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BCL2 (B-Cell Leukemia/Lymphoma 2)

Written1998-05Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2017-12Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA; amohamed@dmc.org

Abstract BCL2 is the milestone of apoptosis-regulatory genes. It contributes to tumorigenesis by blocking programmed cell death as such, promoting cell survival. The aberrant expression of BCL2 gene is strongly associated with resistance to chemotherapy and radiation. This review outlines the structure, function, and role of BCL2 gene in cancer.

Keywords BCL2, apoptosis, antiapoptotic proteins, proapoptoic proteins, t(14;18), follicular lymphoma, IGH, BH3-only protein, Bcl-2 family proteins

(Note : for Links provided by Atlas : click)

Identity

Alias_namesregulatory subunit 50
Alias_symbol (synonym)Bcl-2
PPP1R50
Other aliasApoptosis Regulator
Protein Phosphatase 1
Regulatory Subunit 50
HGNC (Hugo) BCL2
LocusID (NCBI) 596
Atlas_Id 49
Location 18q21.33  [Link to chromosome band 18q21]
Location_base_pair Starts at 63123346 and ends at 63319380 bp from pter ( according to hg19-Feb_2009)  [Mapping BCL2.png]
Local_order Telomere to centromere orientation.
 
  Figure 1 BCL2 (18q21) PAC 248E24 - Courtesy Mariano Rocchi
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
AFF3 (2q11.2) / BCL2 (18q21.33)ATRX (Xq21.1) / BCL2 (18q21.33)BCL2 (18q21.33) / BCL2 (18q21.33)
BCL2 (18q21.33) / C18orf8 (18q11.2)BCL2 (18q21.33) / HFE2 (1q21.1)BCL2 (18q21.33) / TRBV20OR9-2 (-)
BCL2 (18q21.33) / TSPO (22q13.2)BCL2 (18q21.33) / VPS4B (18q21.33)BCL6 (3q27.3) / BCL2 (18q21.33)
DHRS12 (13q14.3) / BCL2 (18q21.33)HFE2 (1q21.1) / BCL2 (18q21.33)JCHAIN (4q13.3) / BCL2 (18q21.33)
NEDD4L (18q21.31) / BCL2 (18q21.33)NGB (14q24.3) / BCL2 (18q21.33)STPG1 (1p36.11) / BCL2 (18q21.33)
ZNF791 (19p13.2) / BCL2 (18q21.33)
Note BCL2 is a proto-oncogene, initially cloned as the result of its consistent involvement by t(14;18)(q32;q21) in lymphoma where its transcription becomes driven by the immunoglobulin heavy chain (IGH) gene enhancer on chromosome 14q32, subsequently leading to constitutive expression of BCL2 in B-cell clones (Tsujimoto et al, 1984, Bakhshi et al, 1985). In contrast to many oncogenes, BCL2 does not trigger cell proliferation but promotes cell survival specifically by preventing programmed cell death, apoptosis (Vaux and Adams 1988).

DNA/RNA

Description The human BCL2 gene has a three exon structure with an untranslated first exon, a facultative 220 bp intron I, and a large 370 kb intron II. The native BCL2 gene has a long 3' untranslated regions and two distinct promoters, P1 and P2. The main promoter region, P1, is a TATA-less, GC-rich promoter containing multiple transcriptional start sites and located 1386-1423 bp upstream of the translation start site. The use of alternative promoter results in mRNAs comprised of exons II/III or I/II/III. The t(14;18) translocation in B-cells generates heterogeneous 4.2 - 7.2 kb BCL2-IGH chimeric mRNAs resulting from alternative BCL2 5' exons and varied IGH 3' untranslated regions. The t(14;18) does not interrupt the BCL2 open reading frame, however, inappropriately high levels of BCL2-IGH mRNAs are present. The native BCL2 and BCL2-IGH fusion mRNAs demonstrate the same 2.5-hour short half-life (Clearly et al, 1986, Tsujimoto et al1986, Seta et al1988)

