant compartment, consistent with outer membrane localization. Subcellular fractionation, Nycodenz/Percoll gradient centrifugation, immune electron microscopy, in vitro mitochondrial import assay Cancer Research High 8402648
1993 BCL-2 heterodimerizes in vivo with BAX (a 21 kDa homolog sharing BH1 and BH2 domains); BAX homodimerizes and forms heterodimers with BCL-2, and overexpressed BAX accelerates apoptosis and counters BCL-2's death-repressor activity, establishing that the BCL-2:BAX ratio determines cell fate. Co-immunoprecipitation, yeast two-hybrid, overexpression in IL-3-dependent cell lines, apoptosis assays Cell High 8358790
1993 BCL-2 overexpression protects cells lacking mitochondrial DNA (ρ0 cells) from apoptosis, demonstrating that neither apoptosis nor BCL-2's protective effect requires mitochondrial respiration; BCL-2 in overexpressing cells associates with nuclear envelope and endoplasmic reticulum as well as mitochondria. Overexpression in mtDNA-deficient cell lines, apoptosis induction assays, immunolocalization Nature High 8381212
1994 BH1 and BH2 domains of BCL-2 are required for its death-repressor activity and for heterodimerization with BAX; point mutations Gly145 (BH1) or Trp188 (BH2) completely abolish anti-apoptotic function and BAX heterodimerization while permitting BCL-2 homodimerization. Site-directed mutagenesis, co-immunoprecipitation, apoptosis assays (IL-3 deprivation, γ-irradiation, glucocorticoids) Nature High 8183370
1995 BAD, a BH3-only protein, selectively dimerizes with BCL-XL and BCL-2 (more strongly with BCL-XL), displaces BAX from BCL-XL, and restores apoptosis; when approximately half of BAX is heterodimerized with BCL-2, death is inhibited, showing competing dimerizations govern cell fate. Yeast two-hybrid, lambda expression cloning, co-immunoprecipitation in mammalian cells, apoptosis assays Cell High 7834748
1997 BCL-2 overexpression prevents the efflux of cytochrome c from mitochondria to the cytosol during apoptosis; cytosolic cytochrome c rises during apoptosis and is blocked by BCL-2, placing BCL-2 upstream of cytochrome c release as its mechanism of caspase cascade prevention. Subcellular fractionation, Western blot for cytochrome c in cytosolic vs. mitochondrial fractions, BCL-2 overexpression Science High 9027314
1997 Purified recombinant BCL-2 protein forms ion-conductive, cation-selective channels in lipid membranes; pore formation is pH- and acidic lipid-dependent and requires the two core hydrophobic alpha-helices (helices 5 and 6); a deletion mutant lacking these helices fails to form channels. Chloride efflux assay (KCl-loaded unilamellar vesicles), planar lipid bilayer electrophysiology, mutant BCL-2 (Δh5,6) PNAS High 9144199
1997 Caspase-3 cleaves BCL-2 at Asp34 in the loop domain, generating a C-terminal fragment that acts as a pro-apoptotic Bax-like death effector; this cleavage is BH3- and transmembrane-domain dependent and amplifies the caspase cascade; cleavage-resistant BCL-2 mutants confer enhanced protection from apoptosis. In vitro caspase cleavage assay, overexpression of caspase-3 in cells, Fas ligation/IL-3 withdrawal apoptosis models, site-directed mutagenesis, cell death assays Science High 9395403
1997 BCL-2 can inhibit p53 nuclear import following DNA damage, acting as a 'gatekeeper' to suppress genotoxic stress-induced apoptosis; shown by confocal microscopy and immunoblotting of p53 nuclear/cytoplasmic fractions in BCL-2-overexpressing cells. Confocal microscopy, immunoblotting of subcellular fractions, BCL-2 overexpression Oncogene Medium 9419967
1998 Beclin 1 was identified as a novel BCL-2-interacting protein through yeast two-hybrid screening of an adult mouse brain library, with interaction confirmed by FRET microscopy in mammalian cells; Beclin (with intact BCL-2-binding domain) conferred protection against Sindbis virus encephalitis. Yeast two-hybrid, FRET microscopy, recombinant Sindbis virus in vivo mouse model Journal of Virology High 9765397
1998 The pore-forming alpha5 and alpha6 helices of BCL-2 are essential for its cytoprotective function; deletion or swap of these helices abolishes BCL-2's ability to block apoptosis induced by BAX or staurosporine in human cells and to prevent BAX-induced death in yeast, though they are necessary but not sufficient for anti-apoptotic activity. Domain deletion/chimeric protein expression, apoptosis assays in human cells and yeast (S. cerevisiae), dimerization assays Journal of Biological Chemistry High 9812996
