Bcl-2-associated death promoter: Difference between revisions

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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
{{Infobox protein family
| update_page = yes
| Symbol = Bcl-2_BAD
| require_manual_inspection = no
| Name = Pro-apoptotic Bcl-2 protein, BAD
| update_protein_box = yes
| image = PDB 1g5j EBI.jpg
| update_summary = no
| width =
| update_citations = yes
| caption = complex of bcl-xl with peptide from bad
| Pfam = PF10514
| Pfam_clan =
| InterPro = IPR018868
| SMART =
| PROSITE =
| MEROPS =
| SCOP =
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}
}}
The '''Bcl-2-associated death promoter''' ('''BAD''') [[protein]] is a [[apoptosis|pro-apoptotic]] member of the [[Bcl-2]] gene family which is involved in initiating [[apoptosis]]. BAD is a member of the [[BH3-only family]]
,<ref name="adachi">{{cite journal | vauthors = Adachi M, Imai K | title = The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2 | journal = Cell Death Differ. | volume = 9 | issue = 11 | pages = 1240–7 | year = 2002 | pmid = 12404123 | doi = 10.1038/sj.cdd.4401097 | url = http://www.nature.com/cdd/journal/v9/n11/abs/4401097a.html }}</ref> a subfamily of the [[Bcl-2|Bcl-2 family]]. It does not contain a [[C-terminal]] transmembrane [[protein domain|domain]] for outer [[mitochondrial membrane]] and [[nuclear envelope]] targeting, unlike most other members of the [[Bcl-2|Bcl-2 family]].<ref name="sheau">{{cite journal | vauthors = Hsu SY, Kaipia A, Zhu L, Hsueh AJ | title = Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11 | journal = Mol. Endocrinol. | volume = 11 | issue = 12 | pages = 1858–67 | year = 1997 | pmid = 9369453 | doi = 10.1210/me.11.12.1858 | url = http://mend.endojournals.org/cgi/content/full/11/12/1858}}</ref> After activation, it is able to form a [[heterodimer]] with anti-apoptotic proteins and prevent them from stopping apoptosis.


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Mechanism of action ==
{{GNF_Protein_box
[[Bcl-2-associated X protein|Bax]]/[[Bcl-2 homologous antagonist killer|Bak]] are believed to initiate apoptosis by forming a pore in the mitochondrial outer membrane that allows [[cytochrome c]] to escape into the cytoplasm and activate the pro-apoptotic caspase cascade.  The anti-apoptotic [[Bcl-2]] and [[Bcl-xL]] proteins inhibit cytochrome c release through the mitochondrial pore and also inhibit activation of the cytoplasmic caspase cascade by cytochrome c.<ref>Helmreich, E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 238-43</ref>
| image = 
| image_source =
| PDB =  
| Name = BCL2-antagonist of cell death
| HGNCid = 936
| Symbol = BAD
| AltSymbols =; BBC2; BCL2L8
| OMIM = 603167
| ECnumber =
| Homologene = 3189
| MGIid = 1096330
| GeneAtlas_image1 = PBB_GE_BAD_1861_at_tn.png
| GeneAtlas_image2 = PBB_GE_BAD_209364_at_tn.png
| Function = {{GNF_GO|id=GO:0005515 |text = protein binding}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0005741 |text = mitochondrial outer membrane}}
| Process = {{GNF_GO|id=GO:0006007 |text = glucose catabolic process}} {{GNF_GO|id=GO:0008624 |text = induction of apoptosis by extracellular signals}} {{GNF_GO|id=GO:0008632 |text = apoptotic program}} {{GNF_GO|id=GO:0042593 |text = glucose homeostasis}} {{GNF_GO|id=GO:0042981 |text = regulation of apoptosis}} {{GNF_GO|id=GO:0045579 |text = positive regulation of B cell differentiation}} {{GNF_GO|id=GO:0045582 |text = positive regulation of T cell differentiation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 572
    | Hs_Ensembl = ENSG00000002330
    | Hs_RefseqProtein = NP_004313
    | Hs_RefseqmRNA = NM_004322
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 11
    | Hs_GenLoc_start = 63793878
    | Hs_GenLoc_end = 63808740
    | Hs_Uniprot = Q92934
    | Mm_EntrezGene = 12015
    | Mm_Ensembl = ENSMUSG00000024959
    | Mm_RefseqmRNA = NM_007522
    | Mm_RefseqProtein = NP_031548
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 19
    | Mm_GenLoc_start = 7008905
    | Mm_GenLoc_end = 7018937
    | Mm_Uniprot = Q3TFU7
  }}
}}
The '''Bcl-2-associated death promoter''' (BAD) [[protein]] is a [[apoptosis|pro-apoptotic]] member of the [[Bcl-2]] gene family which is involved in initiating [[apoptosis]]. It does not contain a [[C-terminal]] transmembrane [[protein domain|domain]] for outer [[mitochondrial membrane]] and [[nuclear envelope]] targeting, unlike most other members of the Bcl-2 family
<ref name="sheau">{{cite journal | author=Sheau Yu Hsu, ''et al.''| title=Interference of BAD (Bcl-xL/Bcl-2-Associated Death Promoter)-Induced Apoptosis in Mammalian Cells by 14–3-3 Isoforms and P11| journal=Molecular Endocrinology| year=1997| volume=11| issue=12| page=1858-1867| url=http://mend.endojournals.org/cgi/content/full/11/12/1858}}</ref>.
Pro-apoptotic activation of this protein occurs through [[phosphorylation]]<ref name="entrez">{{Cite web|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=572|title=Entrez Gene entry for BAD|accessdate=[[2006-12-19]]|publisher=NCBI}}</ref>. After activation, it is able to form a [[heterodimer]] with anti-apoptotic proteins and prevent them from stopping apoptosis.
 
