BCL2 (Danio rerio)
Description [+]
- Synonyms: BCL2, BCL-2, B-CELL LEUKEMIA/LYMPHOMA 2, ZBLP2
- Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Pisces; Danio rerio
- Short gene description: Bcl2 (B-cell leukemia/lymphoma 2). [Source:UniProtKB/TrEMBL;Acc:Q564A4]
- Family: Bcl-2 family : multidomain Bcl-2
- Process: apoptosis,
- Pathways: intrinsic pathway, pre-mitochondrial signaling events,
- Criteria: manually curated
- Curator comment: Ectopic expression of Bcl2 in zebrafish embryos inhibits apoptosis induced by multiple stimuli including death receptors [16888647], ectopic expression of several pro-apoptotic Bcl2 family members [16888646], and gamma-irradiation [16888646]. full-length zebrafish bcl2 protein binds strongly to the BH3 domain peptide from zebrafish bim, binds weakly to bida, bad, and bbc3, and does not bind at all to pmaip1 [18404156]. Zebrafish Bcl2 promotes survival following growth factor withdrawal in murine FL5.12 cells and binds directly to human Bim, Bax, and Puma in this context [18510930].
- Human ortholog(s): BCL2
- WIKI: BCL2-D_rerio
References [+]
- Delineation of the cell-extrinsic apoptosis pathway in the zebrafish.
- Eimon PM, Kratz E, Varfolomeev E, Hymowitz SG, Stern H, Zha J, Ashkenazi A
- The mammalian extrinsic apoptosis pathway is triggered by Fas ligand (FasL) and Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL). Ligand binding to cognate receptors activates initiator caspases directly in a death-inducing signaling complex. In Drosophila, TNF ligand binding activates initiator caspases indirectly, through JNK. We characterized the extrinsic pathway in zebrafish to determine how it operates in a nonmammalian vertebrate. We identified homologs of FasL and Apo2L/TRAIL, their receptors, and other components of the cell death machinery. Studies with three Apo2L/TRAIL homologs demonstrated that they bind the receptors zHDR (previously linked to hematopoiesis) and ovarian TNFR (zOTR). Ectopic expression of these ligands during embryogenesis induced apoptosis in erythroblasts and notochord cells. Inhibition of zHDR, zOTR, the adaptor zFADD, or caspase-8-like proteases blocked ligand-induced apoptosis, as did antiapoptotic Bcl-2 family members. Thus, the extrinsic apoptosis pathway in zebrafish closely resembles its mammalian counterpart and cooperates with the intrinsic pathway to trigger tissue-specific apoptosis during embryogenesis in response to ectopic Apo2L/TRAIL expression. Cell Death Differ. 2006 Oct;13(10):1619-30. Epub 2006 Aug 4.
- Functional characterization of the Bcl-2 gene family in the zebrafish.
- Kratz E, Eimon PM, Mukhyala K, Stern H, Zha J, Strasser A, Hart R, Ashkenazi A
- Members of the Bcl-2 protein family control the intrinsic apoptosis pathway. To evaluate the importance of this family in vertebrate development, we investigated it in the zebrafish (Danio rerio). We found that the zebrafish genome encodes structural and functional homologs of most mammalian Bcl-2 family members, including multi-Bcl-2-homology (BH) domain proteins and BH3-only proteins. Apoptosis induction by gamma-irradiation required zBax1 and zPuma, and could be prevented by overexpression of homologs of prosurvival Bcl-2 family members. Surprisingly, zebrafish Bax2 (zBax2) was homologous to mammalian Bax by sequence and synteny, yet demonstrated functional conservation with human Bak. Morpholino knockdown of both zMcl-1a and zMcl-1b revealed their critical role in early embryonic zebrafish development, and in the modulation of apoptosis activation through the extrinsic pathway. These data indicate substantial functional similarity between zebrafish and mammalian Bcl-2 family members, and establish the zebrafish as a relevant model for studying the intrinsic apoptosis pathway. Cell Death Differ. 2006 Oct;13(10):1631-40. Epub 2006 Aug 4.
- BIM and other BCL-2 family proteins exhibit cross-species conservation of function between zebrafish and mammals.
