{"gene":"BCL2L11","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2003,"finding":"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.","method":"In vitro kinase assay, site-directed mutagenesis (S65A), co-expression studies, pharmacological JNK pathway inhibition/activation","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation assay plus mutagenesis, replicated across multiple labs (PMID:12818176, PMID:15470142, PMID:16818494)","pmids":["12818176"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro kinase assay, RNAi knockdown, dominant-negative BimEL expression in primary neurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation assay plus genetic knockdown in primary neurons, corroborates PMID:12818176","pmids":["15470142"],"is_preprint":false},{"year":2006,"finding":"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.","method":"In vitro kinase assay, S65A mutagenesis, pharmacological p38 inhibition, ectopic expression in PC12 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, single lab but multiple orthogonal methods","pmids":["16818494"],"is_preprint":false},{"year":2005,"finding":"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.","method":"In vitro Akt kinase assay with GST-BimEL fusion protein, site-directed mutagenesis (S87A), co-immunoprecipitation with 14-3-3 proteins, PI3K inhibitor (LY294002)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, mutagenesis, and binding assay in single study with multiple orthogonal methods","pmids":["16282323"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Knock-in mouse models with phosphorylation-defective Bim alleles, in vivo apoptosis assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo genetic model (knock-in mice) with multiple phosphosite mutations, rigorous functional readouts","pmids":["18498746"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-immunoprecipitation, phosphorylation-defective mutants, siRNA knockdown of βTrCP and Rsk1/2, ubiquitination assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, mutagenesis, and functional apoptosis assays; replicated with PMID:23912711","pmids":["19150432"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Co-immunoprecipitation of endogenous complexes, ERK1/2 activation/inhibition, phospho-specific antibodies, Bim-/- cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with endogenous proteins, pharmacological and genetic tools, replicated in multiple cell types","pmids":["17525735"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Domain deletion/point mutagenesis, subcellular fractionation, Bax conformational change assay, isolated mitochondria assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with isolated mitochondria plus mutagenesis and fractionation in single study","pmids":["12198137"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Biochemical fractionation, co-immunoprecipitation with tubulin, caspase cleavage assays, overexpression of cleaved BimEL variants","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and fractionation with functional follow-up, single lab","pmids":["14732682"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Inducible Gadd45a expression, subcellular fractionation, co-immunoprecipitation, siRNA knockdown of Bim, domain deletion mutants","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation and Co-IP with genetic perturbations, single lab","pmids":["15899854"],"is_preprint":false},{"year":2005,"finding":"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.","method":"In vitro protein binding assay, immunoprecipitation, coimmunolocalization, isolated mitochondria assay with Bax-/- cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro binding plus reconstituted mitochondria assay with isogenic Bax-/- controls, multiple orthogonal methods","pmids":["15661735"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Cell-free assay with isolated mitochondria, cytochrome c release assay, overexpression in cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstituted cell-free assay, single lab, single study","pmids":["12095614"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Regulated expression with conditional system, subcellular fractionation, co-immunoprecipitation, mutagenesis, yeast reconstitution assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis plus yeast reconstitution (Bcl-2-independent system) plus fractionation, multiple orthogonal methods in single study","pmids":["17517961"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo tumor models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with in vivo confirmation, single lab","pmids":["18420585"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Ubiquitin-binding domain pulldowns, proteasome assay with purified 20S proteasome, lysine mutants, Rpn2 knockdown, β-TrCP inhibition","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro 20S proteasome assay plus mutagenesis and genetic perturbation, multiple orthogonal methods","pmids":["21378313"],"is_preprint":false},{"year":2013,"finding":"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.","method":"In vitro kinase assay, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, pharmacological inhibition of PP2A/Aurora A","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with Co-IP and ubiquitination assay, multiple orthogonal methods in single study","pmids":["23912711"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, in vitro kinase assay with recombinant Cdk1/cyclin B1, Cdk1 inhibitors, siRNA, phospho-site mapping","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus Co-IP of endogenous proteins plus phosphosite identification, multiple methods","pmids":["22071694"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression and knockdown (siRNA) of Usp27x, apoptosis assays in melanoma/NSCLC cells","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with loss- and gain-of-function experiments, single lab","pmids":["27013495"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mutagenesis (K3 site), in vivo xenograft","journal":"Journal of pineal research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with genetic perturbations and in vivo validation, single lab","pmids":["34826170"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, autophagy assays, JNK inhibition/phosphorylation analysis, siRNA knockdown","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating novel complex, functional autophagy readout, single lab","pmids":["23064249"],"is_preprint":false},{"year":2003,"finding":"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.","method":"RNAi knockdown, EGFR overexpression, pharmacological ERK inhibition, suspension culture assays, siRNA","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi loss-of-function with specific phenotypic readout, gain-of-function complementation, multiple genetic tools","pmids":["12844146"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Inducible FOXO3 and Bim expression systems, siRNA knockdown, live-cell MitoTrackerRed microscopy, dominant-negative FOXO3","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression and knockdown with live imaging, single lab","pmids":["22349704"],"is_preprint":false},{"year":2010,"finding":"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.","method":"RT-PCR isoform analysis, siRNA of SRp55, B-RAFV600E inhibitor (PLX4720), B-RAFV600E enforced expression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi functional assay demonstrating splicing factor requirement, single lab","pmids":["21364673"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Bim mini-gene construct with deletion analysis, UV cross-linking/Western blot, mutagenesis, pharmacological inhibition (TG003)","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct RNA-binding assay plus mini-gene mutagenesis and pharmacological tools, multiple orthogonal