Affinage

BCL2L11

Bcl-2-like protein 11 · UniProt O43521

Length
198 aa
Mass
22.2 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 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

BCL2L11 (Bim) is a BH3-only pro-apoptotic protein that triggers the intrinsic mitochondrial apoptosis pathway, acting as a convergence point that senses loss of survival signals — integrin/EGFR/ERK signaling during anoikis (PMID:12844146), trophic factor withdrawal (PMID:12818176), and cytokine deprivation (PMID:27525555) — to commit cells to death. Bim engages mitochondrial death through two mechanistically separable activities: its BH3 domain neutralizes anti-apoptotic proteins Bcl-2, Bcl-xL and Mcl-1, while its C-terminal sequence is required for both mitochondrial membrane insertion and direct Bax activation (PMID:12198137, PMID:31976859). In living cells BimL primarily binds Bcl-xL rather than Bax, releasing Bax indirectly (PMID:19427863), and Bim associates dominantly with Mcl-1 in some contexts to enforce Mcl-1 dependence (PMID:15459900); the short isoform BimS inserts into mitochondria and activates Bax even independently of anti-apoptotic Bcl-2 family binding (PMID:17517961). Bim activity is tightly restrained by multisite phosphorylation with opposing consequences: phosphorylation by ERK1/2/Rsk drives βTrCP-dependent and ubiquitin-independent 20S proteasomal degradation (PMID:19150432, PMID:21378313), Akt and Aurora-pathway phosphorylation at Ser87 attenuates and destabilizes it (PMID:16282323, PMID:34388376), Cdk1/cyclin B1 and Aurora A phosphorylate it during mitosis to promote degradation (PMID:23912711, PMID:22071694), whereas JNK/p38 phosphorylation at Ser65 potentiates its pro-death activity (PMID:12818176, PMID:16818494, PMID:18498746). The deubiquitinases Usp27x and OTUD1 stabilize Bim to promote apoptosis (PMID:27013495, PMID:34826170), and Bim is sequestered on microtubules via tubulin/DYNLL1 until released by phosphorylation or apoptotic stimuli (PMID:14732682, PMID:15899854). Bim transcription is governed by FOXO3 (PMID:22349704, PMID:16888645), c-Jun/AP-1 and Runx2 downstream of p38 (PMID:22825467), and is epigenetically repressed via EZH2/PRC2 recruited by the lncRNA Morrbid or viral EBNA3 factors (PMID:27490482, PMID:27525555), while alternative splicing to the potent BimS isoform is controlled by SRSF6/SRp55 (PMID:21364673, PMID:23648111). Beyond apoptosis, Bim bridges Beclin 1 and DYNLL1 to tether Beclin 1 to microtubules and inhibit autophagy until JNK phosphorylation relieves this restraint (PMID:23064249).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 Medium

    Established that Bim acts indirectly at mitochondria — distinct from a direct Bax activator like Bid — by inhibiting anti-apoptotic Bcl-2/Bcl-xL rather than activating Bax itself, and that its C-terminal hydrophobic region is needed for mitochondrial targeting.

    Evidence Cell-free assays with isolated mitochondria, domain mutagenesis, and Bax conformational change assays

    PMID:12095614 PMID:12198137

    Open questions at the time
    • Whether BH3-independent C-terminal Bax activation operates at physiological concentrations was not resolved here
    • Single-study reconstitution for the FEBS Letters cell-free claim
  2. 2003 High

    Defined Bim as a sensor of cell-survival cues, linking trophic factor deprivation and integrin/EGFR/ERK loss to apoptosis through both transcriptional induction and post-translational activation.

    Evidence JNK in vitro kinase assay with S65A mutagenesis in neurons, and RNAi knockdown in epithelial anoikis assays

    PMID:12818176 PMID:12844146

    Open questions at the time
    • Did not resolve how transcriptional and phosphorylation inputs are quantitatively integrated
    • Downstream Bax/Bak engagement mechanism left to later work
  3. 2006 High

    Identified stress kinases JNK and p38 as activating Bim via a shared Ser65 phosphosite, and FOXO3 as a transcriptional inducer driving mitochondrial apoptosis.

    Evidence In vitro kinase assays with S65A mutants, inducible FKHRL1/FoxO3a transgenes, and RNAi

    PMID:15470142 PMID:16818494 PMID:16888645

    Open questions at the time
    • Did not reconcile activating versus degradative phosphorylation at neighboring sites
    • FOXO3-Bim axis tested in restricted cell contexts
  4. 2005 High

    Showed that survival kinase Akt phosphorylates Bim at Ser87 to promote 14-3-3 binding and dampen its pro-apoptotic potency, and that Bim is held on microtubules via tubulin until released.

    Evidence In vitro Akt kinase assay, S87A mutagenesis, 14-3-3 co-IP, and microtubule/tubulin fractionation with Gadd45a-induced translocation

    PMID:14732682 PMID:15899854 PMID:16282323

    Open questions at the time
    • Cytoskeletal sequestration mechanism rested on single-lab Co-IP
    • How 14-3-3 sequestration intersects with degradation was not defined
  5. 2007 High

    Resolved that ERK1/2 phosphorylation at Ser65 first dissociates BimEL from Mcl-1/Bcl-xL and then channels it into βTrCP/Rsk-dependent proteasomal degradation, defining the principal survival-signaling off-switch.