- Jette CA, Flanagan AM, Ryan J, Pyati UJ, Carbonneau S, Stewart RA, Langenau DM, Look AT, Letai A
- Here we investigate the function of zebrafish Bcl-2 family proteins and demonstrate important conservation of function across zebrafish and mammalian systems. We have isolated a zebrafish ortholog of mammalian BIM and show that it is the most toxic of the zebrafish BH3-only genes examined, sharing this characteristic with the mammalian BIM gene. The zebrafish bad gene shows a complete lack of embryonic lethality, but like mammalian BAD, its pro-apoptotic activity is regulated through phosphorylation of critical serines. We also found that the pattern of mitochondrial dysfunction observed by zebrafish BH3 domain peptides in a mammalian cytochrome c release assay recapitulates the pattern of embryonic lethality induced by the respective mRNA injections in vivo. In contrast to zebrafish Bim, Bid exhibited only weak binding to zebrafish Bcl-2 and moderate-to-weak overall lethality in zebrafish embryos and isolated mitochondria. Given that zebrafish Bcl-2 binds strongly to mammalian BID and BIM peptides and proteins, the protein identified as the zebrafish Bid ortholog has different properties than mammalian BID. Overall, our results demonstrate the high degree of functional conservation between zebrafish and mammalian Bcl-2 family proteins, thus validating the zebrafish as a model system to further dissect the molecular mechanisms that regulate apoptosis in future forward genetic and chemical modifier screens. Cell Death Differ. 2008 Jun;15(6):1063-72. Epub 2008 Apr 11.
- Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3.
- Sidi S,Sanda T,Kennedy RD,Hagen AT,Jette CA,Hoffmans R,Pascual J,Imamura S,Kishi S,Amatruda JF,Kanki JP,Green DR,D Andrea AA,Look AT
- Evasion of DNA damage-induced cell death, via mutation of the p53 tumor suppressor or overexpression of prosurvival Bcl-2 family proteins, is a key step toward malignant transformation and therapeutic resistance. We report that depletion or acute inhibition of checkpoint kinase 1 (Chk1) is sufficient to restore gamma-radiation-induced apoptosis in p53 mutant zebrafish embryos. Surprisingly, caspase-3 is not activated prior to DNA fragmentation, in contrast to classical intrinsic or extrinsic apoptosis. Rather, an alternative apoptotic program is engaged that cell autonomously requires atm (ataxia telangiectasia mutated), atr (ATM and Rad3-related) and caspase-2, and is not affected by p53 loss or overexpression of bcl-2/xl. Similarly, Chk1 inhibitor-treated human tumor cells hyperactivate ATM, ATR, and caspase-2 after gamma-radiation and trigger a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl-2. The evolutionarily conserved Chk1-suppressed pathway defines a novel apoptotic process, whose responsiveness to Chk1 inhibitors and insensitivity to p53 and BCL2 alterations have important implications for cancer therapy. Cell. 2008 May 30;133(5):864-77.
- References from Human ortholog(s):
- Oncogenic potential of bcl-2 demonstrated by gene transfer.
- Reed JC, Cuddy M, Slabiak T, Croce CM, Nowell PC
- Follicular lymphoma is the most common human B-cell malignancy in the United States and Western Europe. Most of the tumours contain t(14;18) chromosome translocations involving the human bcl-2 gene. Translocation of bcl-2 sequences from chromosome 18 into the transcriptionally active immunoglobulin locus at chromosome band 14q32 in B cells deregulates bcl-2 gene expression, resulting in the accumulation of high levels of bcl-2 messenger. Human bcl-2 transcripts generate two proteins, p26 bcl-2-alpha and p22 bcl-2-beta, by virtue of alternative splice-site selection. Both proteins have in common their first 196 NH2-terminal amino acids but share little similarity with other sequences in a data bank. Although the biological and biochemical functions of bcl-2 are unknown, recent subcellular localization studies indicate that p26 bcl-2-alpha associates with cellular membranes, consistent with a stretch of hydrophobic amino acids in its carboxy terminus. The bcl-2 gene may represent a novel oncogene having no known retroviral counterpart. Here we demonstrate the oncogenic potential of bcl-2 through a gene transfer approach. Nature. 1988 Nov 17;336(6196):259-61.
Structure & Sequence [+]
Pfam domains:
(Pfam is a large collection of protein families.)
| Source | Domain Name | Start | End |
|---|---|---|---|
| PFAM A | BH4 | 5 | 31 |
| PFAM A | Bcl-2 | 86 | 184 |
Protein sequence [+]
bcl2 | Danio rerio | 7955 | length:228
MANEISYDNRNIVEKYLKHKLSKRGYVWKCQSSAEEDDTFNKAVEESSPNSDRRLQAPSA
GGGNNSECLIARVTRSDPHLRLYRVLRDAGDEIERIYQREFEEMSQQMVFNPNSAQRSFL
TVAEELFRDGVNWGRIIAFFEFGGTMCVESVNREMASQVDNIAHWMTDYLNGPLENWIEE
NGGWDAFVEMYGQQRDSVFHPFSYLTKVLGLAALGLAGVTIGAFFAQK
GGGNNSECLIARVTRSDPHLRLYRVLRDAGDEIERIYQREFEEMSQQMVFNPNSAQRSFL
TVAEELFRDGVNWGRIIAFFEFGGTMCVESVNREMASQVDNIAHWMTDYLNGPLENWIEE
NGGWDAFVEMYGQQRDSVFHPFSYLTKVLGLAALGLAGVTIGAFFAQK
Structure links:
Evolution [+]
View protein alignment and tree with Jalview:
Explore tree at phylomeDB: Click here.