methods","pmids":["23648111"],"is_preprint":false},{"year":2009,"finding":"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.","method":"RNAi knockdown of EZH2, chromatin immunoprecipitation (ChIP), Bim promoter analysis, apoptosis assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and RNAi functional assays, single lab","pmids":["19893569"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Chromatin conformation capture, ChIP, EZH2 inhibitor treatment, enhancer-promoter interaction mapping","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and chromatin conformation assays with pharmacological validation, single study","pmids":["27490482"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Chromatin immunoprecipitation (PRC2/H3K27me3 at Bcl2l11 promoter), allele-specific expression analysis, Morrbid knockout mouse model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP in KO model with allele-specific analysis, replicated in multiple cell types and human disease context","pmids":["27525555"],"is_preprint":false},{"year":2010,"finding":"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.","method":"RNAi knockdown, pharmacological inhibition, ChIP for histone modifications, Western blot, promoter methylation analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, RNAi, and pharmacological tools across three mechanisms, single lab","pmids":["20086250"],"is_preprint":false},{"year":2006,"finding":"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.","method":"4OH-tamoxifen-inducible FKHRL1 transgene, RNAi knockdown, dominant-negative FADD, Bcl-2 overexpression, caspase and cytochrome c assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible transgene system with RNAi loss-of-function and pathway epistasis, single lab","pmids":["16888645"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Conditional KO mice, genetic epistasis (ASCIZ KO × Bim KO double mutant rescue), ectopic DYNLL1 expression","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with double KO rescue in vivo, multiple genetic tools","pmids":["22891272"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Domain deletion and point mutants of Bim, mitochondrial permeabilization assays with isolated mitochondria, cell-based apoptosis assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution assay with isolated mitochondria plus systematic mutagenesis, multiple orthogonal methods","pmids":["31976859"],"is_preprint":false},{"year":2009,"finding":"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.","method":"FRET in living cells, endogenous co-immunoprecipitation, RNAi knockdown of BimL","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET in living cells plus Co-IP, single lab, supports indirect activation model","pmids":["19427863"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Phospho-mimetic and non-phosphorylatable Bim mutants, co-immunoprecipitation, Mcl-1 stability assays","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mutagenesis plus Co-IP, single lab, single study","pmids":["29775995"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Conditional Raf-ER activation, pharmacological MEK inhibition, Western blot for BimEL phosphorylation and degradation, suspension culture assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional inducible system with pharmacological tools and isoform-specific readouts, single lab","pmids":["14676826"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Focused siRNA miniscreen, subcellular fractionation, co-immunoprecipitation, caspase activation assay, epistasis by double knockdown","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis with multiple readouts in infection model, single lab","pmids":["19300516"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic tools with mechanistic phosphosite validation, single study","pmids":["34388376"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Chromatin immunoprecipitation (c-Jun binding to Bim promoter), dominant-negative c-Jun, Runx2 shRNA, p38 inhibitor (SB203580), GC receptor antagonist (RU486)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with genetic perturbations identifying promoter-bound transcription factors, single lab","pmids":["22825467"],"is_preprint":false},{"year":2020,"finding":"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.","method":"SMS genetic disruption, FOXO3a nuclear translocation assays, Bim promoter reporter, miR-19a/b overexpression/inhibition, siRNA Bim knockdown, xenograft tumor regression","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic perturbations with in vivo validation, single lab","pmids":["32591507"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Co-immunoprecipitation of endogenous Bim with Mcl-1 and Bcl-2, IL-6 withdrawal, apoptosis assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — endogenous Co-IP single lab, single method for interaction specificity","pmids":["15459900"],"is_preprint":false}],"current_model":"BCL2L11/Bim is a BH3-only pro-apoptotic protein that activates the intrinsic mitochondrial apoptosis pathway by binding anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL, Mcl-1) to release Bax/Bak, and by directly activating Bax through its C-terminal sequence; its activity is tightly controlled by multisite phosphorylation (by JNK, p38, ERK1/2, Akt, Aurora A, and Cdk1/cyclin B1) that regulates its subcellular localization, binding partner interactions, proteasomal degradation (via βTrCP/Rsk, CIS/RACK1, and ubiquitin-independent 20S pathways), and stabilization (by deubiquitinases Usp27x and OTUD1), while its transcription is governed by FOXO transcription factors, c-Jun/AP-1, Runx2, and epigenetic repressors (EZH2/PRC2 recruited by lncRNA Morrbid or viral factors EBNA3A/3C), and its alternative splicing to generate the most potent isoform BimS is regulated by the splicing factor SRSF6."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2002,"claim":"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","pmids":["12095614","12198137"],"confidence":"Medium","gaps":["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"]},{"year":2003,"claim":"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","pmids":["12818176","12844146"],"confidence":"High","gaps":["Did not resolve how transcriptional and phosphorylation inputs are quantitatively integrated","Downstream Bax/Bak engagement mechanism left to later work"]},{"year":2006,"claim":"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","pmids":["16818494","15470142","16888645"],"confidence":"High","gaps":["Did not reconcile activating versus degradative phosphorylation at neighboring sites","FOXO3-Bim axis tested in restricted cell contexts"]},{"year":2005,"claim":"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","pmids":["16282323","14732682","15899854"],"confidence":"High","gaps":["Cytoskeletal sequestration mechanism rested on single-lab Co-IP","How 14-3-3 sequestration intersects with degradation was not defined"]},{"year":2007,"claim":"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","pmids":["17525735","19150432"],"confidence":"High","gaps":["Did not establish whether dissociation and degradation are obligatorily coupled","Other survival kinases feeding the degron not enumerated"]},{"year":2009,"claim":"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","pmids":["21378313"],"confidence":"High","gaps":["Relative in vivo contribution of ubiquitin-dependent versus 20S degradation unquantified","Structural basis of Mcl-1 protection not defined"]},{"year":2007,"claim":"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","pmids":["17517961"],"confidence":"High","gaps":["Physiological frequency of Bcl-2-independent killing not established","Did not address how BimS membrane insertion is regulated"]},{"year":2008,"claim":"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","pmids":["18498746"],"confidence":"High","gaps":["Upstream kinases for each site not all assigned in vivo","Tissue