Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

BCL2L15 (BCL2-like 15)

Written2011-09Maria-Angeliki S Pavlou, Christos K Kontos
Westfalische Wilhelms-Universitat Munster, ZMBE, Institute of Cell Biology, Stem Cell Biology, Regeneration Group, Von-Esmarch-Str 56, 48149 Munster, Germany (MASP); Department of Biochemistry, Molecular Biology, Faculty of Biology, University of Athens, 15701, Panepistimiopolis, Athens, Greece (CKK)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesC1orf178
chromosome 1 open reading frame 178
Alias_symbol (synonym)Bfk
FLJ22588
Other alias
HGNC (Hugo) BCL2L15
LocusID (NCBI) 440603
Atlas_Id 46259
Location 1p13.2  [Link to chromosome band 1p13]
Location_base_pair Starts at 113876814 and ends at 113887547 bp from pter ( according to hg19-Feb_2009)  [Mapping BCL2L15.png]
Local_order Centromere to telomere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

 
  Figure 1. Schematic representation of the BCL2L15 gene. Exons are shown as boxes and introns as connecting lines. The coding sequences are highlighted as red, while 5' and 3' untranslated regions (UTRs) are shown in white. Numbers inside or outside boxes indicate lengths (nt) of exons and introns, respectively, while numbers in parentheses indicate lengths (aa) of protein isoforms. Arrows (↓) show the position of the start codons (ATG) and asterisks (*) denote the position of the stop codons (TGA). Question marks (?) indicate that the full-length sequence was not determined. Roman numerals indicate intron phases. The intron phase refers to the location of the intron within the codon; I denotes that the intron occurs after the first nucleotide of the codon, II denotes that the intron occurs after the second nucleotide, and 0 means that the intron occurs between distinct codons. The figure is drawn to scale, except for the introns containing the (//) symbol.
Description The BCl2L15 gene has a total length of 10734 nt and consists of 4 exons and 3 intervening introns (Coultas et al., 2003). The organization of the BCL2L15 gene, with the BH3 domain located on a single exon (exon 2) and the BH2 domain split between two exons (exons 3 and 4), is similar to that of other BCL2 family members, including BCL2, BCL2L1 (BCLX), BAX, and BAK1 (BAK) (Petros et al., 2004).
Transcription The BCL2L15 gene is subjected to alternative splicing, generating four splice variants, three of which are considered as coding transcripts. Each coding splice variant consists of a distinctive exon combination and encodes a different protein isoform. The predominant transcript, consisting of 4973 nt, includes all 4 exons and encodes isoform a. The second transcript, predicted to encode isoform b, contains exons 1, 2 and 4. The deletion of exon 3 does not result in frameshifting. The third transcript, putatively encoding isoform d, consists of exons 1 and 4. The lack of exons 2 and 3 shifts the open reading frame.
As aforementioned, except for alternatively spliced BCL2L15 coding variants, another noncoding transcript has also been identified. This one is composed of exons 1, 3 and 4, and was initially considered to encode isoform c. Nonetheless, this transcript is a nonsense-mediated mRNA decay (NMD) candidate, since deletion of exon 2 generates a premature translation termination codon in exon 3.
Interestingly, transcription of all BCL2L15 alternatively spliced variants was noticed only in colon, while the full-length transcript was also detected in stomach, rectum, small intestine, cerebellum, testis and uterus (Dempsey et al., 2005). Moreover, despite the fact that a p53 consensus binding site was identified upstream of the transcription initiation site of BCL2L15, this gene does not constitute a transcriptional target of p53 (TP53) (Ozören et al., 2009).
Pseudogene Not identified so far.