Homologs list [+]
| Name | Relationship | Species |
|---|---|---|
| BCL2_CHICK | orthology | Chicken |
| BCL2 | orthology | Chimpanzee |
| Q462R3_BOVIN | orthology | Cow |
| BCL2 | orthology | Dog |
| BCL2 | orthology | Fugu |
| BCL2 | orthology | Gasterosteus |
| BCL2 | orthology | Gorilla |
| BCL2 | orthology | Horse |
| BCL2 | orthology | Human |
| BCL2 | orthology | Lyzard |
| BCL2 | orthology | Macaca |
| BCL2 | orthology | Medaka |
| BCL2 | orthology | Monodelphis |
| Bcl2 | orthology | Mouse |
| BCL2 | orthology | Orangutan |
| Bcl2 | orthology | Rat |
| BCL2 | orthology | Tetraodon |
| BCL2 | orthology | Xenopus |
| BCL2 | orthology | Zebra finch |
| A_aegypti_AAEL001515-PA | paralogy | Aedes |
| A_aegypti_AAEL001521-PA | paralogy | Aedes |
| Q2PHG8_ANOGA | paralogy | Anopheles |
| BOK_CHICK | paralogy | Chicken |
| BCLX_CHICK | paralogy | Chicken |
| NP_001026091.1 | paralogy | Chicken |
| BAX | paralogy | Chimpanzee |
| BCL2L1 | paralogy | Chimpanzee |
| XR_024448.1 | paralogy | Chimpanzee |
| BCL2A1 | paralogy | Chimpanzee |
| MCL1 | paralogy | Chimpanzee |
| BCL2L2 | paralogy | Chimpanzee |
| C_intestinalis_ENSCINP00000000654 | paralogy | Ciona |
| NP_001092676.1 | paralogy | Cow |
| BCLW_BOVIN | paralogy | Cow |
| IPI00908204.1 | paralogy | Cow |
| NP_001071386.1 | paralogy | Cow |
| B2LA1_BOVIN | paralogy | Cow |
| NP_001070954.1 | paralogy | Cow |
| BAX_BOVIN | paralogy | Cow |
| NP_001018644.1 | paralogy | Dog |
| NP_001003072.1 | paralogy | Dog |
| MCL1_CANFA | paralogy | Dog |
| BCL2A1 | paralogy | Dog |
| debcl | paralogy | Fly |
| Buffy | paralogy | Fly |
| BAX | paralogy | Fugu |
| BCL2L1 (4 of 6) | paralogy | Fugu |
| MCL1 | paralogy | Fugu |
| BCL2L1 (6 of 6) | paralogy | Fugu |
| T_rubripes_ENSTRUP00000006891 | paralogy | Fugu |
| BCL2L1 (5 of 6) | paralogy | Fugu |
| BCL2L1 (1 of 6) | paralogy | Fugu |
| BCL2L1 (2 of 6) | paralogy | Fugu |
| BCL2L1 (3 of 6) | paralogy | Fugu |
| G_aculeatus_ENSGACP00000021797 | paralogy | Gasterosteus |
| BCL2L1 (1 of 2) | paralogy | Gasterosteus |
| BOK (1 of 2) | paralogy | Gasterosteus |
| BCL2L1 (2 of 2) | paralogy | Gasterosteus |
| MCL1 | paralogy | Gasterosteus |
| BOK (2 of 2) | paralogy | Gasterosteus |
| BAX | paralogy | Gasterosteus |
| G_aculeatus_ENSGACP00000018978 | paralogy | Gasterosteus |
| BCL2L2 | paralogy | Gorilla |
| BCL2A1 | paralogy | Gorilla |
| BAX | paralogy | Gorilla |
| BOK | paralogy | Gorilla |
| MCL1 | paralogy | Gorilla |
| BAK1 | paralogy | Gorilla |
| BCL2A1 | paralogy | Horse |
| BCL2L2 | paralogy | Horse |
| BCL2L1 | paralogy | Horse |
| MCL1 | paralogy | Horse |
| BAK1 | paralogy | Horse |
| BCL2L2 | paralogy | Human |
| BCL2A1 | paralogy | Human |
| BAX | paralogy | Human |
| BOK | paralogy | Human |
| MCL1 | paralogy | Human |
| BAK1 | paralogy | Human |
| BCL2L1 | paralogy | Human |
| BOK | paralogy | Lyzard |
| MCL1 | paralogy | Lyzard |
| BCL2L1 | paralogy | Lyzard |
| BCL2A1 | paralogy | Lyzard |
| BAK1 | paralogy | Lyzard |
| BAX | paralogy | Lyzard |
| BCL2L1 | paralogy | Macaca |