    Evidence Endogenous reciprocal Co-IP, phospho-specific antibodies, Bim-/- cells, βTrCP/Rsk1/2 siRNA and ubiquitination assays

    PMID:17525735 PMID:19150432

    Open questions at the time
    • Did not establish whether dissociation and degradation are obligatorily coupled
    • Other survival kinases feeding the degron not enumerated
  6. 2009 High

    Demonstrated that BimEL, as an intrinsically disordered protein, can be degraded by the 20S proteasome without poly-ubiquitination, with Mcl-1 binding protecting it from this turnover.

    Evidence Purified 20S proteasome assays, K48 lysine mutants (BimEL-ΔKK), Rpn2 knockdown, and βTrCP inhibition

    PMID:21378313

    Open questions at the time
    • Relative in vivo contribution of ubiquitin-dependent versus 20S degradation unquantified
    • Structural basis of Mcl-1 protection not defined
  7. 2007 High

    Showed the BimS isoform kills via mitochondrial insertion and Bax activation independent of anti-apoptotic Bcl-2 binding, distinguishing isoform-specific death mechanisms.

    Evidence Conditional expression, fractionation, mutagenesis, and yeast reconstitution lacking anti-apoptotic Bcl-2 proteins

    PMID:17517961

    Open questions at the time
    • Physiological frequency of Bcl-2-independent killing not established
    • Did not address how BimS membrane insertion is regulated
  8. 2008 High

    Used phosphorylation-defective knock-in mice to assign opposing in vivo functions to distinct Bim phosphosites — Thr112 enhancing Bcl-2 binding (pro-death), Ser55/65/73 promoting degradation (anti-death).

    Evidence Knock-in mouse alleles with site-specific Bim mutations and in vivo apoptosis assays

    PMID:18498746

    Open questions at the time
    • Upstream kinases for each site not all assigned in vivo
    • Tissue specificity of each phosphosite's dominance unresolved
  9. 2012 High

    Expanded Bim regulation to ubiquitin/cytoskeleton machinery and a non-apoptotic role: RACK1/CIS-Cullin2 ligase degrades Bim conferring taxane resistance, ASCIZ→DYNLL1 controls Bim genetically in B cells, and Bim bridges Beclin 1 to DYNLL1 to inhibit autophagy.

    Evidence Y2H, Co-IP, ubiquitination assays, conditional/double-knockout epistasis (ASCIZ × Bim), and autophagy assays with JNK inhibition

    PMID:18420585 PMID:22891272 PMID:23064249

    Open questions at the time
    • Autophagy and RACK1/CIS arms each from single labs
    • Structural detail of the Bim-DYNLL1-Beclin1 bridge unresolved
  10. 2013 High

    Linked mitotic kinases Cdk1/cyclin B1 and Aurora A to Bim degradation during mitosis, explaining antimitotic drug sensitivity, and defined SRSF6-controlled splicing as a switch generating potent BimS.

    Evidence In vitro kinase assays, Co-IP, ubiquitination assays, PP2A/Aurora inhibition, and Bim mini-gene UV-crosslinking with SRSF6

    PMID:21364673 PMID:22071694 PMID:23648111 PMID:23912711

    Open questions at the time
    • Crosstalk between mitotic and survival-kinase phosphorylation not integrated
    • Splicing control studied largely in melanoma/cell-line contexts
  11. 2016 High

    Identified deubiquitinases (Usp27x, OTUD1) that stabilize Bim to enable apoptosis, and epigenetic repression of the BCL2L11 locus by EZH2/PRC2 recruited via lncRNA Morrbid or viral EBNA3 factors.

    Evidence Co-IP, ubiquitination assays, ChIP and chromatin conformation capture, Morrbid knockout mice, and EZH2 inhibitor treatment

    PMID:27013495 PMID:27490482 PMID:27525555 PMID:34826170

    Open questions at the time
    • DUB and epigenetic arms tested in distinct disease contexts
    • How transcriptional, splicing, DUB and degradation layers are coordinated in one cell unresolved
  12. 2021 Medium

    Connected Bim phosphorylation regulation to therapy resistance — Aurora B/ATR-CHK1 phosphorylation of Ser87 destabilizes BIM in EGFR-inhibitor resistance — and showed Bim phosphorylation enforces Mcl-1 dependence.

    Evidence Drug screens, phospho-Ser87 detection, Aurora B inhibition, BIM knockdown in cell/mouse models, and phospho-mutant Mcl-1 stability assays

    PMID:29775995 PMID:34388376

    Open questions at the time
    • Ser87 destabilization mechanism rested on single-study pharmacology
    • Generalizability beyond EGFR-driven resistance not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple layers of Bim control — transcription, splicing, multisite phosphorylation, ubiquitin-dependent and 20S degradation, deubiquitination, and cytoskeletal sequestration — are quantitatively integrated to set the apoptotic threshold in a given cell remains unresolved.
  • No unified model linking the regulatory layers
  • Stoichiometry of Bim partitioning among Bcl-2/Bcl-xL/Mcl-1 versus Bax in vivo undefined
  • Structural basis of CTS-mediated Bax activation versus indirect activation not reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 3
Localization
GO:0005739 mitochondrion 4 GO:0005856 cytoskeleton 3
Pathway
R-HSA-5357801 Programmed Cell Death 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-9612973 Autophagy 1
Partners
BAXBCL2BCL2L1BECN1BTRCDYNLL1MCL1YWHAH