specificity of each phosphosite's dominance unresolved"]},{"year":2012,"claim":"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","pmids":["18420585","22891272","23064249"],"confidence":"High","gaps":["Autophagy and RACK1/CIS arms each from single labs","Structural detail of the Bim-DYNLL1-Beclin1 bridge unresolved"]},{"year":2013,"claim":"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","pmids":["23912711","22071694","23648111","21364673"],"confidence":"High","gaps":["Crosstalk between mitotic and survival-kinase phosphorylation not integrated","Splicing control studied largely in melanoma/cell-line contexts"]},{"year":2016,"claim":"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","pmids":["27013495","27490482","27525555","34826170"],"confidence":"High","gaps":["DUB and epigenetic arms tested in distinct disease contexts","How transcriptional, splicing, DUB and degradation layers are coordinated in one cell unresolved"]},{"year":2021,"claim":"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","pmids":["34388376","29775995"],"confidence":"Medium","gaps":["Ser87 destabilization mechanism rested on single-study pharmacology","Generalizability beyond EGFR-driven resistance not established"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,11,30,31]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[11,31,38]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7,9,12,30]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8,9,19]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,7,12,20,30]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[21,25,26,36]}],"complexes":[],"partners":["BCL2","BCL2L1","MCL1","BAX","DYNLL1","BECN1","YWHAH","BTRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43521","full_name":"Bcl-2-like protein 11","aliases":["Bcl2-interacting mediator of cell death"],"length_aa":198,"mass_kda":22.2,"function":"Induces apoptosis and anoikis. Isoform BimL is more potent than isoform BimEL. Isoform Bim-alpha1, isoform Bim-alpha2 and isoform Bim-alpha3 induce apoptosis, although less potent than isoform BimEL, isoform BimL and isoform BimS. Isoform Bim-gamma induces apoptosis. Isoform Bim-alpha3 induces apoptosis possibly through a caspase-mediated pathway. Isoform BimAC and isoform BimABC lack the ability to induce apoptosis","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/O43521/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BCL2L11","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BCL2L11","total_profiled":1310},"omim":[{"mim_id":"618450","title":"RHOTEKIN 2; RTKN2","url":"https://www.omim.org/entry/618450"},{"mim_id":"617144","title":"MICRO RNA 4435-2 HOST GENE, NONCODING; MIR4435-2HG","url":"https://www.omim.org/entry/617144"},{"mim_id":"617081","title":"OMA1 ZINC METALLOPEPTIDASE; OMA1","url":"https://www.omim.org/entry/617081"},{"mim_id":"615675","title":"MICRO RNA 301A; MIR301A","url":"https://www.omim.org/entry/615675"},{"mim_id":"614470","title":"RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER; RALD","url":"https://www.omim.org/entry/614470"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BCL2L11"},"hgnc":{"alias_symbol":["BOD","BimL","BimEL","BimS","BIM"],"prev_symbol":[]},"alphafold":{"accession":"O43521","domains":[{"cath_id":"1.20.5","chopping":"144-198","consensus_level":"medium","plddt":76.5109,"start":144,"end":198}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43521","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43521-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43521-F1-predicted_aligned_error_v6.png","plddt_mean":60.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BCL2L11","jax_strain_url":"https://www.jax.org/strain/search?query=BCL2L11"},"sequence":{"accession":"O43521","fasta_url":"https://rest.uniprot.org/uniprotkb/O43521.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43521/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43521"}},"corpus_meta":[{"pmid":"12818176","id":"PMC_12818176","title":"JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis.","date":"2003","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/12818176","citation_count":434,"is_preprint":false},{"pmid":"12844146","id":"PMC_12844146","title":"Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis.","date":"2003","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12844146","citation_count":434,"is_preprint":false},{"pmid":"22145099","id":"PMC_22145099","title":"BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors.","date":"2011","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/22145099","citation_count":249,"is_preprint":false},{"pmid":"27525555","id":"PMC_27525555","title":"The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27525555","citation_count":242,"is_preprint":false},{"pmid":"20206402","id":"PMC_20206402","title":"Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis.","date":"2010","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/20206402","citation_count":208,"is_preprint":false},{"pmid":"16282323","id":"PMC_16282323","title":"Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16282323","citation_count":194,"is_preprint":false},{"pmid":"18498746","id":"PMC_18498746","title":"Multisite phosphorylation regulates Bim stability and apoptotic activity.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18498746","citation_count":188,"is_preprint":false},{"pmid":"16818494","id":"PMC_16818494","title":"p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16818494","citation_count":186,"is_preprint":false},{"pmid":"26405162","id":"PMC_26405162","title":"Regulation of Bim in Health and Disease.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26405162","citation_count":176,"is_preprint":false},{"pmid":"19150432","id":"PMC_19150432","title":"betaTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis.","date":"2009","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/19150432","citation_count":164,"is_preprint":false},{"pmid":"22349704","id":"PMC_22349704","title":"FOXO3-induced reactive oxygen species are regulated by BCL2L11 (Bim) and SESN3.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22349704","citation_count":163,"is_preprint":false},{"pmid":"19543226","id":"PMC_19543226","title":"CD95, BIM and T cell homeostasis.","date":"2009","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19543226","citation_count":153,"is_preprint":false},{"pmid":"17525735","id":"PMC_17525735","title":"ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17525735","citation_count":148,"is_preprint":false},{"pmid":"16888645","id":"PMC_16888645","title":"FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells.","date":"2006","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/16888645","citation_count":142,"is_preprint":false},{"pmid":"34388376","id":"PMC_34388376","title":"Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis.","date":"2021","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/34388376","citation_count":138,"is_preprint":false},{"pmid":"17881896","id":"PMC_17881896","title":"Bim and the pro-survival Bcl-2 proteins: opposites attract, ERK repels.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17881896","citation_count":133,"is_preprint":false},{"pmid":"19934277","id":"PMC_19934277","title":"Bim-targeted cancer therapy: a link between drug action and underlying molecular changes.","date":"2009","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/19934277","citation_count":123,"is_preprint":false},{"pmid":"23064249","id":"PMC_23064249","title":"BCL2L11/BIM: a novel molecular link between autophagy and apoptosis.","date":"2012","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/23064249","citation_count":108,"is_preprint":false},{"pmid":"19893569","id":"PMC_19893569","title":"Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression.","date":"2009","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/19893569","citation_count":106,"is_preprint":false},{"pmid":"19641506","id":"PMC_19641506","title":"Bim and Bmf in tissue homeostasis and malignant disease.