Protein

 
  Figure 2. Alignment of amino acid sequences and structural motifs of the BC2L15 protein isoforms. Light blue and pink denote the BH2 and BH3 domains, respectively, while the amino acid residues constituting the consensus sequence of each BCL2 homology domain are shown in dark blue and red color. Yellow highlights the site of caspase-3/7 cleavage (DEVD tetrapeptide), which is considered to be critical for the activation of the proapoptotic action of BCL2L15, at least in certain cell types and/or after certain stimuli, including DNA damage-induced apoptosis. Finally, light green highlights the ECIxNxLxxxFL peptide, which BCL2L15 isoforms share with BID; its conserved amino acid residues are shown in dark green.
Description The full-length BCL2L15 isoform (isoform a) is the predominant one. It consists of 163 amino acid residues and has a molecular mass of 17.7 kDa. BCL2L15 isoform a contains a BH3 and a BH2 domain, but no BH1, BH4 or hydrophobic tail (Coultas et al., 2003). Isoform a is the predominant BCL2L15 isoform and the only one that has been in vivo detected so far.
The amino acid sequences of isoforms b and c are deduced from the mRNA sequences of the BCL2L15 alternatively spliced variants, and remain to be experimentally validated and in vivo detected. Isoform b is a putative BH3-only protein of 88 amino acid residues, with a calculated molecular mass of 9.6 kDa. This isoform shares the same termini with BCL2L15 isoform; still, it bears no BH2 domain. Finally, isoform d is the smallest predicted BCL2L15 isoform. This protein of 56 amino acid residues, with a molecular mass of 6.3 kDa, possesses no BCL2-homology (BH) domains (Dempsey et al., 2005).
The N-terminal region of all BCL2L15 isoforms shares partial homology (ECIxNxLxxxFL peptide) with BID (Dempsey et al., 2005), a BH3-only proapoptotic member of the BCL2 family (Lomonosova and Chinnadurai, 2008). Moreover, all BCL2L15 isoforms contain a caspase-3/caspase-7 cleavage site (DEVD peptide) (Dempsey et al., 2005). This tetrapeptide, corresponding to amino acid residues 38-41, is responsible for the removal of an N-terminal peptide fragment and the subsequent activation of the predominant BCL2L15 isoform, at least during DNA damage-induced apoptosis (Dempsey et al., 2005; Ozören et al., 2009).
Expression The BCL2L15 protein is mainly expressed in tissues of the gastrointestinal tract, including the stomach, small intestine, colon and rectum (Dempsey et al., 2005; Ozören et al., 2009). The full-length isoform has also been detected in several colorectal cancer cell lines, such as SW480, HT-29 and HCT116 (Ozören et al., 2009).
Localisation The BCL2L15 protein is localized to the cytoplasm of intestinal epithelial cells (Ozören et al., 2009). It does not possess any signal peptide or C-terminal membrane anchor and, consequently, it is not associated with any cellular organelles (Coultas et al., 2003; Ozören et al., 2009), unlike other members of the BCL2 family (Thomadaki and Scorilas, 2006). The localization of the cleaved BCL2L15 has not been elucidated yet.
Function BCL2L15 is a weakly proapoptotic member of the BCL2 family (Coultas et al., 2003; Dempsey et al., 2005; Pujianto et al., 2007). When overexpressed, the full-length BCL2L15 isoform interacts with BCL2L1 long isoform (BCLXL) and BCL2L2 (BCLW), but not with BCL2 or BAD, as revealed by co-immunoprecipitation experiments (Ozören et al., 2009). Furthermore, it has been speculated that BCL2L15 acts most probably as an amplifier of the apoptotic signal rather than a trigger of programmed cell death (Pujianto et al., 2007; Ozören et al., 2009).
Given the weak proapoptotic activity of BCL2L15, it was initially suggested that the full-length BCL2L15 could represent the latent form of a potent BH3-only protein exerting its proapoptotic action once activated through proteolytic cleavage (Coultas et al., 2003), like caspase-8 cleavage of BID (Li et al., 1998; Luo et al., 1998), at least in certain cell types or after certain stimuli. In support of this notion, it was shown that BCL2L15 becomes cleaved in a caspase-dependent manner during DNA damage-induced apoptosis and that truncated BCL2L15 (~13 kDa), corresponding to the part of protein downstream of the caspase-3/7 cleavage site, is capable of inducing apoptosis in HCT116 cells, in contrast to the full-length BCL2L15 isoform, which seems to be incapable of inducing apoptosis in HCT116 or SW480 colorectal cancer cells. Interestingly, the ability of the cleaved form of the BCL2L15 protein to induce apoptosis is dependent on the presence of the BAX or BAK1 (BAK). Furthermore, co-expression of the antiapoptotic BCL2L1 long isoform (BCLXL) or BCL2L2 (BCLW) antagonizes efficiently the killing activity of truncated BCL2L15 (Ozören et al., 2009).
On the other hand, it has been proposed that the proapoptotic role of BCL2L15 may resemble more that of BAX and BAK1 (BAK) than that of BH3-only proteins, since it most probably has a structure similar to that of BCL2 and BAX. In fact, the position of BH3 and BH2 domains in the BCL2L15 protein is conserved relative to BAX and BCL2 (Coultas et al., 2003).
Potential phosphorylation at Ser-96 and/or Ser-42 as well as other post-translational modifications of BCL2L15 might change its subcellular localization and further regulate its physiological function (Dempsey et al., 2005; Pujianto et al., 2007).
Homology Human BCL2L15 shares 71% amino acid identity and 80% similarity with the mouse ortholog. BCL2L15 bears the same combination of BCL2-homology domains (BH2 and BH3) as the BCL2L14 long isoform (BCLGL) and BCL2L12 full-length isoform, thus lacking other domains that are common among BCL2 family members (BH1 and BH4) or a hydrophobic tail (Youle and Strasser, 2008).