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 JNK (mitochondrially localized) directly phosphorylates BimEL at Ser65, potentiating its proapoptotic activity during trophic factor deprivation. JNK also transcriptionally induces BimEL expression, and both transcriptional and posttranslational regulation converge to promote BAX-dependent cytochrome c release and apoptosis. In vitro kinase assay, site-directed mutagenesis (S65A), co-expression studies, pharmacological JNK pathway inhibition/activation Neuron High 12818176
2004 JNK catalyzes phosphorylation of BimEL at Ser65 both in vitro and in vivo; this phosphorylation promotes BimEL's proapoptotic effect in primary cerebellar granule neurons and mediates p75NTR-induced neuronal apoptosis. Genetic knockdown of BimEL by RNAi significantly impaired p75NTR-induced apoptosis. In vitro kinase assay, RNAi knockdown, dominant-negative BimEL expression in primary neurons The Journal of neuroscience High 15470142
2006 p38 MAP kinase directly phosphorylates BimEL at Ser65 in vitro and in vivo, potentiating apoptosis induced by sodium arsenite. A non-phosphorylatable S65A mutant of BimEL failed to potentiate apoptosis, identifying Ser65 as a shared regulatory target for both JNK and p38. In vitro kinase assay, S65A mutagenesis, pharmacological p38 inhibition, ectopic expression in PC12 cells The Journal of biological chemistry High 16818494
2005 Akt directly phosphorylates BimEL at Ser87 in vitro. IL-3-stimulated Akt activity promotes BimEL phosphorylation and binding to 14-3-3 proteins. Mutation of Ser87 dramatically increases BimEL apoptotic potency, indicating Akt phosphorylation attenuates BimEL's proapoptotic function. In vitro Akt kinase assay with GST-BimEL fusion protein, site-directed mutagenesis (S87A), co-immunoprecipitation with 14-3-3 proteins, PI3K inhibitor (LY294002) The Journal of biological chemistry High 16282323
2008 Multisite phosphorylation regulates Bim by distinct mechanisms in vivo: phosphorylation at Thr112 increases Bim binding to Bcl-2 (promoting death), while phosphorylation at Ser55, Ser65, and Ser73 promotes proteasomal degradation of Bim (reducing death). These were demonstrated using knock-in mice expressing phosphorylation-defective Bim alleles. Knock-in mouse models with phosphorylation-defective Bim alleles, in vivo apoptosis assays Molecular cell High 18498746
2009 BimEL is targeted for proteasomal degradation via the F-box protein βTrCP following phosphorylation of a conserved degron by Rsk1/2, with ERK1/2 phosphorylation of BimEL at Ser69 promoting this process. A phosphorylation-defective BimEL mutant unable to bind βTrCP was stabilized and more potently induced apoptosis. Co-immunoprecipitation, phosphorylation-defective mutants, siRNA knockdown of βTrCP and Rsk1/2, ubiquitination assays Molecular cell High 19150432
2007 ERK1/2-dependent phosphorylation of BimEL at Ser65 causes rapid dissociation of preformed BimEL/Mcl-1 and BimEL/Bcl-xL complexes in response to survival factors. This dissociation is specific to BimEL and is a prerequisite step in ERK1/2-driven proteasomal degradation of BimEL. Co-immunoprecipitation of endogenous complexes, ERK1/2 activation/inhibition, phospho-specific antibodies, Bim-/- cells The EMBO journal High 17525735
2002 BimEL requires both its BH3 domain and C-terminal hydrophobic region for mitochondrial targeting and proapoptotic activity. A BH3 domain mutant (L→A) that cannot bind Bcl-XL still activates Bax and induces apoptosis, but removal of the C-terminal domain from this mutant abolishes mitochondrial targeting and Bax activation. Bcl-XL suppresses BimEL-induced Bax conformational change through a mechanism independent of direct heterodimerization with Bax or BimEL. Domain deletion/point mutagenesis, subcellular fractionation, Bax conformational change assay, isolated mitochondria assay The Journal of biological chemistry High 12198137
2004 Unphosphorylated BimEL is sequestered to microtubules via direct interaction with tubulin in T cells; phosphorylated BimEL is released from microtubules. Released BimEL is cleaved by caspases at an early stage of apoptosis to generate a hyperactive N-terminally truncated form that more efficiently targets Bcl-2, creating a positive feedback amplification of apoptotic signaling. Biochemical fractionation, co-immunoprecipitation with tubulin, caspase cleavage assays, overexpression of cleaved BimEL variants Proceedings of the National Academy of Sciences Medium 14732682
2005 Gadd45a expression causes dissociation of Bim from microtubule-associated components and its translocation to mitochondria. At mitochondria, Bim accumulates and interacts with Bcl-2, displacing Bax from Bcl-2 complexes to release cytochrome c. Gadd45a acts upstream by interacting with EF-1α and inhibiting microtubule bundling; deletion of the EF-1α-binding domain of Gadd45a prevents Bim translocation. Inducible Gadd45a expression, subcellular fractionation, co-immunoprecipitation, siRNA knockdown of Bim, domain deletion mutants Molecular and cellular biology Medium 15899854