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19641506","citation_count":105,"is_preprint":false},{"pmid":"15470142","id":"PMC_15470142","title":"Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis.","date":"2004","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15470142","citation_count":104,"is_preprint":false},{"pmid":"23532334","id":"PMC_23532334","title":"PUMA and BIM are required for oncogene inactivation-induced apoptosis.","date":"2013","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/23532334","citation_count":101,"is_preprint":false},{"pmid":"18715233","id":"PMC_18715233","title":"Oncogenic BRAF(V600E) inhibits BIM expression to promote melanoma cell survival.","date":"2007","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/18715233","citation_count":100,"is_preprint":false},{"pmid":"14676826","id":"PMC_14676826","title":"Role of Bim in the survival pathway induced by Raf in epithelial cells.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/14676826","citation_count":97,"is_preprint":false},{"pmid":"15661735","id":"PMC_15661735","title":"Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15661735","citation_count":96,"is_preprint":false},{"pmid":"15899854","id":"PMC_15899854","title":"Gadd45a expression induces Bim dissociation from the cytoskeleton and translocation to mitochondria.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15899854","citation_count":95,"is_preprint":false},{"pmid":"32591507","id":"PMC_32591507","title":"Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32591507","citation_count":86,"is_preprint":false},{"pmid":"27490482","id":"PMC_27490482","title":"MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27490482","citation_count":83,"is_preprint":false},{"pmid":"31752117","id":"PMC_31752117","title":"miRNA-29b Inhibits Prostate Tumor Growth and Induces Apoptosis by Increasing Bim Expression.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31752117","citation_count":83,"is_preprint":false},{"pmid":"21364673","id":"PMC_21364673","title":"Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS.","date":"2010","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/21364673","citation_count":82,"is_preprint":false},{"pmid":"26660116","id":"PMC_26660116","title":"MicroRNA-9 Mediates the Cell Apoptosis by Targeting Bcl2l11 in Ischemic Stroke.","date":"2015","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26660116","citation_count":80,"is_preprint":false},{"pmid":"20086250","id":"PMC_20086250","title":"IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20086250","citation_count":80,"is_preprint":false},{"pmid":"19557009","id":"PMC_19557009","title":"Bax activation by Bim?","date":"2009","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/19557009","citation_count":79,"is_preprint":false},{"pmid":"12198137","id":"PMC_12198137","title":"Bcl-XL protects BimEL-induced Bax conformational change and cytochrome C release independent of interacting with Bax or BimEL.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12198137","citation_count":79,"is_preprint":false},{"pmid":"15459900","id":"PMC_15459900","title":"The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells.","date":"2004","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15459900","citation_count":76,"is_preprint":false},{"pmid":"17517961","id":"PMC_17517961","title":"BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins.","date":"2007","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17517961","citation_count":72,"is_preprint":false},{"pmid":"14732682","id":"PMC_14732682","title":"Caspase cleavage of BimEL triggers a positive feedback amplification of apoptotic signaling.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/14732682","citation_count":72,"is_preprint":false},{"pmid":"29100606","id":"PMC_29100606","title":"BH3-only protein BIM: An emerging target in chemotherapy.","date":"2017","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29100606","citation_count":71,"is_preprint":false},{"pmid":"26758252","id":"PMC_26758252","title":"Onco-miR-24 regulates cell growth and apoptosis by targeting BCL2L11 in gastric cancer.","date":"2016","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/26758252","citation_count":68,"is_preprint":false},{"pmid":"27182556","id":"PMC_27182556","title":"T cell Bim levels reflect responses to anti-PD-1 cancer therapy.","date":"2016","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/27182556","citation_count":64,"is_preprint":false},{"pmid":"22628193","id":"PMC_22628193","title":"miR-301a promotes pancreatic cancer cell proliferation by directly inhibiting Bim expression.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22628193","citation_count":64,"is_preprint":false},{"pmid":"21378313","id":"PMC_21378313","title":"BIM(EL), an intrinsically disordered protein, is degraded by 20S proteasomes in the absence of poly-ubiquitylation.","date":"2011","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/21378313","citation_count":60,"is_preprint":false},{"pmid":"15941767","id":"PMC_15941767","title":"BimEL up-regulation potentiates AIF translocation and cell death in response to MPTP.","date":"2005","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/15941767","citation_count":57,"is_preprint":false},{"pmid":"22825467","id":"PMC_22825467","title":"Glucocorticoid-mediated BIM induction and apoptosis are regulated by Runx2 and c-Jun in leukemia cells.","date":"2012","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/22825467","citation_count":56,"is_preprint":false},{"pmid":"18420585","id":"PMC_18420585","title":"RACK1 and CIS mediate the degradation of BimEL in cancer cells.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18420585","citation_count":55,"is_preprint":false},{"pmid":"20861305","id":"PMC_20861305","title":"Hypoxia suppression of Bim and Bmf blocks anoikis and luminal clearing during mammary morphogenesis.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/20861305","citation_count":55,"is_preprint":false},{"pmid":"15843898","id":"PMC_15843898","title":"Zinc pyrithione induces apoptosis and increases expression of Bim.","date":"2005","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/15843898","citation_count":53,"is_preprint":false},{"pmid":"26109645","id":"PMC_26109645","title":"IL-6 and ICOS Antagonize Bim and Promote Regulatory T Cell Accrual with Age.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26109645","citation_count":53,"is_preprint":false},{"pmid":"23912711","id":"PMC_23912711","title":"BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1.","date":"2013","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/23912711","citation_count":50,"is_preprint":false},{"pmid":"27013495","id":"PMC_27013495","title":"The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis.","date":"2016","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/27013495","citation_count":49,"is_preprint":false},{"pmid":"28899969","id":"PMC_28899969","title":"TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression.","date":"2017","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/28899969","citation_count":49,"is_preprint":false},{"pmid":"26517093","id":"PMC_26517093","title":"The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26517093","citation_count":47,"is_preprint":false},{"pmid":"16520387","id":"PMC_16520387","title":"Loss of the proapoptotic protein, Bim, breaks B cell anergy.","date":"2006","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16520387","citation_count":45,"is_preprint":false},{"pmid":"31332289","id":"PMC_31332289","title":"SOX7 regulates MAPK/ERK-BIM mediated apoptosis in cancer cells.