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BCL2L11 (BCL2-like 11 (apoptosis facilitator))

Written2008-11Maybelline Giam, Andreas Strasser, Philippe Bouillet
The Walter, Eliza Hall Institute, Melbourne, Australia

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)BAM
BIM
BIM-alpha6
BIM-beta6
BIM-beta7
BOD
BimEL
BimL
HGNC (Hugo) BCL2L11
HGNC Alias symbBOD
BimL
BimEL
BimS
BIM
HGNC Previous nameBCL2-like 11 (apoptosis facilitator)
LocusID (NCBI) 10018
Atlas_Id 772
Location 2q13  [Link to chromosome band 2q13]
Location_base_pair Starts at 111120914 and ends at 111168444 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping BCL2L11.png]
Local_order According to GeneLoc and NCBI Map Viewer, genes flanking BCL2L11 in plus strand direction are: ACOXL 2q13 (acyl-Coenzyme A oxidase-like); PAFAH1P2 2q13 (platelet-activating factor acetylhydrolase, isoform Ib, pseudogene 2).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
BCL2L11 (2q13) / ACOXL (2q13)BCL2L11 (2q13) / AFMID (17q25.3)BCL2L11 (2q13) / BRAF (7q34)
MAP1LC3B (16q24.2) / BCL2L11 (2q13)
Note BCL2L11/BIM is a BH3-only protein from the Bcl-2 family. Bcl-2 family members are the main regulators of programmed cell death via the mitochondrial (intrinsic) apoptotic pathway. Interactions between pro- and anti-apoptotic proteins of the Bcl-2 family decide the fate of cells after a stress signals. BH3-only proteins are activated in response to cellular stresses such as DNA damage. BCL2L11/BIM is one of the most potent BH3-only proteins, shown to mediate apoptosis in response to stimuli such as cytokine deprivation, deregulated calcium flux and microtubule perturbation. In vivo, BCL2L11/BIM is essential for hematopoietic homeostasis, thymocyte negative selection and as a barrier against autoimmunity.

DNA/RNA

 
  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.
Description 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.
Transcription 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 . There are alternative promoters located in intron 1.
Pseudogene There are no known pseudogenes for BIM.

Protein

Description 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.
Expression 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.
Localisation 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.
Function 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.

Regulation:
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 BIM's half life.

Interactions:
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.

Homology 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

    Note 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

    Note
      
    Entity Mantle cell lymphoma
    Note 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).
    Disease Mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma characterized by the 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 Alzheimer's disease
    Disease Alzheimer's 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).
      

    Bibliography

    Nomenclature of dynein light chain-linked BH3-only protein Bim isoforms.
    Adachi M, Zhao X, Imai K.
    Cell Death Differ. 2005 Feb;12(2):192-3. Erratum in: Cell Death Differ. 2005 Jun;12(6):690.
    PMID 15592437
     
    Bim is elevated in Alzheimer's disease neurons and is required for beta-amyloid-induced neuronal apoptosis.
    Biswas SC, Shi Y, Vonsattel JP, Leung CL, Troy CM, Greene LA.
    J Neurosci. 2007 Jan 24;27(4):893-900.
    PMID 17251431
     
    BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes.
    Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM, Strasser A.
    Nature. 2002 Feb 21;415(6874):922-6.
    PMID 11859372
     
    Bim is a suppressor of Myc-induced mouse B cell leukemia.
    Egle A, Harris AW, Bouillet P, Cory S.
    Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6164-9. Epub 2004 Apr 12.
    PMID 15079075
     
    Identification of a candidate alternative promoter region of the human Bcl2L11 (Bim) gene.
    Gaviraghi M, Caricasole A, Costanzo C, Diamanti D, Dandrea M, Donadelli M, Scarpa A, Palmieri M.
    BMC Mol Biol. 2008 Jun 12;9:56.
    PMID 18549468
     
    Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas.
    Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA, Siebert R, Climent J, Fresquet V, Beltran E, Agirre X, Marugan I, Marin M, Rosenwald A, Sugimoto KJ, Wheat LM, Karran EL, Garcia JF, Sanchez L, Prosper F, Staudt LM, Pinkel D, Dyer MJ, Martinez-Climent JA.
    Blood. 2007 Jan 1;109(1):271-80. Epub 2006 Sep 7.
    PMID 16960149
     
    Bim: a novel member of the Bcl-2 family that promotes apoptosis.
    O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC.
    EMBO J. 1998 Jan 15;17(2):384-95.
    PMID 9430630
     