Mutations

Note A single nucleotide polymorphism (SNP) has been detected in the coding sequence (GAC→AAC) of the BCL2L15 gene, which results in the substitution of an amino acid residue bearing a negatively charged side chain by an amino acid with a polar uncharged side chain (D→N).

Implicated in

Note
  
Entity Gastrointestinal cancer, particularly colorectal carcinoma
Prognosis BCL2L15 mRNA expression is clearly reduced in a wide range of gastrointestinal malignancies. BCL2L15 mRNA levels are lower in colon tumors, compared to levels detected in matched normal colon tissue. Moreover, BCL2L15 mRNA expression is significantly downregulated in tumors of the small intestine, stomach and rectum. This reduction of BCL2L15 mRNA levels in gastrointestinal neoplasms implies that BCL2L15 may contribute to the protective effect of proapoptotic BCL2 family proteins against malignant transformation of the gastrointestinal tract (Dempsey et al., 2005).
  

Bibliography

Bfk: a novel weakly proapoptotic member of the Bcl-2 protein family with a BH3 and a BH2 region.
Coultas L, Pellegrini M, Visvader JE, Lindeman GJ, Chen L, Adams JM, Huang DC, Strasser A.
Cell Death Differ. 2003 Feb;10(2):185-92.
PMID 12700646
 
Expression of pro-apoptotic Bfk isoforms reduces during malignant transformation in the human gastrointestinal tract.
Dempsey CE, Dive C, Fletcher DJ, Barnes FA, Lobo A, Bingle CD, Whyte MK, Renshaw SA.
FEBS Lett. 2005 Jul 4;579(17):3646-50.
PMID 15961081
 
Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.
Li H, Zhu H, Xu CJ, Yuan J.
Cell. 1998 Aug 21;94(4):491-501.
PMID 9727492
 
BH3-only proteins in apoptosis and beyond: an overview.
Lomonosova E, Chinnadurai G.
Oncogene. 2008 Dec;27 Suppl 1:S2-19. (REVIEW)
PMID 19641503
 
Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors.
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X.
Cell. 1998 Aug 21;94(4):481-90.
PMID 9727491
 
A putative role for human BFK in DNA damage-induced apoptosis.
Ozoren N, Inohara N, Nunez G.
Biotechnol J. 2009 Jul;4(7):1046-54.
PMID 19557800
 
Structural biology of the Bcl-2 family of proteins.
Petros AM, Olejniczak ET, Fesik SW.
Biochim Biophys Acta. 2004 Mar 1;1644(2-3):83-94. (REVIEW)
PMID 14996493
 
Bfk, a novel member of the bcl2 gene family, is highly expressed in principal cells of the mouse epididymis and demonstrates a predominant nuclear localization.
Pujianto DA, Damdimopoulos AE, Sipila P, Jalkanen J, Huhtaniemi I, Poutanen M.
Endocrinology. 2007 Jul;148(7):3196-204. Epub 2007 Apr 5.
PMID 17412810
 
BCL2 family of apoptosis-related genes: functions and clinical implications in cancer.
Thomadaki H, Scorilas A.
Crit Rev Clin Lab Sci. 2006 Jan;43(1):1-67.
PMID 16531274
 
The BCL-2 protein family: opposing activities that mediate cell death.
Youle RJ, Strasser A.
Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59. (REVIEW)
PMID 18097445
 

Citation

This paper should be referenced as such :
Pavlou, MAS ; Kontos, CK
BCL2L15 (BCL2-like 15)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(2):115-118.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/BCL2L15ID46259ch1p13.html