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31332289","citation_count":43,"is_preprint":false},{"pmid":"21958719","id":"PMC_21958719","title":"Efavirenz and 8-hydroxyefavirenz induce cell death via a JNK- and BimEL-dependent mechanism in primary human hepatocytes.","date":"2011","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21958719","citation_count":42,"is_preprint":false},{"pmid":"35063650","id":"PMC_35063650","title":"Bim- and Bax-mediated mitochondrial pathway dominates abivertinib-induced apoptosis and ferroptosis.","date":"2022","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35063650","citation_count":41,"is_preprint":false},{"pmid":"18174237","id":"PMC_18174237","title":"Activation of the JNK pathway promotes phosphorylation and degradation of BimEL--a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia.","date":"2008","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/18174237","citation_count":41,"is_preprint":false},{"pmid":"12095614","id":"PMC_12095614","title":"Direct addition of BimL to mitochondria does not lead to cytochrome c release.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12095614","citation_count":37,"is_preprint":false},{"pmid":"31976859","id":"PMC_31976859","title":"The carboxyl-terminal sequence of bim enables bax activation and killing of unprimed cells.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31976859","citation_count":37,"is_preprint":false},{"pmid":"19100522","id":"PMC_19100522","title":"A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells.","date":"2009","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/19100522","citation_count":36,"is_preprint":false},{"pmid":"30224718","id":"PMC_30224718","title":"Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30224718","citation_count":36,"is_preprint":false},{"pmid":"22891272","id":"PMC_22891272","title":"The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim.","date":"2012","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22891272","citation_count":35,"is_preprint":false},{"pmid":"19737817","id":"PMC_19737817","title":"Toxoplasma gondii infection confers resistance against BimS-induced apoptosis by preventing the activation and mitochondrial targeting of pro-apoptotic Bax.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19737817","citation_count":34,"is_preprint":false},{"pmid":"26334669","id":"PMC_26334669","title":"cAMP signalling of Bordetella adenylate cyclase toxin through the SHP-1 phosphatase activates the BimEL-Bax pro-apoptotic cascade in phagocytes.","date":"2015","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26334669","citation_count":34,"is_preprint":false},{"pmid":"23047821","id":"PMC_23047821","title":"PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortium.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23047821","citation_count":33,"is_preprint":false},{"pmid":"29573636","id":"PMC_29573636","title":"POH1 Knockdown Induces Cancer Cell Apoptosis via p53 and Bim.","date":"2018","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29573636","citation_count":32,"is_preprint":false},{"pmid":"29735550","id":"PMC_29735550","title":"miR-339 Promotes Development of Stem Cell Leukemia/Lymphoma Syndrome via Downregulation of the BCL2L11 and BAX Proapoptotic Genes.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29735550","citation_count":32,"is_preprint":false},{"pmid":"32579941","id":"PMC_32579941","title":"Targeting Bim via a lncRNA Morrbid Regulates the Survival of Preleukemic and Leukemic Cells.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32579941","citation_count":32,"is_preprint":false},{"pmid":"19427863","id":"PMC_19427863","title":"BimL directly neutralizes Bcl-xL to promote Bax activation during UV-induced apoptosis.","date":"2009","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/19427863","citation_count":30,"is_preprint":false},{"pmid":"18275825","id":"PMC_18275825","title":"Fas Bim boom!","date":"2008","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18275825","citation_count":30,"is_preprint":false},{"pmid":"36720853","id":"PMC_36720853","title":"Regorafenib induces Bim-mediated intrinsic apoptosis by blocking AKT-mediated FOXO3a nuclear export.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36720853","citation_count":30,"is_preprint":false},{"pmid":"33087587","id":"PMC_33087587","title":"MicroRNA-338-5p alleviates neuronal apoptosis via directly targeting BCL2L11 in APP/PS1 mice.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33087587","citation_count":30,"is_preprint":false},{"pmid":"19300516","id":"PMC_19300516","title":"Bim and Bmf synergize to induce apoptosis in Neisseria gonorrhoeae infection.","date":"2009","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/19300516","citation_count":30,"is_preprint":false},{"pmid":"17913922","id":"PMC_17913922","title":"Bim expression indicates the pathway to retinal cell death in development and degeneration.","date":"2007","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17913922","citation_count":28,"is_preprint":false},{"pmid":"27511131","id":"PMC_27511131","title":"Insulin-like growth factor 1 rescues R28 retinal neurons from apoptotic death through ERK-mediated BimEL phosphorylation independent of Akt.","date":"2016","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/27511131","citation_count":27,"is_preprint":false},{"pmid":"35068339","id":"PMC_35068339","title":"Circular RNA Rbms1 inhibited the development of myocardial ischemia reperfusion injury by regulating miR-92a/BCL2L11 signaling pathway.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35068339","citation_count":25,"is_preprint":false},{"pmid":"32346136","id":"PMC_32346136","title":"JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/32346136","citation_count":25,"is_preprint":false},{"pmid":"35257265","id":"PMC_35257265","title":"Ambra1 regulates apoptosis and chemosensitivity in breast cancer cells through the Akt-FoxO1-Bim pathway.","date":"2022","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/35257265","citation_count":25,"is_preprint":false},{"pmid":"35699193","id":"PMC_35699193","title":"Protective Effects of MicroRNA-200b-3p Encapsulated by Mesenchymal Stem Cells-Secreted Extracellular Vesicles in Myocardial Infarction Via Regulating BCL2L11.","date":"2022","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/35699193","citation_count":25,"is_preprint":false},{"pmid":"29775995","id":"PMC_29775995","title":"Phosphorylation alters Bim-mediated Mcl-1 stabilization and priming.","date":"2018","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/29775995","citation_count":24,"is_preprint":false},{"pmid":"32550905","id":"PMC_32550905","title":"Renal tubular Bim mediates the tubule-podocyte crosstalk via NFAT2 to induce podocyte cytoskeletal dysfunction.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32550905","citation_count":24,"is_preprint":false},{"pmid":"15336653","id":"PMC_15336653","title":"Potential utility of BimS as a novel apoptotic therapeutic molecule.","date":"2004","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/15336653","citation_count":23,"is_preprint":false},{"pmid":"22071694","id":"PMC_22071694","title":"Cyclin B1 interacts with the BH3-only protein Bim and mediates its phosphorylation by Cdk1 during mitosis.","date":"2011","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22071694","citation_count":23,"is_preprint":false},{"pmid":"26296767","id":"PMC_26296767","title":"HCV upregulates Bim through the ROS/JNK signalling pathway, leading to Bax-mediated apoptosis.","date":"2015","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/26296767","citation_count":23,"is_preprint":false},{"pmid":"26339371","id":"PMC_26339371","title":"Mir-192 suppresses apoptosis and promotes proliferation in esophageal aquamous cell caicinoma by targeting Bim.