1998 BCL-2 prevents caspase-independent cell death induced by nitric oxide; NO-induced death proceeds via chromatin condensation, nuclear compaction, mitochondrial swelling without caspase activation, and BCL-2 blocks this process independently of caspase inhibition. NO donor treatment, peptide caspase inhibitor controls, p35 expression, BCL-2/BAX overexpression, cell death assays Journal of Biological Chemistry Medium 9852091
1998 BIM, identified by expression screening for BCL-2-binding proteins, is a BH3-only protein that promotes apoptosis; it localizes to intracytoplasmic membranes, requires its BH3 region for BCL-2 binding and cytotoxicity, and is inhibited by wild-type BCL-2 but not by BCL-2 mutants lacking survival function. Expression library screen, co-immunoprecipitation, subcellular localization, apoptosis assays with BCL-2 mutants EMBO Journal High 9430630
1998 BID, a BH3-domain protein, is cleaved by caspase-8 upon death receptor activation; the C-terminal cleavage product translocates to mitochondria and triggers cytochrome c release, which is antagonized by BCL-2; BH3 domain mutation abolishes cytochrome c releasing activity. Protein purification, peptide mass fingerprinting, in vitro caspase-8 cleavage, mitochondrial fractionation, BCL-2 antagonism assay, BH3 mutagenesis Cell High 9727491
2000 NOXA, a BH3-only BCL-2 family member induced by p53, localizes to mitochondria and interacts with anti-apoptotic BCL-2 family members via its BH3 motif, resulting in caspase-9 activation; endogenous NOXA knockdown suppresses p53-dependent apoptosis. Ectopic expression, subcellular localization, co-immunoprecipitation, antisense knockdown, apoptosis assays Science High 10807576
2000 The v-cyclin–CDK6 kinase complex of KSHV phosphorylates BCL-2 at S70 and S87 in its unstructured loop, inactivating its anti-apoptotic function; a BCL-2 S70A/S87A double mutant is resistant to phosphorylation and retains protection against apoptosis; CDK6 and BCL-2 are found in a complex in cell lysates. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (S70A, S87A), apoptosis assays, IHC in KS tissue Nature Cell Biology High 11056537
2001 NMR solution structures of two BCL-2 isoforms were determined; both consist of 6 alpha-helices with a hydrophobic groove similar to BCL-XL; subtle differences in the groove between isoforms translate into differential binding affinities for BAD and BAK BH3 peptides, suggesting isoform-specific anti-apoptotic activities. NMR spectroscopy of BCL-2/BCL-XL chimeras, BH3 peptide binding assays PNAS High 11248023
2001 p53 directly binds BCL-XL and BCL-2 via its DNA binding domain at mitochondria, inducing cytochrome c release and outer mitochondrial membrane permeabilization independently of transcription; tumor-derived transactivation-deficient p53 mutants concomitantly lose ability to interact with BCL-XL and promote cytochrome c release. Mitochondrial p53 targeting, complex formation assays, cytochrome c release assay, p53 mutant analysis, in vivo irradiated thymocyte model Molecular Cell High 12667443
2001 BCL-2 and BCL-XL sequester BH3-only molecules in stable mitochondrial complexes, preventing activation of multidomain proapoptotic BAX and BAK; cells lacking BAX and BAK show long-term resistance to all BH3-only molecules, while downstream caspase-deficient cells show only transient protection. Genetic knockout (BAX/BAK double KO, Apaf-1 KO, caspase-9 KO), BCL-2/BCL-XL mutant analysis, cell death assays Molecular Cell High 11583631
2001 p53 represses bcl-2 transcription by binding to the TATA sequence in the bcl-2 P2 minimal promoter through interaction with TBP; p53-TBP-HDAC1-mSin3a complex co-immunoprecipitates from nuclear extract; HDAC inhibition (trichostatin A) independently increases bcl-2 promoter activity. Transient transfection promoter analysis, co-immunoprecipitation, ChIP-like analysis, endogenous mRNA/protein quantification, HDAC inhibitor treatment Oncogene High 11313951
2001 c-Myc and E2F-1 overexpression suppresses BCL-2 protein and RNA levels in a DNA-binding-dependent manner; restoration of BCL-2 effectively blocks accelerated apoptosis upon IL-3 deprivation in these cells, and this suppression is independent of the ARF/p53 pathway. Overexpression of oncoproteins and DNA-binding mutants, Western blot, RT-PCR, apoptosis rescue assays Oncogene Medium 11704823