Protein

 
Description The BCL2 gene encodes a 26 kd protein consisting of 239 amino acids with a single highly hydrophobic domain at its C-terminus, which enables it to localize mainly in the mitochondrial outer membrane, and to a lesser extent in the nuclear envelope and the membrane of the endoplasmic reticulum (Chen-Levy 1989). The main role of BCL2 protein is to maintain the integrity of the mitochondrial membrane, preventing cytochrome c release and its subsequent binding to APAF1 (apoptosis activating factor-1). The protein contains all four BCL2 homology (BH) domains (BH1 to BH4). BH1, BH2 and BH3 constitute the hydrophobic cleft through which the protein interacts and forms homo- and heterodimers with the pro-apoptotic members of the BCL2 family of proteins (Thomadaki 2006, Reed 2006). BCL2 increases the survival kinetics of the cell specifically by blocking apoptosis. Thus it prevents the cell from going into suicidal activities that usually require ATP, new RNA, and protein synthesis, and inducing a variety of cellular ultra-structural changes such as cell shrinkage, nuclear fragmentation, and DNA degradation.
Expression BCL2 expression is widespread in immature tissues prenatally whereas its expression becomes highly restricted with maturation. BCL2 is extensively expressed in immature B-cells and memory B cells but is temporarily down-regulated in germinal center B-cells, partially because of repression by BCL6. High levels of BCL2 have been detected in thymus throughout the medulla, in spleen and in lymph nodes as well as early in the embryonic kidney. Decrease in its expression levels is observed in motor-neurons as well as in pre-B cells being prepared to differentiate (Thomadaki 2006).
Function BCL2 Protein Family and Apoptosis
The BCL2 family is a prototype of a large family of evolutionarily related proteins that share a high degree of homology although they exert different functions. This family consists of 25 pro-apoptotic and anti-apoptotic members which interact to maintain a balance between newly forming cells and old dying cells. These proteins are localized to the membrane of mitochondria and endoplasmic reticulum, operating as guardians of these organelles (Thomadaki 2006, Reed 2008, Aki etal 2014)). BCL2 family proteins play central roles in cell death regulation and can regulate diverse cell death mechanisms including apoptosis, necrosis and autophagy. They are the key regulators of the mitochondrial pathway of apoptosis. This pathway is required for normal embryonic development and for preventing cancer. These proteins control the permeabilization of the mitochondrial outer membrane (MOM) that releases cytochrome c and other apoptotic factors into the cytosol. BCL2 family proteins share up to four BCL2 homology domains (BH1, BH2, BH3, & BH4) and are generally divided into two categories, anti-apoptotic and pro-apoptotic proteins based on their intracellular function and sequence homology. The anti-apoptotic proteins, BCL2, BCL2L1 (BCL-XL), BCL2L2 (BCL-W), MCL1, BCL2A1 (A1/BFL-1), share homology within four domains (BH1-4). These proteins form a characteristic helical bundle fold, which is critical for their ability to bind to the pro-apoptotic BCL2 family members and thereby exert their antiapoptotic function. The pro-apoptotic proteins such as BAX, BAK1, and BOK share BH1-3 domains whereas other pro-apoptotic proteins, such as BCL2L11 (BIM), BAD, and BID, contain only the BH3 domain and are known as BH3-only proteins (Figure 3). In normal situations, the BH3-only proteins are inactive or exist at low levels in the cell. However, in the presence of apoptotic stimuli the BH-only proteins become activated by post-translational modifications or their expression are increased. The stimulation of BH3-only proteins induces BAX-BAK oligomerization. After their oligomerization, BAX and BAK directly cause MOM permeabilization, a critical step in apoptosis (Aki et al 2014). The role of anti-apoptotic BCL2 proteins is to neutralize pro-apoptotic BH3-only proteins and thus inhibit their effect on BAX-BAK activity and MOM permeabilization. The balance between pro-survival and pro-death BCL-2 proteins is a major factor in determining if cells undergo apoptosis in response to cell stress.
Control of Proliferation by BCL2
Although BCL2-family proteins are key players in the control of mitochondria-based apoptosis, they can also control cell proliferation. High levels of BCL2 protein were reported to be associated with a lower proliferative capacity of human lymphoma, suggesting a negative control on proliferation. The anti-proliferative effect of BCL2 acts mainly at the level of the G0/G1 phase of the cell cycle. Deletions and point mutations in the BCL2 gene show that in some cases the anti-proliferative activity of BCL2 can be dissociated from its anti-apoptotic function (Bonnefoy et al, 2004). This indicates that the effect of BCL2 on cell cycle progression can be a direct effect and not only a consequence of its anti-apoptotic activity. BCL2 appears to mediate its anti-proliferative effect by acting on both signal transduction pathways ( NFAT, ERK) and on specific cell cycle regulators. In addition, BCL2 cooperated with MYC to promote proliferation of B-cell precursors.
 
  Figure 3 BCL-family proteins have 1-4 domains (BH1, BH2, BH3 or BH4) and a transmembrane domain (TM). Anti-apoptotic BCL2-family members contain all four BH domains. Proapoptotic BCL2-family members are either multi-domain or BH3-only proteins.

Implicated in

Note Apoptosis is essential for normal embryonic development, maintenance of tissue homeostasis, and development and function of the immune system. In contrast, processes that interfere with normal apoptosis promote cell survival and, potentially, oncogenesis. Therefore, dysregulation of BCL2 family has a major role in tumor formation. The BCL2 family is also involved in other diseases, such as autoimmune, infectious and neurodegenerative disorders. The autoimmune disease such as type I diabetes can be caused by defective apoptosis, and schizophrenia may result from an abnormal ratio of pro- and anti-apoptotic factors (Strasser et al, 2011). On the other hand, there is increasing evidence that BCL2 family proteins also have additional functions in other cellular processes, such as mitochondrial morphology and metabolism, which remain largely unexplored. Apoptosis is regulated by a balance of pro-apoptotic factors and anti-apoptotic factors.
  