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26339371","citation_count":23,"is_preprint":false},{"pmid":"34826170","id":"PMC_34826170","title":"Melatonin induces apoptotic cell death through Bim stabilization by Sp1-mediated OTUD1 upregulation.","date":"2021","source":"Journal of pineal research","url":"https://pubmed.ncbi.nlm.nih.gov/34826170","citation_count":22,"is_preprint":false},{"pmid":"21247487","id":"PMC_21247487","title":"Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival.","date":"2011","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21247487","citation_count":22,"is_preprint":false},{"pmid":"17884340","id":"PMC_17884340","title":"c-Cbl is not required for ERK1/2-dependent degradation of BimEL.","date":"2007","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/17884340","citation_count":22,"is_preprint":false},{"pmid":"24269611","id":"PMC_24269611","title":"The role of DAPK-BimEL pathway in neuronal death induced by oxygen-glucose deprivation.","date":"2013","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24269611","citation_count":21,"is_preprint":false},{"pmid":"31105834","id":"PMC_31105834","title":"LINC00261 functions as a competing endogenous RNA to regulate BCL2L11 expression by sponging miR-132-3p in endometriosis.","date":"2019","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/31105834","citation_count":21,"is_preprint":false},{"pmid":"20497470","id":"PMC_20497470","title":"BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin.","date":"2010","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20497470","citation_count":20,"is_preprint":false},{"pmid":"23648111","id":"PMC_23648111","title":"Zinc-induced modulation of SRSF6 activity alters Bim splicing to promote generation of the most potent apoptotic isoform BimS.","date":"2013","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/23648111","citation_count":20,"is_preprint":false},{"pmid":"29540858","id":"PMC_29540858","title":"miR-9-5p, miR-124-3p, and miR-132-3p regulate BCL2L11 in tuberous sclerosis complex angiomyolipoma.","date":"2018","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29540858","citation_count":20,"is_preprint":false},{"pmid":"34153292","id":"PMC_34153292","title":"Bim transfer between Bcl-2-like protein and Hsp70 underlines Bcl-2/Hsp70 crosstalk to regulate apoptosis.","date":"2021","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34153292","citation_count":19,"is_preprint":false},{"pmid":"20857401","id":"PMC_20857401","title":"Dual regulation of hepatocyte apoptosis by reactive oxygen species: Increases in transcriptional expression and decreases in proteasomal degradation of BimEL.","date":"2011","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20857401","citation_count":19,"is_preprint":false},{"pmid":"15827557","id":"PMC_15827557","title":"Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis.","date":"2005","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15827557","citation_count":19,"is_preprint":false},{"pmid":"25852302","id":"PMC_25852302","title":"Bim and VDAC1 are hierarchically essential for mitochondrial ATF2 mediated cell death.","date":"2015","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/25852302","citation_count":19,"is_preprint":false},{"pmid":"23532333","id":"PMC_23532333","title":"BIM, PUMA, and the achilles' heel of oncogene addiction.","date":"2013","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/23532333","citation_count":19,"is_preprint":false},{"pmid":"24658302","id":"PMC_24658302","title":"Role of BH3-only molecules Bim and Puma in β-cell death in Pdx1 deficiency.","date":"2014","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/24658302","citation_count":19,"is_preprint":false},{"pmid":"33296806","id":"PMC_33296806","title":"Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy.","date":"2020","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/33296806","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47803,"output_tokens":10028,"usd":0.146915,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20175,"output_tokens":4789,"usd":0.1103,"stage2_stop_reason":"end_turn"},"total_usd":0.257215,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (S65A), co-expression studies, pharmacological JNK pathway inhibition/activation\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation assay plus mutagenesis, replicated across multiple labs (PMID:12818176, PMID:15470142, PMID:16818494)\",\n      \"pmids\": [\"12818176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, RNAi knockdown, dominant-negative BimEL expression in primary neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation assay plus genetic knockdown in primary neurons, corroborates PMID:12818176\",\n      \"pmids\": [\"15470142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, S65A mutagenesis, pharmacological p38 inhibition, ectopic expression in PC12 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16818494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro Akt kinase assay with GST-BimEL fusion protein, site-directed mutagenesis (S87A), co-immunoprecipitation with 14-3-3 proteins, PI3K inhibitor (LY294002)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, mutagenesis, and binding assay in single study with multiple orthogonal methods\",\n      \"pmids\": [\"16282323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Knock-in mouse models with phosphorylation-defective Bim alleles, in vivo apoptosis assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo genetic model (knock-in mice) with multiple phosphosite mutations, rigorous functional readouts\",\n      \"pmids\": [\"18498746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation-defective mutants, siRNA knockdown of βTrCP and Rsk1/2, ubiquitination assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, mutagenesis, and functional apoptosis assays; replicated with PMID:23912711\",\n      \"pmids\": [\"19150432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of endogenous complexes, ERK1/2 activation/inhibition, phospho-specific antibodies, Bim-/- cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with endogenous proteins, pharmacological and genetic tools, replicated in multiple cell types\",\n      \"pmids\": [\"17525735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Domain deletion/point mutagenesis, subcellular fractionation, Bax conformational change assay, isolated mitochondria assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with isolated mitochondria plus mutagenesis and fractionation in single study\",\n      \"pmids\": [\"12198137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation with tubulin, caspase cleavage assays, overexpression of cleaved BimEL variants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and fractionation with functional follow-up, single lab\",\n      \"pmids\": [\"14732682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Inducible Gadd45a expression, subcellular fractionation, co-immunoprecipitation, siRNA knockdown of Bim, domain deletion mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation and Co-IP with genetic perturbations, single lab\",\n      \"pmids\": [\"15899854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro protein binding assay, immunoprecipitation, coimmunolocalization, isolated mitochondria assay with Bax-/- cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro binding plus reconstituted mitochondria assay with isogenic Bax-/- controls, multiple orthogonal methods\",\n      \"pmids\": [\"15661735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-free assay with isolated mitochondria, cytochrome c release assay, overexpression in cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstituted cell-free assay, single lab, single study\",\n      \"pmids\": [\"12095614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Regulated expression with conditional system, subcellular fractionation, co-immunoprecipitation, mutagenesis, yeast reconstitution assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis plus yeast reconstitution (Bcl-2-independent system) plus fractionation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17517961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo tumor models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with in vivo confirmation, single lab\",\n      \"pmids\": [\"18420585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Ubiquitin-binding domain pulldowns, proteasome assay with purified 20S proteasome, lysine mutants, Rpn2 knockdown, β-TrCP inhibition\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro 20S proteasome assay plus mutagenesis and genetic perturbation, multiple orthogonal methods\",\n      \"pmids\": [\"21378313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, pharmacological inhibition of PP2A/Aurora A\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with Co-IP and ubiquitination assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"23912711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay with recombinant Cdk1/cyclin B1, Cdk1 inhibitors, siRNA, phospho-site mapping\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus Co-IP of endogenous proteins plus phosphosite identification, multiple methods\",\n      \"pmids\": [\"22071694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression and knockdown (siRNA) of Usp27x, apoptosis assays in melanoma/NSCLC cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with loss- and gain-of-function experiments, single lab\",\n      \"pmids\": [\"27013495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mutagenesis (K3 site), in vivo xenograft\",\n      \"journal\": \"Journal of pineal research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with genetic perturbations and in vivo validation, single lab\",\n      \"pmids\": [\"34826170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, autophagy assays, JNK inhibition/phosphorylation analysis, siRNA knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating novel complex, functional autophagy readout, single lab\",\n      \"pmids\": [\"23064249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown, EGFR overexpression, pharmacological ERK inhibition, suspension culture assays, siRNA\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi loss-of-function with specific phenotypic readout, gain-of-function complementation, multiple genetic tools\",\n      \"pmids\": [\"12844146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Inducible FOXO3 and Bim expression systems, siRNA knockdown, live-cell MitoTrackerRed microscopy, dominant-negative FOXO3\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression and knockdown with live imaging, single lab\",\n      \"pmids\": [\"22349704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR isoform analysis, siRNA of SRp55, B-RAFV600E inhibitor (PLX4720), B-RAFV600E enforced expression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi functional assay demonstrating splicing factor requirement, single lab\",\n      \"pmids\": [\"21364673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Bim mini-gene construct with deletion analysis, UV cross-linking/Western blot, mutagenesis, pharmacological inhibition (TG003)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct RNA-binding assay plus mini-gene mutagenesis and pharmacological tools, multiple orthogonal methods\",\n      \"pmids\": [\"23648111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown of EZH2, chromatin immunoprecipitation (ChIP), Bim promoter analysis, apoptosis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and RNAi functional assays, single lab\",\n      \"pmids\": [\"19893569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin conformation capture, ChIP, EZH2 inhibitor treatment, enhancer-promoter interaction mapping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and chromatin conformation assays with pharmacological validation, single study\",\n      \"pmids\": [\"27490482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation (PRC2/H3K27me3 at Bcl2l11 promoter), allele-specific expression analysis, Morrbid knockout mouse model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP in KO model with allele-specific analysis, replicated in multiple cell types and human disease context\",\n      \"pmids\": [\"27525555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown, pharmacological inhibition, ChIP for histone modifications, Western blot, promoter methylation analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, RNAi, and pharmacological tools across three mechanisms, single lab\",\n      \"pmids\": [\"20086250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"4OH-tamoxifen-inducible FKHRL1 transgene, RNAi knockdown, dominant-negative FADD, Bcl-2 overexpression, caspase and cytochrome c assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible transgene system with RNAi loss-of-function and pathway epistasis, single lab\",\n      \"pmids\": [\"16888645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional KO mice, genetic epistasis (ASCIZ KO × Bim KO double mutant rescue), ectopic DYNLL1 expression\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with double KO rescue in vivo, multiple genetic tools\",\n      \"pmids\": [\"22891272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Domain deletion and point mutants of Bim, mitochondrial permeabilization assays with isolated mitochondria, cell-based apoptosis assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution assay with isolated mitochondria plus systematic mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"31976859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"FRET in living cells, endogenous co-immunoprecipitation, RNAi knockdown of BimL\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET in living cells plus Co-IP, single lab, supports indirect activation model\",\n      \"pmids\": [\"19427863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Phospho-mimetic and non-phosphorylatable Bim mutants, co-immunoprecipitation, Mcl-1 stability assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mutagenesis plus Co-IP, single lab, single study\",\n      \"pmids\": [\"29775995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Raf-ER activation, pharmacological MEK inhibition, Western blot for BimEL phosphorylation and degradation, suspension culture assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional inducible system with pharmacological tools and isoform-specific readouts, single lab\",\n      \"pmids\": [\"14676826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Focused siRNA miniscreen, subcellular fractionation, co-immunoprecipitation, caspase activation assay, epistasis by double knockdown\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis with multiple readouts in infection model, single lab\",\n      \"pmids\": [\"19300516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic tools with mechanistic phosphosite validation, single study\",\n      \"pmids\": [\"34388376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation (c-Jun binding to Bim promoter), dominant-negative c-Jun, Runx2 shRNA, p38 inhibitor (SB203580), GC receptor antagonist (RU486)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with genetic perturbations identifying promoter-bound transcription factors, single lab\",\n      \"pmids\": [\"22825467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"SMS genetic disruption, FOXO3a nuclear translocation assays, Bim promoter reporter, miR-19a/b overexpression/inhibition, siRNA Bim knockdown, xenograft tumor regression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic perturbations with in vivo validation, single lab\",\n      \"pmids\": [\"32591507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of endogenous Bim with Mcl-1 and Bcl-2, IL-6 withdrawal, apoptosis assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — endogenous Co-IP single lab, single method for interaction specificity\",\n      \"pmids\": [\"15459900\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BCL2L11/Bim is a BH3-only pro-apoptotic protein that activates the intrinsic mitochondrial apoptosis pathway by binding anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL, Mcl-1) to release Bax/Bak, and by directly activating Bax through its C-terminal sequence; its activity is tightly controlled by multisite phosphorylation (by JNK, p38, ERK1/2, Akt, Aurora A, and Cdk1/cyclin B1) that regulates its subcellular localization, binding partner interactions, proteasomal degradation (via βTrCP/Rsk, CIS/RACK1, and ubiquitin-independent 20S pathways), and stabilization (by deubiquitinases Usp27x and OTUD1), while its transcription is governed by FOXO transcription factors, c-Jun/AP-1, Runx2, and epigenetic repressors (EZH2/PRC2 recruited by lncRNA Morrbid or viral factors EBNA3A/3C), and its alternative splicing to generate the most potent isoform BimS is regulated by the splicing factor SRSF6.