Apoptosis Database

Description [+]

Synonyms: BAD, BCL2-ANTAGONIST OF CELL DEATH, WU:FA01B12, PROAPOPTOTIC BH3-ONLY PROTEIN, FA01B12, WU:FA01B12, WU:FA96D04
Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Pisces; Danio rerio
Short gene description: BCL2-antagonist of cell death [Source:RefSeq_peptide;Acc:NP_571654]
Family: Bcl-2 family : BH3-only
Process: apoptosis,
Pathways: intrinsic pathway,
Criteria: manually curated
Curator comment: Overexpression of Zebrafish Bad induces apoptosis.
Human ortholog(s): BAD
WIKI: BAD-D_rerio

References [+]

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.

Cloning of zebrafish BAD, a BH3-only proapoptotic protein, whose overexpression leads to apoptosis in COS-1 cells and zebrafish embryos.
Hsieh YC, Chang MS, Chen JY, Yen JJ, Lu IC, Chou CM, Huang CJ
The BH3-only proapoptotic protein, BAD, was cloned from zebrafish embryos and its properties were characterized. Zebrafish BAD (zBAD) is a protein with 147 amino acids that contains a BH3 domain and a putative 14-3-3 binding site with the sequence of RPRSRS(84)AP, corresponding to S(136) in mouse BAD (mBAD). zBAD shares 34%, 28%, and 29% amino acid sequence identity to the human, mouse, and rat BAD, respectively. RT-PCR analysis revealed that the expression of zBAD gene is found in various parts of zebrafish tissues. The treatment with the z-VAD fmk, a broad-range caspase inhibitor, in COS-1 cells significantly increased the expression of zebrafish BAD fusion proteins (GFP-zBAD and HA-zBAD), indicating that zebrafish BAD fusion proteins may be cleaved by caspase(s). zBAD was shown to induce apoptosis when it was overexpressed in COS-1 cells. In addition, zBAD was also expressed in muscle cells under the muscle-specific promoter from zebrafish alpha-actin gene. Abnormality in the skeletal muscles and the loss of green fluorescence signal in the same region were observed. Taken together, our results indicate that zBAD could induce apoptosis in vitro and in vivo and may have biological implications in apoptosis during zebrafish development. Biochem Biophys Res Commun. 2003 May 16;304(4):667-75.

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.

References from Human ortholog(s):

Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death.
Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ
To extend the mammalian cell death pathway, we screened for further Bcl-2 interacting proteins. Both yeast two-hybrid screening and lambda expression cloning identified a novel interacting protein, Bad, whose homology to Bcl-2 is limited to the BH1 and BH2 domains. Bad selectively dimerized with Bcl-xL as well as Bcl-2, but not with Bax, Bcl-xs, Mcl-1, A1, or itself. Bad binds more strongly to Bcl-xL than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-xL, but not that of Bcl-2. When Bad dimerized with Bcl-xL, Bax was displaced and apoptosis was restored. When approximately half of Bax was heterodimerized, death was inhibited. The susceptibility of a cell to a death signal is determined by these competing dimerizations in which levels of Bad influence the effectiveness of Bcl-2 versus Bcl-xL in repressing death. Cell. 1995 Jan 27;80(2):285-91.

Structure & Sequence [+]

Source	Domain Name	Start	End
PFAM A	Bcl-2_BAD	4	147

Evolution [+]

Name	Relationship	Species
BAD	orthology	Chimpanzee
NP_001030536.1	orthology	Cow
Q45KI9_CANFA	orthology	Dog
BAD	orthology	Fugu
BAD	orthology	Gasterosteus
BAD	orthology	Gorilla
BAD	orthology	Horse
BAD	orthology	Human
BAD	orthology	Macaca
BAD	orthology	Medaka
Bad	orthology	Mouse
BAD	orthology	Orangutan
Bad_v2	orthology	Rat
BAD	orthology	Tetraodon

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0006917	induction of apoptosis	biological_proccess	IDA
GO:0043065	positive regulation of apoptosis	biological_proccess	IGI
GO:0005515	protein binding	mollecular_function	IPI
GO:0005575	cellular_component	cell_component	ND

KEGG Pathways [+]

Information from other databases [+]

BAD (Danio rerio)