2005 The cytoprotective peptide humanin (HN) directly binds BimEL (but not BimL or BimS) as demonstrated by in vitro protein binding, immunoprecipitation, and coimmunolocalization. HN inhibits BimEL-induced cytochrome c and SMAC release from isolated Bax-/- mitochondria and prevents BimEL-induced Bak oligomerization, showing HN suppresses BimEL activity independently of Bax. In vitro protein binding assay, immunoprecipitation, coimmunolocalization, isolated mitochondria assay with Bax-/- cells The Journal of biological chemistry High 15661735
2002 BimL added directly to isolated mitochondria does not trigger cytochrome c release or activate Bax, but can directly inhibit Bcl-2 or Bcl-xL. This distinguishes Bim functionally from Bid, which directly activates Bax at the mitochondria. Cell-free assay with isolated mitochondria, cytochrome c release assay, overexpression in cells FEBS letters Medium 12095614
2007 BimS undergoes rapid mitochondrial translocation and membrane insertion without detectable binding to anti-apoptotic Bcl-2 proteins, leading to Bax recruitment/activation and apoptosis. Mutational analysis showed mitochondrial targeting, but not Bcl-2/Mcl-1 binding, is required for BimS-induced apoptosis. In yeast (lacking anti-apoptotic Bcl-2 proteins), BimS enhanced Bax killing activity, demonstrating Bcl-2-family-independent apoptosis induction. Regulated expression with conditional system, subcellular fractionation, co-immunoprecipitation, mutagenesis, yeast reconstitution assay The Journal of cell biology High 17517961
2008 RACK1 forms a complex with dynein light chain 1 (DLC1/DYNLL1) and BimEL. Upon paclitaxel treatment, this complex together with CIS promotes BimEL ubiquitination and degradation via an ElonginB/C-Cullin2-CIS E3 ligase complex, conferring paclitaxel resistance. Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo tumor models The Journal of biological chemistry Medium 18420585
2009 BimEL is an intrinsically disordered protein (IDP) that can be degraded by uncapped 20S proteasomes in the absence of poly-ubiquitylation. Although BimEL undergoes K48-linked poly-ubiquitylation at two lysine residues, a double lysine mutant (BimELΔKK) without ubiquitination still undergoes ERK1/2-driven proteasome-dependent turnover. MCL-1 binding to BimEL prevents 20S proteasome degradation. Ubiquitin-binding domain pulldowns, proteasome assay with purified 20S proteasome, lysine mutants, Rpn2 knockdown, β-TrCP inhibition Journal of cell science High 21378313
2013 BimEL is phosphorylated by Aurora A kinase during early mitosis and dephosphorylated by PP2A after mitotic exit. Aurora A phosphorylation stimulates BimEL binding to βTrCP, promoting BimEL ubiquitination and degradation during mitosis. Knockdown of Bim significantly increased resistance to Aurora A inhibitor MLN8054. In vitro kinase assay, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, pharmacological inhibition of PP2A/Aurora A Cell death and differentiation High 23912711
2011 Cyclin B1 co-immunoprecipitates with endogenous Bim in mitotic extracts, and active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro. Ser44 on BimL was identified as a Cdk1 phosphorylation site. Cdk1 inhibitors block Bim phosphorylation in mitotically arrested cells, and siRNA silencing of Bim reduces sensitivity to Taxol-induced cell death. Co-immunoprecipitation, in vitro kinase assay with recombinant Cdk1/cyclin B1, Cdk1 inhibitors, siRNA, phospho-site mapping Cell cycle High 22071694
2016 Usp27x, a deubiquitinase, binds BimEL upon ERK-dependent phosphorylation, reduces BimEL ubiquitination, stabilizes phosphorylated BimEL, and promotes apoptosis. Loss of endogenous Usp27x enhances Bim-degrading activity of oncogenic Raf. Usp27x acts as a tumor suppressor by counteracting ERK-mediated BimEL degradation. Co-immunoprecipitation, ubiquitination assay, overexpression and knockdown (siRNA) of Usp27x, apoptosis assays in melanoma/NSCLC cells EMBO reports Medium 27013495
2021 Melatonin induces upregulation of the deubiquitinase OTUD1 via Sp1-mediated transcription. OTUD1 directly interacts with Bim, deubiquitinates it at lysine 3, and stabilizes Bim protein, leading to apoptosis. OTUD1 knockdown inhibited melatonin-induced Bim upregulation and apoptosis. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mutagenesis (K3 site), in vivo xenograft Journal of pineal research Medium 34826170