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#20], trophic factor withdrawal [#0], and cytokine deprivation [#26] — 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 [#7, #30]. In living cells BimL primarily binds Bcl-xL rather than Bax, releasing Bax indirectly [#31], and Bim associates dominantly with Mcl-1 in some contexts to enforce Mcl-1 dependence [#38]; the short isoform BimS inserts into mitochondria and activates Bax even independently of anti-apoptotic Bcl-2 family binding [#12]. 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 [#5, #14], Akt and Aurora-pathway phosphorylation at Ser87 attenuates and destabilizes it [#3, #35], Cdk1/cyclin B1 and Aurora A phosphorylate it during mitosis to promote degradation [#15, #16], whereas JNK/p38 phosphorylation at Ser65 potentiates its pro-death activity [#0, #2, #4]. The deubiquitinases Usp27x and OTUD1 stabilize Bim to promote apoptosis [#17, #18], and Bim is sequestered on microtubules via tubulin/DYNLL1 until released by phosphorylation or apoptotic stimuli [#8, #9]. Bim transcription is governed by FOXO3 [#21, #28], c-Jun/AP-1 and Runx2 downstream of p38 [#36], and is epigenetically repressed via EZH2/PRC2 recruited by the lncRNA Morrbid or viral EBNA3 factors [#25, #26], while alternative splicing to the potent BimS isoform is controlled by SRSF6/SRp55 [#22, #23]. Beyond apoptosis, Bim bridges Beclin 1 and DYNLL1 to tether Beclin 1 to microtubules and inhibit autophagy until JNK phosphorylation relieves this restraint [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cell-free assays with isolated mitochondria, domain mutagenesis, and Bax conformational change assays\",\n      \"pmids\": [\"12095614\", \"12198137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"JNK in vitro kinase assay with S65A mutagenesis in neurons, and RNAi knockdown in epithelial anoikis assays\",\n      \"pmids\": [\"12818176\", \"12844146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how transcriptional and phosphorylation inputs are quantitatively integrated\", \"Downstream Bax/Bak engagement mechanism left to later work\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified stress kinases JNK and p38 as activating Bim via a shared Ser65 phosphosite, and FOXO3 as a transcriptional inducer driving mitochondrial apoptosis.\",\n      \"evidence\": \"In vitro kinase assays with S65A mutants, inducible FKHRL1/FoxO3a transgenes, and RNAi\",\n      \"pmids\": [\"16818494\", \"15470142\", \"16888645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile activating versus degradative phosphorylation at neighboring sites\", \"FOXO3-Bim axis tested in restricted cell contexts\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro Akt kinase assay, S87A mutagenesis, 14-3-3 co-IP, and microtubule/tubulin fractionation with Gadd45a-induced translocation\",\n      \"pmids\": [\"16282323\", \"14732682\", \"15899854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoskeletal sequestration mechanism rested on single-lab Co-IP\", \"How 14-3-3 sequestration intersects with degradation was not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Endogenous reciprocal Co-IP, phospho-specific antibodies, Bim-/- cells, βTrCP/Rsk1/2 siRNA and ubiquitination assays\",\n      \"pmids\": [\"17525735\", \"19150432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether dissociation and degradation are obligatorily coupled\", \"Other survival kinases feeding the degron not enumerated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Purified 20S proteasome assays, K48 lysine mutants (BimEL-ΔKK), Rpn2 knockdown, and βTrCP inhibition\",\n      \"pmids\": [\"21378313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of ubiquitin-dependent versus 20S degradation unquantified\", \"Structural basis of Mcl-1 protection not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed the BimS isoform kills via mitochondrial insertion and Bax activation independent of anti-apoptotic Bcl-2 binding, distinguishing isoform-specific death mechanisms.\",\n      \"evidence\": \"Conditional expression, fractionation, mutagenesis, and yeast reconstitution lacking anti-apoptotic Bcl-2 proteins\",\n      \"pmids\": [\"17517961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological frequency of Bcl-2-independent killing not established\", \"Did not address how BimS membrane insertion is regulated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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).\",\n      \"evidence\": \"Knock-in mouse alleles with site-specific Bim mutations and in vivo apoptosis assays\",\n      \"pmids\": [\"18498746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream kinases for each site not all assigned in vivo\", \"Tissue specificity of each phosphosite's dominance unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Y2H, Co-IP, ubiquitination assays, conditional/double-knockout epistasis (ASCIZ × Bim), and autophagy assays with JNK inhibition\",\n      \"pmids\": [\"18420585\", \"22891272\", \"23064249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Autophagy and RACK1/CIS arms each from single labs\", \"Structural detail of the Bim-DYNLL1-Beclin1 bridge unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assays, Co-IP, ubiquitination assays, PP2A/Aurora inhibition, and Bim mini-gene UV-crosslinking with SRSF6\",\n      \"pmids\": [\"23912711\", \"22071694\", \"23648111\", \"21364673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between mitotic and survival-kinase phosphorylation not integrated\", \"Splicing control studied largely in melanoma/cell-line contexts\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ChIP and chromatin conformation capture, Morrbid knockout mice, and EZH2 inhibitor treatment\",\n      \"pmids\": [\"27013495\", \"27490482\", \"27525555\", \"34826170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DUB and epigenetic arms tested in distinct disease contexts\", \"How transcriptional, splicing, DUB and degradation layers are coordinated in one cell unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Drug screens, phospho-Ser87 detection, Aurora B inhibition, BIM knockdown in cell/mouse models, and phospho-mutant Mcl-1 stability assays\",\n      \"pmids\": [\"34388376\", \"29775995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ser87 destabilization mechanism rested on single-study pharmacology\", \"Generalizability beyond EGFR-driven resistance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 11, 30, 31]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [11, 31, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7, 9, 12, 30]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8, 9, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 7, 12, 20, 30]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [21, 25, 26, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BCL2\", \"BCL2L1\", \"MCL1\", \"BAX\", \"DYNLL1\", \"BECN1\", \"YWHAH\", \"BTRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}