    The proapoptotic BH3-only protein bim is expressed in hematopoietic, epithelial, neuronal, and germ cells.
    O'Reilly LA, Cullen L, Visvader J, Lindeman GJ, Print C, Bath ML, Huang DC, Strasser A.
    Am J Pathol. 2000 Aug;157(2):449-61.
    PMID 10934149
     
    The pro-apoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex.
    Puthalakath H, Huang DC, O'Reilly LA, King SM, Strasser A.
    Mol Cell. 1999 Mar;3(3):287-96.
    PMID 10198631
     
    Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM.
    Tagawa H, Karnan S, Suzuki R, Matsuo K, Zhang X, Ota A, Morishima Y, Nakamura S, Seto M.
    Oncogene. 2005 Feb 17;24(8):1348-58.
    PMID 15608680
     
    Constitutive association of the proapoptotic protein Bim with Bcl-2-related proteins on mitochondria in T cells.
    Zhu Y, Swanson BJ, Wang M, Hildeman DA, Schaefer BC, Liu X, Suzuki H, Mihara K, Kappler J, Marrack P.
    Proc Natl Acad Sci U S A. 2004 May 18;101(20):7681-6. Epub 2004 May 10.
    PMID 15136728
     

    Citation

    This paper should be referenced as such :
    Giam, M ; Strasser, A ; Bouillet, P
    BCL2L11 (BCL2-like 11 (apoptosis facilitator))
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(10):716-718.
    Free journal version : [ pdf ]   [ DOI ]


    Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ]
      t(2;18)(p11;q21)IGK/BCL2 and IGK/KDSR
    t(4;11)(q21;q23) KMT2A/AFF1


    External links

    Nomenclature
    HGNC (Hugo)BCL2L11   994
    LRG (Locus Reference Genomic)LRG_620
    Cards
    AtlasBCL2L11ID772ch2q13
    Entrez_Gene (NCBI)BCL2L11    BCL2 like 11
    AliasesBAM; BIM; BOD
    GeneCards (Weizmann)BCL2L11
    Ensembl hg19 (Hinxton)ENSG00000153094 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000153094 [Gene_View]  ENSG00000153094 [Sequence]  chr2:111120914-111168444 [Contig_View]  BCL2L11 [Vega]
    ICGC DataPortalENSG00000153094
    TCGA cBioPortalBCL2L11
    AceView (NCBI)BCL2L11
    Genatlas (Paris)BCL2L11
    SOURCE (Princeton)BCL2L11
    Genetics Home Reference (NIH)BCL2L11
    Genomic and cartography
    GoldenPath hg38 (UCSC)BCL2L11  -     chr2:111120914-111168444 +  2q13   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)BCL2L11  -     2q13   [Description]    (hg19-Feb_2009)
    GoldenPathBCL2L11 - 2q13 [CytoView hg19]  BCL2L11 - 2q13 [CytoView hg38]
    ImmunoBaseENSG00000153094
    genome Data Viewer NCBIBCL2L11 [Mapview hg19]  
    OMIM603827   
    Gene and transcription
    Genbank (Entrez)AA854054 AA890664 AB071195 AB071196 AB071197
    RefSeq transcript (Entrez)NM_001204106 NM_001204107 NM_001204108 NM_001204109 NM_001204110 NM_001204111 NM_001204112 NM_001204113 NM_006538 NM_138621 NM_138622 NM_138623 NM_138624 NM_138625 NM_138626 NM_138627 NM_207002 NM_207003
    Consensus coding sequences : CCDS (NCBI)BCL2L11
    Alternative Splicing GalleryENSG00000153094
    Gene ExpressionBCL2L11 [ NCBI-GEO ]   BCL2L11 [ EBI - ARRAY_EXPRESS ]   BCL2L11 [ SEEK ]   BCL2L11 [ MEM ]
    Gene Expression Viewer (FireBrowse)BCL2L11 [ Firebrowse - Broad ]
    GenevisibleExpression of BCL2L11 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)10018
    GTEX Portal (Tissue expression)BCL2L11
    Human Protein AtlasENSG00000153094-BCL2L11 [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    Domain families : Pfam (Sanger)
    Domain families : Pfam (NCBI)
    Conserved Domain (NCBI)BCL2L11
    Human Protein Atlas [tissue]ENSG00000153094-BCL2L11 [tissue]
    HPRD04828
    Protein Interaction databases
    BioGRIDBCL2L11
    STRING (EMBL)BCL2L11
    ZODIACBCL2L11
    Ontologies - Pathways
    Litterature
    PubMed485 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    EVEXBCL2L11
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Wed Sep 15 23:40:57 CEST 2021

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