Entity t(14;18)(q32;q21)
Disease The t(14;18) Breakpoints in Lymphoma
The t(14;18)(q32;q21) constitutes the most common chromosomal translocation in human lymphomas, being present in over 85% of follicular lymphoma (FL) and in up to 30% of diffuse large B-cell lymphoma (DLBCL). BCL2 is normally located on chromosome 18q21.33 in a telomere to centromere orientation. The molecular consequence of the t(14;18) juxtaposes of the BCL2 gene next to IGH locus on the der(14) chromosome, in the same transcriptional orientation as the IGH gene. The breakpoints on chromosome 18 are clustered with 50-60% fall within a 2.8 kb major breakpoint region (MBR), located in the untranslated 3? UTR of the BCL2 gene, and another 25% falls in the minor cluster region (MCR) (Bakhshi 1987, Willis and Dyer 2000). Others cluster within a third, intermediate cluster region midway between the MBR and MCR while other breakpoints have been described scattered through this region. In rare variant translocations involving the IG light chain loci, t(2;18)(p12;q21) and t(18;22)(q21;q11.2), the breakpoints are located in the 5? noncoding region of the BCL2 gene. The breakpoints on chromosome 14 occur most commonly just 5? of IGH JH segments within sequences that typically show evidence of exonucleolytic "nibbling", N-bp additions, and D segment addition, events that occur normally during attempted V(D)J recombination. Less commonly, IGH breakpoints may occur at sites 3? of the JH segments, or rarely even in IG switch regions. BCL2 mRNA expression is up-regulated in the translocated allele through the action of IGH E[] enhancer sequences, which are highly active in germinal center B cells. In the cases of rearrangements falling in the MBR, a BCL2/IGH fusion mRNA transcript is produced whereas rearrangements in the MCR lead to increased levels of a normal BCL2 mRNA (Aster and longtine 2002). The t(14;18) translocation or its variants does not interrupt the protein-encoding region of BCL2 gene so that the normal and the translocated alleles produce the same-sized, 26-kd protein, a member of a family of proteins involved in the regulation of apoptosis. The somatic hypermutation mechanism associated with the IGH gene often induces mutations in the BCL2 gene which may further dysregulate its expression and can also lead to point mutations in the coding regions of the BCL2 protein (Seto 1988, Tanaka et al 1992). Therefore, a subset of t(14;18) positive lymphomas do not express intact BCL2 protein due to somatic mutations of the gene.
The majority of follicular lymphomas in adults depend on BCL2 overexpression which is almost always the result of t(14;18) translocation or its variants. BCL2 overexpression sustains cell survival but is not sufficient for FL development, thus other genetic lesions or epigenetic events are required. This is supported by the observation that BCL2 transgenic mice develop polyclonal hyperplasia of mature, long lived non-dividing B cells. With time, a fraction of BCL2 transgenic mice develops aggressive, clonal large cell lymphomas, which have acquired additional genetic lesions (McDonnell et al 1988).
Cytogenetics Diagnostic use of BCL2
Fluorescence in situ hybridization (FISH) is widely used in clinical laboratories to detect BCL2 gene rearrangement in fresh tissue and paraffin embedded tissue sections using dual color translocation DNA probes (Figure 4). BCL2 protein expression by immuno-histochemistry represents a rapid and inexpensive method to identify BCL2 overexpression. In normal tissue, BCL2 antibodies react with B-cells in the mantle zone, as well as some T-cells. Because BCL2 expression is down-regulated in normal germinal centers, the presence of BCL2 protein can help to distinguish follicular lymphomas from reactive follicular hyperplasia. However, positive cells increase considerably in follicular lymphoma, as well as many other forms of cancer. In some cases, the presence or absence of BCL2 staining in biopsies may be significant for the patient's prognosis or likelihood of relapse.
 
Figure 4 Karyotype from follicular lymphoma showing t(14;18)(q32;q21) [arrow]; Insert: FISH with IGH/BCL2 DNA probes showing a double fusion signals confirming t(14;18) [red &green fused signals]
  