2012 BCL2L11 (Bim) interacts with BECN1 (Beclin 1), and this interaction is facilitated by DYNLL1 (LC8). Bim recruits Beclin 1 to microtubules by bridging Beclin 1 and DYNLL1, thereby inhibiting autophagy. JNK-mediated phosphorylation of Bim (in starvation) abolishes the Bim-DYNLL1 interaction, releasing Beclin 1 and relieving autophagy inhibition. Co-immunoprecipitation, autophagy assays, JNK inhibition/phosphorylation analysis, siRNA knockdown Autophagy Medium 23064249
2003 Bim is a critical mediator of anoikis in epithelial cells. Detachment-induced Bim expression requires loss of β1-integrin engagement, downregulation of EGFR, and inhibition of ERK signaling. RNAi-mediated knockdown of Bim inhibits anoikis. Overexpressed EGFR maintains ERK activation in suspension, blocking Bim expression and anoikis, demonstrating Bim functions as a sensor of integrin/growth factor signals to the ERK pathway. RNAi knockdown, EGFR overexpression, pharmacological ERK inhibition, suspension culture assays, siRNA Nature cell biology High 12844146
2009 FOXO3 (FKHRL1) transcriptionally induces Bim expression. Bim induction by FOXO3 is essential for FOXO3-induced mitochondrial ROS production and apoptosis; Bim knockdown or Bcl-xL overexpression prevents FOXO3-mediated ROS overproduction. Tetracycline-controlled Bim expression impairs mitochondrial respiration and causes ROS production, suggesting Bim induces mitochondrial uncoupling. Inducible FOXO3 and Bim expression systems, siRNA knockdown, live-cell MitoTrackerRed microscopy, dominant-negative FOXO3 Journal of cell science Medium 22349704
2010 BimS preferential splicing is controlled by B-RAFV600E signaling: inhibition of B-RAFV600E triggers upregulation of all Bim isoforms but preferentially promotes BimS splicing. The splicing factor SRp55 mediates this effect, as siRNA against SRp55 blocks BimS induction and apoptosis by PLX4720. RT-PCR isoform analysis, siRNA of SRp55, B-RAFV600E inhibitor (PLX4720), B-RAFV600E enforced expression Cell death & disease Medium 21364673
2013 Zinc modulates Bim splicing by inhibiting SRSF6 (SRp55) activity, promoting elimination of exon 4 and preferential generation of the potent apoptotic isoform BimS. UV cross-linking assay showed SRSF6 directly binds the intronic region adjacent to exon 4; Zn2+ suppresses this binding and induces SRSF6 hyper-phosphorylation. Mutations in predicted SRSF6-binding sites abolished BimS generation from a Bim mini-gene. Bim mini-gene construct with deletion analysis, UV cross-linking/Western blot, mutagenesis, pharmacological inhibition (TG003) The FEBS journal High 23648111
2009 EZH2 epigenetically suppresses Bim expression downstream of E2F1 to prevent E2F1-dependent apoptosis. RNAi-mediated depletion of EZH2 enhances E2F1-dependent Bim expression and promotes apoptosis, identifying a feedback circuit by which E2F1 induces EZH2 to restrain Bim-mediated apoptosis in cancer cells. RNAi knockdown of EZH2, chromatin immunoprecipitation (ChIP), Bim promoter analysis, apoptosis assays Cell death and differentiation Medium 19893569
2016 EBV repressors EBNA3A and EBNA3C silence the BCL2L11 locus by recruiting the H3K27 methyltransferase EZH2 to a haematopoietic enhancer hub, inactivating enhancer-promoter interactions. Pharmacological reversal using an EZH2 inhibitor upregulates BCL2L11 and induces apoptosis. Chromatin conformation capture, ChIP, EZH2 inhibitor treatment, enhancer-promoter interaction mapping eLife Medium 27490482
2016 The lncRNA Morrbid controls Bim (Bcl2l11) transcription in cis by promoting PRC2 complex enrichment at the Bcl2l11 promoter, maintaining it in a poised (repressed) state. Morrbid regulates allele-specific control of Bcl2l11 transcription in neutrophils, eosinophils, and classical monocytes in response to pro-survival cytokines. Chromatin immunoprecipitation (PRC2/H3K27me3 at Bcl2l11 promoter), allele-specific expression analysis, Morrbid knockout mouse model Nature High 27525555
2010 IGF-1 suppresses Bim expression in multiple myeloma by three mechanisms: (1) Akt activation inactivates FoxO3a transcription factor to reduce Bim transcription; (2) MAPK activation promotes proteasomal degradation of BimEL; (3) epigenetic regulation of the Bim and FoxO3a promoters (reduced H3K9 acetylation and increased H3K9 dimethylation). RNAi knockdown of Bim protected cells from drug-induced death. RNAi knockdown, pharmacological inhibition, ChIP for histone modifications, Western blot, promoter methylation analysis Blood Medium 20086250
2006 FKHRL1/FoxO3a transcriptionally induces Bim (and Noxa) expression in neuroblastoma, driving cytochrome c release and caspase-dependent apoptosis via the mitochondrial pathway. RNAi knockdown of Bim or Noxa individually decreases apoptosis, indicating both cooperate to mediate FKHRL1-induced cell death. Bcl-2 overexpression protects, but dominant-negative FADD does not, confirming the intrinsic pathway. 4OH-tamoxifen-inducible FKHRL1 transgene, RNAi knockdown, dominant-negative FADD, Bcl-2 overexpression, caspase and cytochrome c assays Cell death and differentiation Medium 16888645