2001 PUMA (identified as a p53 target gene) encodes BH3-domain proteins that bind BCL-2 and BCL-XL, localize exclusively to mitochondria, trigger cytochrome c release, and induce rapid apoptosis; antisense inhibition of PUMA reduces p53-induced apoptosis. Expression profiling, co-immunoprecipitation, subcellular localization, antisense knockdown, cytochrome c release assay, apoptosis assays Molecular Cell / Molecular Cell High 11463391 11463392
2002 BCL-2 overexpression results in increased mitochondrial volume and structural complexity without altering membrane potential, delta pH, or intramitochondrial [K+]; these structural changes explain enhanced fluorescent dye accumulation previously misinterpreted as altered membrane potential. Calibrated respirometry, membrane potential measurement, flow cytometry particle sizing, light scattering in digitonin-permeabilized neural cells Journal of Biological Chemistry Medium 12207028
2003 NF-κB2/p100 and its processed product p52 transactivate the bcl-2 promoter via a κB site at position -180, working through association with BCL-3; p50 and p52 homodimers (lacking transactivation domains) drive bcl-2 expression through BCL-3 co-activation; stable p100/p52 overexpression induces endogenous BCL-2 expression. Bcl-2 promoter transfection assays, EMSA, stable overexpression, endogenous BCL-2 protein quantification Leukemia Medium 12835724
2005 BCL-2 anti-apoptotic proteins directly interact with BECLIN 1 and inhibit Beclin 1-dependent autophagy; BCL-2 mutants unable to bind Beclin 1 fail to inhibit autophagy; cardiac BCL-2 transgenic mice show reduced cardiac autophagy, demonstrating BCL-2 is a dual anti-apoptotic/anti-autophagic protein. Co-immunoprecipitation, autophagy assays in yeast and mammalian cells, BCL-2 binding-defective mutants, transgenic mouse cardiac autophagy measurement Cell High 16179260
2005 The binding affinities of eight BH3 peptides for BCL-2 and four other pro-survival proteins vary over 10,000-fold; BCL-2 binds tightly to BAD, BIM, and PUMA but not to NOXA; BAK is sequestered by MCL-1 and BCL-XL but not BCL-2 in healthy cells; complementary BH3/pro-survival pairings cooperate to induce killing. Quantitative binding affinity measurements (fluorescence polarization, surface plasmon resonance), co-immunoprecipitation in cells, cell death assays Molecular Cell / Genes & Development High 15694340 15901672
2005 miR-15a and miR-16-1 negatively regulate BCL-2 expression at the post-transcriptional level; their expression is inversely correlated with BCL-2 protein levels in CLL; BCL-2 repression by these miRNAs induces apoptosis in leukemic cell lines. miRNA expression profiling, transfection of miR-15a/miR-16-1 mimics, Western blot, apoptosis assays PNAS High 16166262
2006 BCL-2 addiction of cancer cells is determined by sequestration of activator BH3-only proteins (BID, BIM) by BCL-2; the pattern of mitochondrial sensitivity to BH3 peptides (BH3 profiling) predicts cellular dependence on specific anti-apoptotic BCL-2 family members for survival; sensitivity to ABT-737 correlates with BIM/BID priming of BCL-2. BH3 profiling (mitochondrial cytochrome c release with BH3 peptides), co-immunoprecipitation, ABT-737 sensitivity assays in cancer cell lines Cancer Cell High 16697956
2008 JNK1 (but not JNK2) mediates starvation-induced multisite phosphorylation of BCL-2 at T69, S70, and S87 in its nonstructured loop, causing BCL-2 dissociation from Beclin 1 and activation of autophagy; viral BCL-2, lacking the phosphorylation loop, fails to dissociate from Beclin 1 during starvation. JNK1/JNK2 siRNA knockdown, dominant-negative JNK1, phosphomimetic/non-phosphorylatable BCL-2 mutants, co-immunoprecipitation, autophagy assays Molecular Cell High 18570871
2010 Parkin E3 ubiquitin ligase directly binds BCL-2 via its C-terminus and mediates mono-ubiquitination of BCL-2, increasing its steady-state levels; parkin overexpression (but not ligase-deficient forms) decreases autophagy (LC3 conversion), and enhances BCL-2/Beclin 1 interaction, linking parkin-mediated BCL-2 ubiquitination to autophagy regulation. Co-immunoprecipitation, in vitro ubiquitination assay, parkin knockdown/overexpression, LC3 conversion assay, ligase-deficient parkin mutants Journal of Biological Chemistry Medium 20889974
2011 AMBRA1 preferentially binds the mitochondrial pool of BCL-2; upon autophagy induction, AMBRA1 is released from BCL-2 and recruited to Beclin 1; AMBRA1 competes with both mito-BCL-2 and ER-BCL-2 to bind Beclin 1, defining a dynamic BCL-2/AMBRA1/Beclin 1 regulatory axis at mitochondria governing both autophagy and apoptosis. Co-immunoprecipitation, subcellular fractionation, mitochondria-targeted BCL-2 constructs, competition binding assays, autophagy induction assays EMBO Journal Medium 21358617