Note BCL2 Expression in Cancer
BCL2 is upregulated in almost 50% of all human cancers, consistent with its role as an apoptotic regulator (Cory et al, 2003, Yip and Reed, 2008, Reed 2008). The majority of small cell lymphoma such as chronic lymphocytic leukemia (CLL), marginal cell lymphoma, and mantle cell lymphoma, over-express BCL2, although less than 5% of those patients have detectable BCL2 gene rearrangement (Hanada et al, 1993). Increased expression of BCL2 is also found in nearly all patients with acute lymphocytic leukemia and frequently in acute myeloid leukemia (Yip and Reed 2008). Most of adult FL cases have overexpression of BCL2 protein however; the pediatric type FL is negative for BCL2 expression. Approximately 30% of DLBCL patients are categorized as having relatively high BCL2 expression (Monni et al, 1997). BCL2 may also play a role in non-hematologic tumors, and inappropriate expression has been observed in solid tumors such as prostate, breast, and small cell and non-small cell lung cancers. In small cell lung cancer, high BCL2 expression in >90% of patients have been reported (Hellemans et al 1995, Jiang et al 1995, Anagnostou et al 2010, Henriksen et al 1995). Ovarian, neuroblastoma, bladder, colorectal, and some head and neck cancers have all exhibited high expression of BCL2.
Mechanisms of BCL2 Activation
Besides chromosomal translocations as a key mechanism for activation of the BCL2 gene in lymphoma, overexpression as a result BCL2 amplification has been demonstrated in non-Hodgkin's lymphomas and small cell lung cancers (Monni O, 1997). Other contributing mechanisms are deletion of endogenous microRNAs (miRs) such as MIR195, MIR24-2 and MIR-365B that normally repress BCL2 gene expression (Cimmino et al., 2005), This mechanism has been documented in CLL, where the genes encoding MIR15 and miR16 become deleted or inactivated by mutations in >70% of these leukemia. Gene hypomethylation is an alternative mechanism implying altered epigenetic regulation of BCL2 is in some malignancies (Hanada et al, 1993). In addition, tumor associated viruses, such as Epstein-Barr virus (EBV) and human herpes virus 8 (HHV8 or Kaposi's sarcoma-associated herpes virus), encode proteins that are homologues of BCL2, and provoke similar anti-apoptotic functions (Henderson et al, 1993).
Expression of BCL2 and Prognosis
Multiple studies have shown that high levels of BCL2 gene expression is a negative risk factor correlated with severity of malignancy. Elevated expression of BCL2 in AML was shown to be associated with poor clinical response to chemotherapy (Campos et al, 2005). BCL2 expression correlates negatively with overall survival within a specific subgroup of DLBCL (Iqbal et al, 2006). Additionally, several studies have demonstrated a correlation between elevated BCL2 expression and poor prognosis in melanoma, breast, prostate, small cell lung, colorectal and bladder cancers (Anagnostou et al, 2010). Further studies have proven that higher BCL2 expression leads to resistance to chemotherapy and radiation (Reed 2008, Review).
BCL2 for Targeted Therapy
Some cancers, particularly non-Hodgkin lymphoma, are dependent on BCL2 for survival. BCL2 is also involved in the development of resistance to chemotherapeutic agents, further stressing the importance of targeting the BCL2 gene in cancer therapeutics. Numerous approaches have been developed to block or modulate the production of BCL2 at the RNA level, at the protein level, or at the DNA level. From a clinical perspective, treatment with novel, potent BCL2 inhibitors either alone or in combination with conventional therapies hold significant promise for providing beneficial clinical outcomes. The BCL2 targeted drug has the potential to enhance cell killing when used alone or in combination with traditional cytotoxic agents, which may lead to greater efficacy and reduce toxicity of chemotherapy (Ebrahim et al 2016, Delbridge et al, 2016).
Antisense Oligonucleotides (ASOs)
Antisense technology involves the use of a sequence that is complementary to a specific mRNA which inhibits its expression and subsequently induces a blockade in the transfer of genetic information from DNA to protein. Oblimersen sodium, an example of ASO agent, is an 18-base antisense phosphorothioate oligonucleotide compound designed to specifically target the first six codons of the human BCL2 mRNA sequence, resulting in degradation of BCL2 mRNA and a subsequent decrease in BCL2 protein translation and intracellular concentration (Herbst et al, 2004). Oblimersen has been evaluated for suitability of the treatment of a number of cancers, including small cell lung cancer, prostate cancer, renal cell carcinoma, as well as non-Hodgkin lymphomas. This compound is already well advanced in clinical trials for the treatment of refractory CLL, multiple myeloma and melanoma. Studies showed that treatment with Oblimersen alone resulted in some long-term disease-free survival, while combination therapy with cyclophosphamide resulted in long-term disease-free survival with no histological or molecular evidence of lymphoma. Of note, treatment with antisense oligonucleotides lowers the concentration of other chemotherapies required for treatment, decreasing side effects and toxicity.
Small-Molecule Protein Inhibitors (SMIs)
Small-molecule inhibitors (SMIs) are a group of drugs designed to mimic BH3-only proteins to inhibit the action of anti-apoptotic BCL2 proteins. They compete with pro-apoptotic BCL2 to occupy BH3 docking grooves on the surfaces of anti-apoptotic family members, thus functioning as valuable anti-neoplastic drugs. One such drug is Obatoclax (GX15-070) D, a new experimental pan inhibitor of BCL2-family proteins, particularly to MCL1, as many hematologic malignancies depend on this protein for survival. Obatoclax can induce oligomerization of BAK in the mitochondria, interrupting its function, and activate caspases leading to cell death and cell cycle arrest. Obatoclax was shown to overcome drug resistance and potentiate the efficacy of traditional chemotherapeutic agents.
DNA interference (DNAi)
DNAi therapeutic drugs, such as PNT2258, are a class of nucleic acid-based therapy that contain sequences designed against noncoding, non-transcribed regions of genomic DNA upstream of gene transcription initiation sites, thus effectively blocking its transcription. DNAi can interact with genomic DNA leading to an apoptotic cell death cascade by gene silencing. This approach is aimed at blocking BCL2 gene transcription. Evaluations of this technology in preclinical and early clinical studies are very encouraging and strongly support further development of DNAi as cancer therapeutics.
  