2012 ASCIZ transcription factor activates DYNLL1 expression; DYNLL1 in turn modulates Bim-dependent apoptosis during B cell development. Loss of ASCIZ causes B cell lymphopenia that can be fully suppressed by deletion of Bim, placing ASCIZ→DYNLL1→Bim in a genetic epistasis pathway controlling B cell survival. Conditional KO mice, genetic epistasis (ASCIZ KO × Bim KO double mutant rescue), ectopic DYNLL1 expression The Journal of experimental medicine High 22891272
2020 The CTS (carboxyl-terminal sequence) of Bim directly interacts with Bax and is required for Bax activation at physiological Bim concentrations; different CTS residues enable Bax activation versus membrane binding. BimL lacking the CTS (BimL-dCTS) inhibits Bcl-XL but cannot activate Bax, demonstrating mechanistically separable functions. Domain deletion and point mutants of Bim, mitochondrial permeabilization assays with isolated mitochondria, cell-based apoptosis assays eLife High 31976859
2009 In living cells during UV-induced apoptosis, BimL directly binds Bcl-xL (not Bax), neutralizing Bcl-xL and releasing Bax for activation. No BimL–Bax interaction was detected by FRET in living cells or endogenous co-IP, supporting an indirect model of Bax activation by BimL. FRET in living cells, endogenous co-immunoprecipitation, RNAi knockdown of BimL FEBS letters Medium 19427863
2018 Bim phosphorylation alters Mcl-1 stability and priming: constitutive Bim phosphorylation stabilizes Mcl-1, and phospho-mimetic or unphosphorylatable Bim mutations result in altered Mcl-1 stability and distinct binding profiles to anti-apoptotic proteins. This identifies Bim phosphorylation as a mechanism enforcing Mcl-1 dependence. Phospho-mimetic and non-phosphorylatable Bim mutants, co-immunoprecipitation, Mcl-1 stability assays The FEBS journal Medium 29775995
2004 Raf/ERK signaling prevents transcriptional induction of BimEL and BimL upon matrix detachment and promotes phosphorylation and proteasomal degradation of the BimEL isoform, protecting epithelial cells from anoikis. Conditional Raf-ER activation, pharmacological MEK inhibition, Western blot for BimEL phosphorylation and degradation, suspension culture assays Oncogene Medium 14676826
2008 Bim and Bmf are released from the cytoskeleton of cells infected with Neisseria gonorrhoeae in a JNK-1- and Rac-1-dependent manner. Loss of Bim and Bmf prevents Bak/Bax activation and caspase activation; apoptosis can be reconstituted in Bim-depleted cells by silencing Mcl-1, placing Bim upstream of Mcl-1 in the Ngo-induced apoptotic pathway. Focused siRNA miniscreen, subcellular fractionation, co-immunoprecipitation, caspase activation assay, epistasis by double knockdown PLoS pathogens Medium 19300516
2021 Aurora B inhibition stabilizes BIM by reducing Ser87 phosphorylation, thereby enhancing BIM-mediated apoptosis. This provides a mechanistic basis for Aurora B inhibitor synergy with EGFR inhibitor osimertinib. EMT-induced osimertinib resistance activates ATR-CHK1-Aurora B signaling, which hyperphosphorylates BIM at Ser87. High-throughput drug screening, phospho-specific antibody detection of Ser87, Aurora B inhibitor treatment, BIM knockdown, EGFR/Aurora B combination studies in cells and mouse models Cancer cell Medium 34388376
2012 Glucocorticoid-induced BIM transcription in leukemia cells requires the transcription factors c-Jun (acting at an AP-1 site ~2.7 kb upstream of the BIM transcription start site) and Runx2, both induced downstream of p38-MAPK. Dominant-negative c-Jun or Runx2 shRNA reduced Dex-induced BIM expression and apoptosis. Chromatin immunoprecipitation (c-Jun binding to Bim promoter), dominant-negative c-Jun, Runx2 shRNA, p38 inhibitor (SB203580), GC receptor antagonist (RU486) Cell death & disease Medium 22825467
2020 In colorectal cancer, SMS depletion causes spermidine accumulation, which inhibits FOXO3a acetylation and promotes its nuclear translocation to transcriptionally induce Bim expression. MYC-driven miR-19a/b repress Bim protein production. Combined SMS and MYC inhibition dramatically induces Bim and apoptosis, with Bim silencing abolishing these effects. SMS genetic disruption, FOXO3a nuclear translocation assays, Bim promoter reporter, miR-19a/b overexpression/inhibition, siRNA Bim knockdown, xenograft tumor regression Nature communications Medium 32591507
2004 BimEL functions downstream of Mcl-1 in myeloma cell survival: Bim is found strongly associated with Mcl-1 in viable myeloma cells, and this interaction is disrupted upon apoptosis induction coinciding with Mcl-1 downregulation. Bim/Bcl-2 interaction is not altered under apoptosis, implicating Mcl-1 as the dominant BimEL neutralizer in myeloma. Co-immunoprecipitation of endogenous Bim with Mcl-1 and Bcl-2, IL-6 withdrawal, apoptosis assays European journal of immunology Medium 15459900