External links

Nomenclature
HGNC (Hugo)BCL2L15   33624
Cards
AtlasBCL2L15ID46259ch1p13
Entrez_Gene (NCBI)BCL2L15  440603  BCL2 like 15
AliasesBfk; C1orf178
GeneCards (Weizmann)BCL2L15
Ensembl hg19 (Hinxton)ENSG00000188761 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000188761 [Gene_View]  chr1:113876814-113887547 [Contig_View]  BCL2L15 [Vega]
ICGC DataPortalENSG00000188761
TCGA cBioPortalBCL2L15
AceView (NCBI)BCL2L15
Genatlas (Paris)BCL2L15
WikiGenes440603
SOURCE (Princeton)BCL2L15
Genetics Home Reference (NIH)BCL2L15
Genomic and cartography
GoldenPath hg38 (UCSC)BCL2L15  -     chr1:113876814-113887547 -  1p13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)BCL2L15  -     1p13.2   [Description]    (hg19-Feb_2009)
EnsemblBCL2L15 - 1p13.2 [CytoView hg19]  BCL2L15 - 1p13.2 [CytoView hg38]
Mapping of homologs : NCBIBCL2L15 [Mapview hg19]  BCL2L15 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AI821052 AK026241 AK289439 AY265861 AY265862
RefSeq transcript (Entrez)NM_001010922 NM_001029944 NM_001029945 NM_001029946
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)BCL2L15
Cluster EST : UnigeneHs.123106 [ NCBI ]
CGAP (NCI)Hs.123106
Alternative Splicing GalleryENSG00000188761
Gene ExpressionBCL2L15 [ NCBI-GEO ]   BCL2L15 [ EBI - ARRAY_EXPRESS ]   BCL2L15 [ SEEK ]   BCL2L15 [ MEM ]
Gene Expression Viewer (FireBrowse)BCL2L15 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)440603
GTEX Portal (Tissue expression)BCL2L15
Human Protein AtlasENSG00000188761-BCL2L15 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ5TBC7   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ5TBC7  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ5TBC7
Splice isoforms : SwissVarQ5TBC7
PhosPhoSitePlusQ5TBC7
Domains : Interpro (EBI)BCL2L15   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)BCL2L15
DMDM Disease mutations440603
Blocks (Seattle)BCL2L15
SuperfamilyQ5TBC7
Human Protein Atlas [tissue]ENSG00000188761-BCL2L15 [tissue]
Peptide AtlasQ5TBC7
HPRD16920
IPIIPI00514645   IPI00470893   IPI00871192   IPI00872173   
Protein Interaction databases
DIP (DOE-UCLA)Q5TBC7
IntAct (EBI)Q5TBC7
FunCoupENSG00000188761
BioGRIDBCL2L15
STRING (EMBL)BCL2L15
ZODIACBCL2L15
Ontologies - Pathways
QuickGOQ5TBC7
Ontology : AmiGOprotein binding  nucleus  cytosol  apoptotic process  regulation of apoptotic process  
Ontology : EGO-EBIprotein binding  nucleus  cytosol  apoptotic process  regulation of apoptotic process  
NDEx NetworkBCL2L15
Atlas of Cancer Signalling NetworkBCL2L15
Wikipedia pathwaysBCL2L15
Orthology - Evolution
OrthoDB440603
GeneTree (enSembl)ENSG00000188761
Phylogenetic Trees/Animal Genes : TreeFamBCL2L15
HOVERGENQ5TBC7
HOGENOMQ5TBC7
Homologs : HomoloGeneBCL2L15
Homology/Alignments : Family Browser (UCSC)BCL2L15
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerBCL2L15 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)BCL2L15
dbVarBCL2L15
ClinVarBCL2L15
1000_GenomesBCL2L15 
Exome Variant ServerBCL2L15
ExAC (Exome Aggregation Consortium)ENSG00000188761
GNOMAD BrowserENSG00000188761
Genetic variants : HAPMAP440603
Genomic Variants (DGV)BCL2L15 [DGVbeta]
DECIPHERBCL2L15 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisBCL2L15 
Mutations
ICGC Data PortalBCL2L15 
TCGA Data PortalBCL2L15 
Broad Tumor PortalBCL2L15
OASIS PortalBCL2L15 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICBCL2L15  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDBCL2L15
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch BCL2L15
DgiDB (Drug Gene Interaction Database)BCL2L15
DoCM (Curated mutations)BCL2L15 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)BCL2L15 (select a term)
intoGenBCL2L15
NCG5 (London)BCL2L15
Cancer3DBCL2L15(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM
Orphanet
MedgenBCL2L15
Genetic Testing Registry BCL2L15
NextProtQ5TBC7 [Medical]
TSGene440603
GENETestsBCL2L15
Target ValidationBCL2L15
Huge Navigator BCL2L15 [HugePedia]
snp3D : Map Gene to Disease440603
BioCentury BCIQBCL2L15
ClinGenBCL2L15
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD440603
Chemical/Pharm GKB GenePA162377411
Clinical trialBCL2L15
Miscellaneous
canSAR (ICR)BCL2L15 (select the gene name)
Probes
Litterature
PubMed9 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineBCL2L15
EVEXBCL2L15
GoPubMedBCL2L15
iHOPBCL2L15
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 12 16:17:10 CEST 2017

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.