Breakpoints

 

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Citation

This paper should be referenced as such :
Mohamed AN
BCL2 (B-Cell Leukemia/Lymphoma 2);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/BCL2ID49.html
History of this paper:
Huret, JL. BCL2 (B-cell leukemia/lymphoma 2). Atlas Genet Cytogenet Oncol Haematol. 1998;2(4):113-114.
http://documents.irevues.inist.fr/bitstream/handle/2042/37449/05-1998-BCL2ID49.pdf


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 22 ]
  3q27 rearrangements (BCL6) in non Hodgkin lymphoma::t(3;Var)(q27;Var) in non Hodgkin lymphoma
Classification of B-cell non-Hodgkin lymphomas (NHL)
Burkitt's lymphoma (BL)
del(13q) in chronic lymphocytic leukemia
Double Hit Lymphoma (DHL)::Triple Hit Lymphoma (THL)
Follicular lymphoma (FL)
i(18)(q10)
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma
HIV-associated lymphomas
Pediatric-type Follicular Lymphoma
t(1;1)(p36;q21) in Non Hodgkin Lymphoma
t(1;14)(q21;q32) FCGR2B/IGH
t(2;18)(q11;q21) AFF3/BCL2
t(4;11)(q21;q23) KMT2A/AFF1
t(7;19)(q34;p13) TRB/LYL1
t(8;14)(q24;q32) IGH/MYC::t(2;8)(p12;q24) IGK/MYC::t(8;22)(q24;q11) IGL/MYC
t(14;15)(q32;q11) IGH/NBEAP1
t(14;18)(q32;q21) IGH/BCL2::t(2;18)(p11;q21) IGK/BCL2::t(18;22)(q21;q11) IGL/BCL2
t(20;21)(q13.2;q22.12) ZFP64/RUNX1
T-cell/histiocyte rich large B-cell lymphoma
+18 or trisomy 18 in lymphoproliferative disorders
Histiocyte-rich B-cell lymphoma


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 9 ]
  Thyroid: Anaplastic (undifferentiated) carcinoma
Neuro-Endocrine/Endocrine System: Carcinoid tumors
Soft Tissues: Desmoid-type fibromatosis
Liver tumors: an overview
Bone: Osteochondroma
Ovary: Choriocarcinoma
Ovary: Epithelial tumors
Penile tumors: an overview
Eye: Posterior uveal melanoma