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 434 12818176
2003 Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nature cell biology 434 12844146
2011 BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer discovery 249 22145099
2016 The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan. Nature 242 27525555
2010 Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. Journal of hepatology 208 20206402
2005 Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. The Journal of biological chemistry 194 16282323
2008 Multisite phosphorylation regulates Bim stability and apoptotic activity. Molecular cell 188 18498746
2006 p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. The Journal of biological chemistry 186 16818494
2015 Regulation of Bim in Health and Disease. Oncotarget 176 26405162
2009 betaTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis. Molecular cell 164 19150432
2012 FOXO3-induced reactive oxygen species are regulated by BCL2L11 (Bim) and SESN3. Journal of cell science 163 22349704
2009 CD95, BIM and T cell homeostasis. Nature reviews. Immunology 153 19543226
2007 ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL. The EMBO journal 148 17525735
2006 FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells. Cell death and differentiation 142 16888645
2021 Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer cell 138 34388376
2007 Bim and the pro-survival Bcl-2 proteins: opposites attract, ERK repels. Cell cycle (Georgetown, Tex.) 133 17881896
2009 Bim-targeted cancer therapy: a link between drug action and underlying molecular changes. Molecular cancer therapeutics 123 19934277
2012 BCL2L11/BIM: a novel molecular link between autophagy and apoptosis. Autophagy 108 23064249
2009 Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression. Cell death and differentiation 106 19893569
2008 Bim and Bmf in tissue homeostasis and malignant disease. Oncogene 105 19641506
2004 Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 104 15470142
2013 PUMA and BIM are required for oncogene inactivation-induced apoptosis. Science signaling 101 23532334
2007 Oncogenic BRAF(V600E) inhibits BIM expression to promote melanoma cell survival. Pigment cell & melanoma research 100 18715233
2004 Role of Bim in the survival pathway induced by Raf in epithelial cells. Oncogene 97 14676826
2005 Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL. The Journal of biological chemistry 96 15661735
2005 Gadd45a expression induces Bim dissociation from the cytoskeleton and translocation to mitochondria. Molecular and cellular biology 95 15899854
2020 Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression. Nature communications 86 32591507
2019 miRNA-29b Inhibits Prostate Tumor Growth and Induces Apoptosis by Increasing Bim Expression. Cells 83 31752117
2016 MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs. eLife 83 27490482
2010 Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS. Cell death & disease 82 21364673
2015 MicroRNA-9 Mediates the Cell Apoptosis by Targeting Bcl2l11 in Ischemic Stroke. Molecular neurobiology 80 26660116
2010 IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms. Blood 80 20086250
2009 Bax activation by Bim? Cell death and differentiation 79 19557009
2002 Bcl-XL protects BimEL-induced Bax conformational change and cytochrome C release independent of interacting with Bax or BimEL. The Journal of biological chemistry 79 12198137
2004 The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells. European journal of immunology 76 15459900
2007 BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins. The Journal of cell biology 72 17517961
2004 Caspase cleavage of BimEL triggers a positive feedback amplification of apoptotic signaling. Proceedings of the National Academy of Sciences of the United States of America 72 14732682
2017 BH3-only protein BIM: An emerging target in chemotherapy. European journal of cell biology 71 29100606
2016 Onco-miR-24 regulates cell growth and apoptosis by targeting BCL2L11 in gastric cancer. Protein & cell 68 26758252
2016 T cell Bim levels reflect responses to anti-PD-1 cancer therapy. JCI insight 64 27182556
2012 miR-301a promotes pancreatic cancer cell proliferation by directly inhibiting Bim expression. Journal of cellular biochemistry 64 22628193
2011 BIM(EL), an intrinsically disordered protein, is degraded by 20S proteasomes in the absence of poly-ubiquitylation. Journal of cell science 60 21378313
2005 BimEL up-regulation potentiates AIF translocation and cell death in response to MPTP. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 57 15941767
2012 Glucocorticoid-mediated BIM induction and apoptosis are regulated by Runx2 and c-Jun in leukemia cells. Cell death & disease 56 22825467
2010 Hypoxia suppression of Bim and Bmf blocks anoikis and luminal clearing during mammary morphogenesis. Molecular biology of the cell 55 20861305
2008 RACK1 and CIS mediate the degradation of BimEL in cancer cells. The Journal of biological chemistry 55 18420585
2015 IL-6 and ICOS Antagonize Bim and Promote Regulatory T Cell Accrual with Age. Journal of immunology (Baltimore, Md. : 1950) 53 26109645
2005 Zinc pyrithione induces apoptosis and increases expression of Bim. Apoptosis : an international journal on programmed cell death 53 15843898
2013 BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1. Cell death and differentiation 50 23912711
2017 TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression. Clinical cancer research : an official journal of the American Association for Cancer Research 49 28899969
2016 The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis. EMBO reports 49 27013495
2015 The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma. Oncotarget 47 26517093
2006 Loss of the proapoptotic protein, Bim, breaks B cell anergy. The Journal of experimental medicine 45 16520387
2019 SOX7 regulates MAPK/ERK-BIM mediated apoptosis in cancer cells. Oncogene 43 31332289
2011 Efavirenz and 8-hydroxyefavirenz induce cell death via a JNK- and BimEL-dependent mechanism in primary human hepatocytes. Toxicology and applied pharmacology 42 21958719
