BCL2L11 (BCL2-like 11 (apoptosis facilitator))

2008-11-01   Maybelline Giam , Andreas Strasser , Philippe Bouillet 

The Walter, Eliza Hall Institute, Melbourne, Australia




Atlas Image
Schematic diagram of the three major BIM isoforms encoded by the human BIM gene. All three isoforms contain exon 5 (contains the BH3 domain) while only BIML and BIMEL possess the dynein light chain-binding domain encoded by exon 4.


The BIM gene spans 47,532 bases, centromere to telomere orientation. Three major isoforms are produced by alternative splicing of 6 exons. These isoforms differ in size and have different apoptotic activity. The three major BIM isoforms are BIMEL (BCL2L11 isoform 1), BIML (BCL2L11 isoform 6) and BIMS (BCL2L11 isoform 9). More than 12 minor BIM isoforms have been cloned from human tissues, and involve exons contained within the large introns. The physiological relevance of these minor isoforms is undetermined.


Based on studies using the mouse BIM gene, it was found that the 800-bp region immediately upstream of exon 1 contains the important elements for control of BIM expression. The BIM promoter does not contain a TATA or CAAT box and has the characteristics of a TATA-less promoter. It is very GC-rich and contains six GGGCGG motifs, the recognition site for the transcription factor SP1. There are alternative promoters located in intron 1.


There are no known pseudogenes for BIM.



There are three major isoforms of BIM. BIMEL is the longest (198 amino acids and 22.0kDa), followed by BIML (138 amino acids long and 15.8kDa), and BIMS (112 amino acids and 12.3kDa). All three isoforms contain a BH3 domain (but not the BH1, BH2 and BH4 domains found in other members of the family). They have different pro-apoptotic potencies suspected to be due at least in part to differences in interaction with the dynein motor complex.


BIM is found in many organs and cell types including brain, heart, kidney, liver, lung, ovary, testis, spleen, thymus and trachea. It is also present in hematopoietic, epithelial, neuronal, and germ cells. BIML and BIMEL were found to be co-expressed at similar levels in many cell types, but BIMS is sometimes not detected.


In healthy cells, most BIM molecules (BIML and BIMEL) are either bound to DLC1 cytoplasmic dynein light chain and sequestered to the microtubule-associated dynein motor complex or associated with the pro-survival proteins on the mitochondria. A C-terminal hydrophobic domain present in all three major isoforms of BIM localizes the protein to intracytoplasmic membranes.


BIM is a pro-apoptotic member of the Bcl-2 family important in mediating apoptosis in response to various intrinsic stimuli. Studies using BIM knockout mice showed that it plays a large part in maintaining hematopoietic homeostasis. BIM-deficient mice have high numbers of B cells, CD4 and CD8 single-positive T cells, macrophages and granulocytes in their periphery. BIM is also needed for the deletion of auto-reactive B and T cells and on a mixed C57BL/6/129Sv genetic background, BIM-deficient mice developed a fatal systemic lupus erythematosus (SLE)-like disease. Lymphocytes lacking BIM are refractory to a number of stimuli including cytokine deprivation, deregulated calcium ion flux. BIM is also important in turning off immune responses following acute viral infection. BIM cooperates with the death ligand Fas (which triggers the extrinsic pathway) to shut down immune responses following chronic viral infection and to prevent autoimmunity. Experiments using mice deficient for both BIM and pro-survival Bcl-2 demonstrated that Bcl-2 is an essential guardian of BIM. Indeed, removal of just one allele of BIM prevented polycystic kidney disease and restored normal growth of Bcl-2-deficient mice. Loss of both alleles restored a robust hematopoietic system and prevented graying.

BIM is regulated by transcriptional control which differs with cell types by transcription factors including FOXO-3a and c-JUN . BIM is also controlled via alternative splicing that produces many different isoforms. BIM is regulated as well by post-translational modifications such as phosphorylation by ERK1, ERK2 and JNK. Phosphorylation-dependant ubiquitylation is thought to regulates BIMs half life.

Unlike some BH3-only proteins, BIM is a promiscuous binder of pro-survival proteins and can bind BCL2, BCLX, BCLW , MCL1 and BCL2A1 with high affinity. There are also some reports that BIMS is able to bind BAX (multidomain pro-apoptotic effector of the pathway) and activate it directly, but whether this binding occurs physiologically is unclear.


BIM belongs to the Bcl-2 family of proteins and contains the BH3 domain which is homologous to the BH3 domains of:
  • The pro-survival proteins: BCL2, BCLX, BCLW, MCL1, BCL2A1/BFL1, Bcl-B/BOO.
  • The multidomain pro-apoptotic proteins: BAX, BAK, BOK.
  • The other BH3-only proteins: PUMA, NOXA, BAD, HRK, BMF, BIK, BID.
  • Mutations


    The BIM gene is located at chromosome 2q13, a region where alterations (mainly deletions) have been reported for 14 cases of human malignancy, mostly hematopoietic in origin. Although loss of Bim by itself does not elevate tumor incidence in mice within the first 12 months of life, it was found that deletion of even a single allele of BIM dramatically accelerates tumor formation in mice expressing the Eµ-myc transgene (which causes myc over-expression in the B cell compartment). These results suggest that, at least in B cells, BIM is an important tumor suppressor.