External links

Nomenclature
HGNC (Hugo)BCL2   990
Cards
AtlasBCL2ID49
Entrez_Gene (NCBI)BCL2  596  BCL2, apoptosis regulator
AliasesBcl-2; PPP1R50
GeneCards (Weizmann)BCL2
Ensembl hg19 (Hinxton)ENSG00000171791 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000171791 [Gene_View]  chr18:63123346-63319380 [Contig_View]  BCL2 [Vega]
ICGC DataPortalENSG00000171791
TCGA cBioPortalBCL2
AceView (NCBI)BCL2
Genatlas (Paris)BCL2
WikiGenes596
SOURCE (Princeton)BCL2
Genetics Home Reference (NIH)BCL2
Genomic and cartography
GoldenPath hg38 (UCSC)BCL2  -     chr18:63123346-63319380 -  18q21.33   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)BCL2  -     18q21.33   [Description]    (hg19-Feb_2009)
EnsemblBCL2 - 18q21.33 [CytoView hg19]  BCL2 - 18q21.33 [CytoView hg38]
Mapping of homologs : NCBIBCL2 [Mapview hg19]  BCL2 [Mapview hg38]
OMIM151430   
Gene and transcription
Genbank (Entrez)AF401211 AI401297 BC027258 DQ891470 DQ894654
RefSeq transcript (Entrez)NM_000633 NM_000657
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)BCL2
Cluster EST : UnigeneHs.150749 [ NCBI ]
CGAP (NCI)Hs.150749
Alternative Splicing GalleryENSG00000171791
Gene ExpressionBCL2 [ NCBI-GEO ]   BCL2 [ EBI - ARRAY_EXPRESS ]   BCL2 [ SEEK ]   BCL2 [ MEM ]
Gene Expression Viewer (FireBrowse)BCL2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)596
GTEX Portal (Tissue expression)BCL2
Human Protein AtlasENSG00000171791-BCL2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP10415   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP10415  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP10415
Splice isoforms : SwissVarP10415
PhosPhoSitePlusP10415
Domaine pattern : Prosite (Expaxy)BCL2_FAMILY (PS50062)    BH1 (PS01080)    BH2 (PS01258)    BH3 (PS01259)    BH4_1 (PS01260)    BH4_2 (PS50063)   
Domains : Interpro (EBI)Apop_reg_Bcl2    Bcl2-like    Bcl2/BclX    Bcl2_BH1_motif_CS    Bcl2_BH2_motif_CS    Bcl2_BH3_motif_CS    Bcl2_BH4    Bcl2_BH4_motif_CS    Blc2_fam   
Domain families : Pfam (Sanger)Bcl-2 (PF00452)    BH4 (PF02180)   
Domain families : Pfam (NCBI)pfam00452    pfam02180   
Domain families : Smart (EMBL)BH4 (SM00265)  
Conserved Domain (NCBI)BCL2
DMDM Disease mutations596
Blocks (Seattle)BCL2
PDB (SRS)1G5M    1GJH    1YSW    2O21    2O22    2O2F    2W3L    2XA0    4AQ3    4IEH    4LVT    4LXD    4MAN    5AGW    5AGX    5FCG    5JSN   
PDB (PDBSum)1G5M    1GJH    1YSW    2O21    2O22    2O2F    2W3L    2XA0    4AQ3    4IEH    4LVT    4LXD    4MAN    5AGW    5AGX    5FCG    5JSN   
PDB (IMB)1G5M    1GJH    1YSW    2O21    2O22    2O2F    2W3L    2XA0    4AQ3    4IEH    4LVT    4LXD    4MAN    5AGW    5AGX    5FCG    5JSN   
PDB (RSDB)1G5M    1GJH    1YSW    2O21    2O22    2O2F    2W3L    2XA0    4AQ3    4IEH    4LVT    4LXD    4MAN    5AGW    5AGX    5FCG    5JSN   
Structural Biology KnowledgeBase1G5M    1GJH    1YSW    2O21    2O22    2O2F    2W3L    2XA0    4AQ3    4IEH    4LVT    4LXD    4MAN    5AGW    5AGX    5FCG    5JSN   
SCOP (Structural Classification of Proteins)1G5M    1GJH    1YSW    2O21    2O22    2O2F    2W3L    2XA0    4AQ3    4IEH    4LVT    4LXD    4MAN    5AGW    5AGX    5FCG    5JSN   
CATH (Classification of proteins structures)1G5M    1GJH    1YSW    2O21    2O22    2O2F    2W3L    2XA0    4AQ3    4IEH    4LVT    4LXD    4MAN    5AGW    5AGX    5FCG    5JSN   
SuperfamilyP10415
Human Protein Atlas [tissue]ENSG00000171791-BCL2 [tissue]
Peptide AtlasP10415
HPRD01045
IPIIPI00020961   IPI00217817   
Protein Interaction databases
DIP (DOE-UCLA)P10415
IntAct (EBI)P10415
FunCoupENSG00000171791
BioGRIDBCL2
STRING (EMBL)BCL2
ZODIACBCL2
Ontologies - Pathways
QuickGOP10415
Ontology : AmiGOprotein polyubiquitination  ossification  ovarian follicle development  metanephros development  branching involved in ureteric bud morphogenesis  behavioral fear response  B cell homeostasis  release of cytochrome c from mitochondria  release of cytochrome c from mitochondria  regulation of cell-matrix adhesion  protease binding  lymphoid progenitor cell differentiation  B cell lineage commitment  response to ischemia  renal system process  protein binding  nucleus  nucleoplasm  cytoplasm  mitochondrion  mitochondrial outer membrane  mitochondrial outer membrane  endoplasmic reticulum  endoplasmic reticulum membrane  cytosol  protein dephosphorylation  melanin metabolic process  regulation of nitrogen utilization  apoptotic process  humoral immune response  cellular response to DNA damage stimulus  actin filament organization  axonogenesis  female pregnancy  cell aging  transcription factor binding  male gonad development  extrinsic apoptotic signaling pathway via death domain receptors  intrinsic apoptotic signaling pathway in response to oxidative stress  response to radiation  response to toxic substance  post-embryonic development  response to iron ion  response to UV-B  response to gamma radiation  regulation of gene expression  negative regulation of autophagy  negative regulation of calcium ion transport into cytosol  regulation of glycoprotein biosynthetic process  mesenchymal cell development  positive regulation of neuron maturation  positive regulation of smooth muscle cell migration  channel activity  membrane  cell growth  channel inhibitor activity  single organismal cell-cell adhesion  peptidyl-serine phosphorylation  peptidyl-threonine phosphorylation  cochlear nucleus development  gland morphogenesis  regulation of transmembrane transporter activity  negative regulation of ossification  positive regulation of cell growth  negative regulation of cell growth  melanocyte differentiation  negative