| MCL1 | paralogy | Macaca |
| BAK1 | paralogy | Macaca |
| BCL2L2 | paralogy | Macaca |
| BCL2A1 | paralogy | Macaca |
| BAX | paralogy | Macaca |
| BOK | paralogy | Macaca |
| BAX | paralogy | Medaka |
| O_latipes_ENSORLP00000015978 | paralogy | Medaka |
| BCL2L1 | paralogy | Medaka |
| MCL1 | paralogy | Medaka |
| M_domestica_ENSMODP00000005598 | paralogy | Monodelphis |
| BAX | paralogy | Monodelphis |
| BAK1 | paralogy | Monodelphis |
| BOK | paralogy | Monodelphis |
| MCL1 | paralogy | Monodelphis |
| BCL2A1 | paralogy | Monodelphis |
| BCL2L1 | paralogy | Monodelphis |
| M_domestica_ENSMODP00000037249 | paralogy | Monodelphis |
| Bcl2l2 | paralogy | Mouse |
| Bok | paralogy | Mouse |
| Bax | paralogy | Mouse |
| Mcl1 | paralogy | Mouse |
| Bak1 | paralogy | Mouse |
| Bcl2l1 | paralogy | Mouse |
| MCL1 | paralogy | Orangutan |
| P_pygmaeus_ENSPPYP00000006150 | paralogy | Orangutan |
| BCL2A1 | paralogy | Orangutan |
| BCL2L1 | paralogy | Orangutan |
| BOK | paralogy | Orangutan |
| BOK | paralogy | Ornithorhynchus |
| BCL2L2 | paralogy | Ornithorhynchus |
| BAK1 | paralogy | Rabbit |
| Q9MYW4_RABIT | paralogy | Rabbit |
| BAX | paralogy | Rabbit |
| BCL2A1 | paralogy | Rabbit |
| MCL1 | paralogy | Rabbit |
| Bak1 | paralogy | Rat |
| Bok | paralogy | Rat |
| Bax | paralogy | Rat |
| Bcl2a1 | paralogy | Rat |
| BCLX_RAT | paralogy | Rat |
| R_norvegicus_ENSRNOP00000052069 | paralogy | Rat |
| RGD1565822_predicted | paralogy | Rat |
| T_nigroviridis_ENSTNIP00000002209 | paralogy | Tetraodon |
| BOK (1 of 2) | paralogy | Tetraodon |
| BCL2L1 (1 of 3) | paralogy | Tetraodon |
| BCL2L1 (2 of 3) | paralogy | Tetraodon |
| BCL2L1 (3 of 3) | paralogy | Tetraodon |
| T_nigroviridis_ENSTNIP00000017211 | paralogy | Tetraodon |
| bcl2l2 | paralogy | Xenopus |
| bax | paralogy | Xenopus |
| BCL2L1 | paralogy | Xenopus |
| BAK1 | paralogy | Xenopus |
| BOK | paralogy | Zebra finch |
| BCL2L1 | paralogy | Zebra finch |
| BAX | paralogy | Zebra finch |
| mcl1b | paralogy | Zebrafish |
| mcl1a | paralogy | Zebrafish |
| baxa | paralogy | Zebrafish |
| D_rerio_ENSDARP00000037180 | paralogy | Zebrafish |
| boka | paralogy | Zebrafish |
| bcl2l | paralogy | Zebrafish |
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Gene Ontology [+]
| GO id | Name | Ontology type | Evidence |
|---|---|---|---|
| GO:0042981 | regulation of apoptosis | biological_proccess | IEA |
| GO:0043066 | negative regulation of apoptosis | biological_proccess | IGI |
| GO:0043154 | negative regulation of caspase activity | biological_proccess | IDA |
Check GO Evidence Codes here
KEGG Pathways [+]
Information from other databases [+]
- Gene info from ZFIN [?] ZDB-GENE-051012-1
- Ensembl genome browser [?] : ENSDARG00000025613
- Expression info from Arrayexpress [?] : ENSDARG00000025613
- Protein expression from Protein Atlas: [?] ENSDARG00000025613
- Community gene edition from Wikigenes: [?] 570772
- entrezgene: 570772
- refseq_dna: NM_001030253
- refseq_peptide: NP_001025424
Click on [?] for more information.