    Implicated in

    Down-regulation of BIM expression was discovered in 5 of 7 mantle cell lymphoma cell lines tested while normal expression was found in two MCL cell lines without deletion of 2q13. These results suggest that BIM is the most likely candidate target gene of 2q13 loss/deletion and that its down-regulation may contribute to tumorigenesis of MCL (Tagawa et al., 2005; Mestre-Escorihuela et al., 2007).
    Mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma characterized by the t(11;14)(q13;q32) translocation that results in the overexpression of the cell cycle regulator CCND1 (cyclin D1). However, experiments with transgenic mice have shown that over-expression of CCND1 is not sufficient to induce lymphomas. Comparative genomic hybridization (CGH) and chromosome banding analyses have been used to identify additional mutations that help CCND1 inducing tumours. Several genomic imbalances have been associated with MCL, and show both gains or losses of genomic DNA. In particular, homozygous deletion at chromosome 2q13, the region that contains the BIM gene, has been observed in several MCL cell lines.
    For more information on mantle cell lymphoma, see: www.leukemia-lymphoma.org/attachments/National/br_1172589724.pdf
    Entity name
    Alzheimers disease
    Alzheimers disease (AD) is a progressive disorder characterized by selective neuron loss and formation of neurofibrillary tangles and of plaques containing amyloid-Beta peptide (ABeta). It results in dementia, a term used to describe a progressive decline in mental functioning. BIM has been implicated in the death of neurons caused by the accumulation of Ab (Biswas et al., 2007).


    Pubmed IDLast YearTitleAuthors
    155924372005Nomenclature of dynein light chain-linked BH3-only protein Bim isoforms.Adachi M et al
    172514312007Bim is elevated in Alzheimer's disease neurons and is required for beta-amyloid-induced neuronal apoptosis.Biswas SC et al
    118593722002BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes.Bouillet P et al
    150790752004Bim is a suppressor of Myc-induced mouse B cell leukemia.Egle A et al
    185494682008Identification of a candidate alternative promoter region of the human Bcl2L11 (Bim) gene.Gaviraghi M et al
    169601492007Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas.Mestre-Escorihuela C et al
    94306301998Bim: a novel member of the Bcl-2 family that promotes apoptosis.O'Connor L et al
    109341492000The proapoptotic BH3-only protein bim is expressed in hematopoietic, epithelial, neuronal, and germ cells.O'Reilly LA et al
    101986311999The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex.Puthalakath H et al
    156086802005Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM.Tagawa H et al
    151367282004Constitutive association of the proapoptotic protein Bim with Bcl-2-related proteins on mitochondria in T cells.Zhu Y et al

    Other Information

    Locus ID:

    NCBI: 10018
    MIM: 603827
    HGNC: 994
    Ensembl: ENSG00000153094


    dbSNP: 10018
    ClinVar: 10018
    TCGA: ENSG00000153094


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    PI3K-Akt signaling pathwayKEGGhsa04151
    PI3K-Akt signaling pathwayKEGGko04151
    MicroRNAs in cancerKEGGhsa05206
    MicroRNAs in cancerKEGGko05206
    Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
    Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
    FoxO signaling pathwayKEGGhsa04068
    Diseases of signal transductionREACTOMER-HSA-5663202
    Signal TransductionREACTOMER-HSA-162582
    Signalling by NGFREACTOMER-HSA-166520
    p75 NTR receptor-mediated signallingREACTOMER-HSA-193704
    Cell death signalling via NRAGE, NRIF and NADEREACTOMER-HSA-204998
    NRAGE signals death through JNKREACTOMER-HSA-193648
    Programmed Cell DeathREACTOMER-HSA-5357801
    Intrinsic Pathway for ApoptosisREACTOMER-HSA-109606
    Activation of BH3-only proteinsREACTOMER-HSA-114452
    Activation of BIM and translocation to mitochondriaREACTOMER-HSA-111446
    BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 membersREACTOMER-HSA-111453
    Apoptosis - multiple speciesKEGGko04215
    Apoptosis - multiple speciesKEGGhsa04215
    EGFR tyrosine kinase inhibitor resistanceKEGGko01521
    EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
    Oncogenic MAPK signalingREACTOMER-HSA-6802957
    Signaling by BRAF and RAF fusionsREACTOMER-HSA-6802952
    Neurodegenerative DiseasesREACTOMER-HSA-8863678
    Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease modelsREACTOMER-HSA-8862803

    Protein levels (Protein atlas)

    Not detected


    Entity IDNameTypeEvidenceAssociationPKPDPMIDs
    PA10804imatinibChemicalClinicalAnnotation, Literature, MultilinkAnnotationassociatedPD24223824
    PA446155Precursor Cell Lymphoblastic Leukemia-LymphomaDiseaseClinicalAnnotationassociatedPD29282361


    Pubmed IDYearTitleCitations
    172899992007Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.474
    118593722002BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes.252
    224264212012A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer.192
    128441462003Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis.187
    145559912003Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function.184
    145279512003FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines.176
    221450992011BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors.125
    156880142005Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells.112
    172763402007BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms.106
    162823232006Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function.97


    Maybelline Giam ; Andreas Strasser ; Philippe Bouillet

    BCL2L11 (BCL2-like 11 (apoptosis facilitator))

    Atlas Genet Cytogenet Oncol Haematol. 2008-11-01

    Online version: http://atlasgeneticsoncology.org/gene/772/bcl2l11-(bcl2-like-11-(apoptosis-facilitator))