2022 Bim- and Bax-mediated mitochondrial pathway dominates abivertinib-induced apoptosis and ferroptosis. Free radical biology & medicine 41 35063650
2008 Activation of the JNK pathway promotes phosphorylation and degradation of BimEL--a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia. Carcinogenesis 41 18174237
2020 The carboxyl-terminal sequence of bim enables bax activation and killing of unprimed cells. eLife 37 31976859
2002 Direct addition of BimL to mitochondria does not lead to cytochrome c release. FEBS letters 37 12095614
2018 Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma. Cell death & disease 36 30224718
2009 A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells. Experimental hematology 36 19100522
2012 The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim. The Journal of experimental medicine 35 22891272
2015 cAMP signalling of Bordetella adenylate cyclase toxin through the SHP-1 phosphatase activates the BimEL-Bax pro-apoptotic cascade in phagocytes. Cellular microbiology 34 26334669
2009 Toxoplasma gondii infection confers resistance against BimS-induced apoptosis by preventing the activation and mitochondrial targeting of pro-apoptotic Bax. Journal of cell science 34 19737817
2012 PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortium. Blood 33 23047821
2020 Targeting Bim via a lncRNA Morrbid Regulates the Survival of Preleukemic and Leukemic Cells. Cell reports 32 32579941
2018 POH1 Knockdown Induces Cancer Cell Apoptosis via p53 and Bim. Neoplasia (New York, N.Y.) 32 29573636
2018 miR-339 Promotes Development of Stem Cell Leukemia/Lymphoma Syndrome via Downregulation of the BCL2L11 and BAX Proapoptotic Genes. Cancer research 32 29735550
2023 Regorafenib induces Bim-mediated intrinsic apoptosis by blocking AKT-mediated FOXO3a nuclear export. Cell death discovery 30 36720853
2020 MicroRNA-338-5p alleviates neuronal apoptosis via directly targeting BCL2L11 in APP/PS1 mice. Aging 30 33087587
2009 Bim and Bmf synergize to induce apoptosis in Neisseria gonorrhoeae infection. PLoS pathogens 30 19300516
2009 BimL directly neutralizes Bcl-xL to promote Bax activation during UV-induced apoptosis. FEBS letters 30 19427863
2008 Fas Bim boom! Immunity 30 18275825
2007 Bim expression indicates the pathway to retinal cell death in development and degeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 17913922
2016 Insulin-like growth factor 1 rescues R28 retinal neurons from apoptotic death through ERK-mediated BimEL phosphorylation independent of Akt. Experimental eye research 27 27511131
2022 Circular RNA Rbms1 inhibited the development of myocardial ischemia reperfusion injury by regulating miR-92a/BCL2L11 signaling pathway. Bioengineered 25 35068339
2022 Ambra1 regulates apoptosis and chemosensitivity in breast cancer cells through the Akt-FoxO1-Bim pathway. Apoptosis : an international journal on programmed cell death 25 35257265
2022 Protective Effects of MicroRNA-200b-3p Encapsulated by Mesenchymal Stem Cells-Secreted Extracellular Vesicles in Myocardial Infarction Via Regulating BCL2L11. Journal of the American Heart Association 25 35699193
2020 JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction. Cell death and differentiation 25 32346136
2020 Renal tubular Bim mediates the tubule-podocyte crosstalk via NFAT2 to induce podocyte cytoskeletal dysfunction. Theranostics 24 32550905
2018 Phosphorylation alters Bim-mediated Mcl-1 stabilization and priming. The FEBS journal 24 29775995
2015 HCV upregulates Bim through the ROS/JNK signalling pathway, leading to Bax-mediated apoptosis. The Journal of general virology 23 26296767
2015 Mir-192 suppresses apoptosis and promotes proliferation in esophageal aquamous cell caicinoma by targeting Bim. International journal of clinical and experimental pathology 23 26339371
2011 Cyclin B1 interacts with the BH3-only protein Bim and mediates its phosphorylation by Cdk1 during mitosis. Cell cycle (Georgetown, Tex.) 23 22071694
2004 Potential utility of BimS as a novel apoptotic therapeutic molecule. Molecular therapy : the journal of the American Society of Gene Therapy 23 15336653
2021 Melatonin induces apoptotic cell death through Bim stabilization by Sp1-mediated OTUD1 upregulation. Journal of pineal research 22 34826170
2011 Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival. BMC cancer 22 21247487
2007 c-Cbl is not required for ERK1/2-dependent degradation of BimEL. Cellular signalling 22 17884340
2019 LINC00261 functions as a competing endogenous RNA to regulate BCL2L11 expression by sponging miR-132-3p in endometriosis. American journal of translational research 21 31105834
2013 The role of DAPK-BimEL pathway in neuronal death induced by oxygen-glucose deprivation. Neuroscience 21 24269611
2018 miR-9-5p, miR-124-3p, and miR-132-3p regulate BCL2L11 in tuberous sclerosis complex angiomyolipoma. Laboratory investigation; a journal of technical methods and pathology 20 29540858
2013 Zinc-induced modulation of SRSF6 activity alters Bim splicing to promote generation of the most potent apoptotic isoform BimS. The FEBS journal 20 23648111
2010 BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin. The European journal of neuroscience 20 20497470
2021 Bim transfer between Bcl-2-like protein and Hsp70 underlines Bcl-2/Hsp70 crosstalk to regulate apoptosis. Biochemical pharmacology 19 34153292
2015 Bim and VDAC1 are hierarchically essential for mitochondrial ATF2 mediated cell death. Cancer cell international 19 25852302
2014 Role of BH3-only molecules Bim and Puma in β-cell death in Pdx1 deficiency. Diabetes 19 24658302
2013 BIM, PUMA, and the achilles' heel of oncogene addiction. Science signaling 19 23532333
2011 Dual regulation of hepatocyte apoptosis by reactive oxygen species: Increases in transcriptional expression and decreases in proteasomal degradation of BimEL. Journal of cellular physiology 19 20857401
2005 Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis. British journal of cancer 19 15827557
2020 Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy. Lung cancer (Amsterdam, Netherlands) 18 33296806

Missed literature

Know a paper Affinage missed for BCL2L11? Flag it for the maintainers and the community.

No submissions yet.