2014 BCL-2 directly inhibits ryanodine receptors (RyR) by binding via its BH4 domain to a conserved sequence on RyR; endogenous BCL-2–RyR complexes were demonstrated by co-immunoprecipitation from rat hippocampi; purified RyR domains bound BCL-2 in pulldown experiments and interacted with BH4 domain in surface plasmon resonance; BCL-2 or BH4 domain expression dampens RyR-mediated Ca²⁺ release in HEK293 cells and hippocampal neurons. Co-immunoprecipitation (ectopic and endogenous), pulldown with purified domains, surface plasmon resonance, Ca²⁺ imaging in HEK293 cells and neurons, patch pipette BH4 loading Journal of Cell Science High 24762814
2017 ARTS (Sept4_i2) brings XIAP and BCL-2 into a ternary complex at the outer mitochondrial membrane upon apoptotic induction, enabling XIAP to act as an E3 ubiquitin ligase for BCL-2; Lys17 of BCL-2 is the primary ubiquitination acceptor; BCL-2 K17A mutant shows increased stability and enhanced protection from apoptosis; BCL-2 ubiquitylation is reduced in XIAP- and ARTS-deficient MEFs. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K17A), MEF knockout models, apoptosis assays Cell Reports High 29020630
1999 Presenilin 1 (PS1) directly interacts with BCL-2, demonstrated by yeast two-hybrid, co-immunoprecipitation, and cross-linking; PS1 and BCL-2 form a macromolecular complex that dissociates in response to staurosporine-induced apoptosis. Yeast two-hybrid, co-immunoprecipitation, chemical cross-linking, apoptotic stimulus (staurosporine) Journal of Biological Chemistry Medium 10521466
1998 BCL-2 promotes migration and invasion of glioma cells by upregulating matrix metalloproteinases MMP-2/-3/-12 and MMP-9/-12, increasing cell surface urokinase-type plasminogen activator (u-PA), and reducing TIMP-2 expression; MMP-2 activation was demonstrated by zymography. Ectopic BCL-2 expression in glioma spheroid and Matrigel invasion assays, fetal rat brain aggregate invasion, zymography, mRNA quantification FEBS Letters Medium 9872414
2002 BCL-2 reduces the filling state of the ER Ca²⁺ store, and this reduction in ER Ca²⁺ renders cells less sensitive to apoptotic stimuli; BCL-2 has a direct effect on ER Ca²⁺ handling as a mechanism of anti-apoptotic action. ER Ca²⁺ store measurement, apoptotic stimuli sensitivity assays, BCL-2 overexpression Cell Calcium Medium 12543100

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 5634 8358790
1997 Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science (New York, N.Y.) 4217 9027314
1990 Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 3646 2250705
2002 The Bcl2 family: regulators of the cellular life-or-death switch. Nature reviews. Cancer 3245 12209154
2005 Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2983 16179260
1998 Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 2970 9727491
2005 miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the United States of America 2843 16166262
2001 PUMA, a novel proapoptotic gene, is induced by p53. Molecular cell 1913 11463392
1995 Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 1887 7834748
2000 Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science (New York, N.Y.) 1690 10807576
2015 Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. The New England journal of medicine 1560 26639348
2005 Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Molecular cell 1538 15694340
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
2003 p53 has a direct apoptogenic role at the mitochondria. Molecular cell 1453 12667443
1998 BCL-2 family: regulators of cell death. Annual review of immunology 1427 9597135
2001 BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Molecular cell 1380 11583631
1997 Double identity for proteins of the Bcl-2 family. Nature 1311 9194558
1994 BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 1228 8183370
1986 Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 1203 2875799
2010 The BCL-2 family reunion. Molecular cell 1199 20159550
2003 The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 1193 14634621
1986 Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proceedings of the National Academy of Sciences of the United States of America 1173 3523487
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