regulation of cell migration  positive regulation of B cell proliferation  hair follicle morphogenesis  axon regeneration  ubiquitin protein ligase binding  regulation of protein stability  nuclear membrane  endoplasmic reticulum calcium ion homeostasis  glomerulus development  negative regulation of cellular pH reduction  negative regulation of myeloid cell apoptotic process  T cell differentiation in thymus  positive regulation of peptidyl-serine phosphorylation  negative regulation of osteoblast proliferation  response to cytokine  response to nicotine  organ growth  positive regulation of multicellular organism growth  B cell proliferation  cellular response to glucose starvation  response to drug  response to drug  response to hydrogen peroxide  identical protein binding  protein homodimerization activity  T cell homeostasis  negative regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of apoptotic process  positive regulation of catalytic activity  myelin sheath  protein complex  CD8-positive, alpha-beta T cell lineage commitment  regulation of protein homodimerization activity  regulation of protein heterodimerization activity  negative regulation of neuron apoptotic process  sequence-specific DNA binding  ear development  regulation of viral genome replication  positive regulation of melanocyte differentiation  negative regulation of retinal cell programmed cell death  regulation of mitochondrial membrane permeability  pore complex  protein heterodimerization activity  focal adhesion assembly  spleen development  thymus development  digestive tract morphogenesis  oocyte development  positive regulation of skeletal muscle fiber development  pigment granule organization  homeostasis of number of cells within a tissue  B cell receptor signaling pathway  response to glucocorticoid  neuron apoptotic process  BH3 domain binding  defense response to virus  protein phosphatase 2A binding  regulation of mitochondrial membrane potential  negative regulation of mitochondrial depolarization  regulation of calcium ion transport  transmembrane transport  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  cellular response to organic substance  cellular response to hypoxia  reactive oxygen species metabolic process  extrinsic apoptotic signaling pathway in absence of ligand  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  negative regulation of G1/S transition of mitotic cell cycle  negative regulation of reactive oxygen species metabolic process  negative regulation of anoikis  negative regulation of apoptotic signaling pathway  negative regulation of extrinsic apoptotic signaling pathway in absence of ligand  negative regulation of intrinsic apoptotic signaling pathway  positive regulation of intrinsic apoptotic signaling pathway  
Ontology : EGO-EBIprotein polyubiquitination  ossification  ovarian follicle development  metanephros development  branching involved in ureteric bud morphogenesis  behavioral fear response  B cell homeostasis  release of cytochrome c from mitochondria  release of cytochrome c from mitochondria  regulation of cell-matrix adhesion  protease binding  lymphoid progenitor cell differentiation  B cell lineage commitment  response to ischemia  renal system process  protein binding  nucleus  nucleoplasm  cytoplasm  mitochondrion  mitochondrial outer membrane  mitochondrial outer membrane  endoplasmic reticulum  endoplasmic reticulum membrane  cytosol  protein dephosphorylation  melanin metabolic process  regulation of nitrogen utilization  apoptotic process  humoral immune response  cellular response to DNA damage stimulus  actin filament organization  axonogenesis  female pregnancy  cell aging  transcription factor binding  male gonad development  extrinsic apoptotic signaling pathway via death domain receptors  intrinsic apoptotic signaling pathway in response to oxidative stress  response to radiation  response to toxic substance  post-embryonic development  response to iron ion  response to UV-B  response to gamma radiation  regulation of gene expression  negative regulation of autophagy  negative regulation of calcium ion transport into cytosol  regulation of glycoprotein biosynthetic process  mesenchymal cell development  positive regulation of neuron maturation  positive regulation of smooth muscle cell migration  channel activity  membrane  cell growth  channel inhibitor activity  single organismal cell-cell adhesion  peptidyl-serine phosphorylation  peptidyl-threonine phosphorylation  cochlear nucleus development  gland morphogenesis  regulation of transmembrane transporter activity  negative regulation of ossification  positive regulation of cell growth  negative regulation of cell growth  melanocyte differentiation  negative regulation of cell migration  positive regulation of B cell proliferation  hair follicle morphogenesis  axon regeneration  ubiquitin protein ligase binding  regulation of protein stability  nuclear membrane  endoplasmic reticulum calcium ion homeostasis  glomerulus development  negative regulation of cellular pH reduction  negative regulation of myeloid cell apoptotic process  T cell differentiation in thymus  positive regulation of peptidyl-serine phosphorylation  negative regulation of osteoblast proliferation  response to cytokine  response to nicotine  organ growth  positive regulation of multicellular organism growth  B cell proliferation  cellular response to glucose starvation  response to drug  response to drug  response to hydrogen peroxide  identical protein binding  protein homodimerization activity  T cell homeostasis  negative regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of apoptotic process  positive regulation of catalytic activity  myelin sheath  protein complex  CD8-positive, alpha-beta T cell lineage commitment  regulation of protein homodimerization activity  regulation of protein heterodimerization activity  negative regulation of neuron apoptotic process  sequence-specific DNA binding  ear development  regulation of viral genome replication  positive regulation of melanocyte differentiation  negative regulation of retinal cell programmed cell death  regulation of mitochondrial membrane permeability  pore complex  protein heterodimerization activity  focal adhesion assembly  spleen development  thymus development  digestive tract morphogenesis  oocyte development  positive regulation of skeletal muscle fiber development  pigment granule organization  homeostasis of number of cells within a tissue  B cell receptor signaling pathway  response to glucocorticoid  neuron apoptotic process  BH3 domain binding  defense response to virus  protein phosphatase 2A binding  regulation of mitochondrial membrane potential  negative regulation of mitochondrial depolarization  regulation of calcium ion transport  transmembrane transport  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  cellular response to organic substance  cellular response to hypoxia  reactive oxygen species metabolic process  extrinsic apoptotic signaling pathway in absence of ligand  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  negative regulation of G1/S transition of mitotic cell cycle  negative regulation of reactive oxygen species metabolic process  negative regulation of anoikis  negative regulation of apoptotic signaling pathway  negative regulation of extrinsic apoptotic signaling pathway in absence of ligand  negative regulation of intrinsic apoptotic signaling pathway  positive regulation of intrinsic apoptotic signaling pathway  
Pathways : BIOCARTACeramide Signaling Pathway [Genes]    IL-7 Signal Transduction [Genes]    Induction of apoptosis through DR3 and DR4/5 Death Receptors [Genes]    Melanocyte Development and Pigmentation Pathway [Genes]    Apoptotic Signaling in Response to DNA Damage [Genes]    IL-2 Receptor Beta Chain in T cell Activation [Genes]    Keratinocyte Differentiation [Genes]    Telomeres, Telomerase, Cellular Aging, and Immortality [Genes]    Role of Mitochondria in Apoptotic Signaling [Genes]    Prion Pathway [Genes]    Regulation of BAD phosphorylation [Genes]    p53 Signaling Pathway [Genes]    Stress Induction of HSP Regulation [Genes]    HIV-I Nef: negative effector of Fas and TNF [Genes]   
Pathways : KEGGNeurodegenerative Disorders    Focal adhesion    Apoptosis    Prion disease    Amyotrophic lateral sclerosis (ALS)    Colorectal cancer   
REACTOMEP10415 [protein]
REACTOME PathwaysR-HSA-844455 [pathway]   
NDEx NetworkBCL2
Atlas of Cancer Signalling NetworkBCL2
Wikipedia pathwaysBCL2
Orthology - Evolution
OrthoDB596
GeneTree (enSembl)ENSG00000171791
Phylogenetic Trees/Animal Genes : TreeFamBCL2
HOVERGENP10415
HOGENOMP10415
Homologs : HomoloGeneBCL2
Homology/Alignments : Family Browser (UCSC)BCL2
Gene fusions - Rearrangements
Fusion : MitelmanAFF3/BCL2 [2q11.2/18q21.33]  [t(2;18)(q11;q21)]  
Fusion : MitelmanATRX/BCL2 [Xq21.1/18q21.33]  [t(X;18)(q21;q21)]  
Fusion : MitelmanIGH/BCL2 [14q32.33/18q21.33]  [t(14;18)(q32;q21)]  [t(3;14;18)(q27;q32;q21)]  
[t(8;14;18)(q24;q32;q21)]  
Fusion : MitelmanIGK/BCL2 [2p11.2/18q21.33]  [t(2;18)(p11;q21)]  
Fusion : MitelmanIGL/BCL2 [22q11.22/18q21.33]  [t(18;22)(q21;q11)]  
Fusion : MitelmanNEDD4L/BCL2 [18q21.31/18q21.33]  [t(18;18)(q21;q21)]  
Fusion: TCGA_MDACCATRX Xq21.1 BCL2 18q21.33 LGG
Fusion: TCGA_MDACCNEDD4L 18q21.31 BCL2 18q21.33 BRCA
Fusion PortalATRX Xq21.1 BCL2 18q21.33 LGG
Fusion PortalNEDD4L 18q21.31 BCL2 18q21.33 BRCA
Fusion : TICdbAFF3 [2q11.2]  -  BCL2 [18q21.33]
Fusion : TICdbBCL2 [18q21.33]  -  Ig []
Fusion : QuiverBCL2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerBCL2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)BCL2
dbVarBCL2
ClinVarBCL2
1000_GenomesBCL2 
Exome Variant ServerBCL2
ExAC (Exome Aggregation Consortium)ENSG00000171791
GNOMAD BrowserENSG00000171791
Genetic variants : HAPMAP596
Genomic Variants (DGV)BCL2 [DGVbeta]
DECIPHERBCL2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisBCL2 
Mutations
ICGC Data PortalBCL2 
TCGA Data PortalBCL2 
Broad Tumor PortalBCL2
OASIS PortalBCL2 [ Somatic mutations - Copy number]
Cancer Gene: CensusBCL2 
Somatic Mutations in Cancer : COSMICBCL2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDBCL2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
LOVD (Leiden Open Variation Database)Pharmacogenomics of Infectious Diseases (PGx_IfD )
BioMutasearch BCL2
DgiDB (Drug Gene Interaction Database)BCL2
DoCM (Curated mutations)BCL2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)BCL2 (select a term)
intoGenBCL2
NCG5 (London)BCL2
Cancer3DBCL2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM151430   
Orphanet8750    13856   
DisGeNETBCL2
MedgenBCL2
Genetic Testing Registry BCL2
NextProtP10415 [Medical]
TSGene596
GENETestsBCL2
Target ValidationBCL2
Huge Navigator BCL2 [HugePedia]
snp3D : Map Gene to Disease596
BioCentury BCIQBCL2
ClinGenBCL2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD596
Chemical/Pharm GKB GenePA25302
Clinical trialBCL2
Miscellaneous
canSAR (ICR)BCL2 (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineBCL2
EVEXBCL2
GoPubMedBCL2
iHOPBCL2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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