BAD is a member of the [[BH3-only family]]
<ref name="adachi">{{cite journal | author=Adachi M. and Imai K. | title=The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2|journal=Cell death and differentiation |year=2002 |volume=9 |issue=11 |page=1240-1247| url=http://www.nature.com/cdd/journal/v9/n11/abs/4401097a.html}}</ref>, a subfamily of the [[Bcl-2|Bcl-2 family]].
 
The Bcl-2-associated death promoter (BAD) protein is a member of the Bcl-2 gene family.  Some members of this family are pro-apoptotic (e.g., Bax, Bak) while others are anti-apoptotic (e.g., Bcl-2, Bcl-xL).  Bax/Bak are believed to initiate apoptosis by forming a pore in the mitochondrial outer membrane that allows cytochrome c to escape into the cytoplasm and activate the pro-apoptotic caspase cascade.  The anti-apoptotic Bcl proteins inhibit cytochrome c release through the mitochondrial pore and also inhibit activation of the cytoplasmic caspase cascade by cytochrome c.<ref>Helmreich, E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 238-43</ref>


BAD does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2 family [1]. BAD is a member of the BH3-only family [3], a subfamily of the Bcl-2 family.
Dephosphorylated BAD forms a heterodimer with [[Bcl-2]] and [[Bcl-xL]], inactivating them and thus allowing [[Bcl-2-associated X protein|Bax]]/[[Bcl-2 homologous antagonist killer|Bak]]-triggered apoptosis. When BAD is phosphorylated by [[AKT|Akt/protein kinase B]] (triggered by PIP<sub>3</sub>), it forms the BAD-([[14-3-3]])protein heterodimer.  This leaves [[Bcl-2]] free to inhibit [[Bcl-2-associated X protein|Bax]]-triggered apoptosis.<ref>E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 242</ref>  BAD phosphorylation is thus anti-apoptotic, and BAD dephosphorylation (e.g., by Ca<sup>2+</sup>-stimulated [[Calcineurin]]) is pro-apoptotic.  The latter may be involved in neural diseases such as schizophrenia.<ref>Foster, T.C. et al. (2001) J. Neurosci. 21, 4066-4073, "Calcineurin Links Ca++ Dysregulation with Brain Aging"(</ref>


Dephosphorylated BAD forms a heterodimer with Bcl-2 and Bcl-xL, inactivating them and thus allowing Bax/Bak-triggered apoptosis.  On the other hand, BAD phosphorylation by Akt/protein kinase B (triggered by PIP<sub>3</sub>), causes formation of the BAD-(14-3-3)protein heterodimer.  This leaves Bcl-2 free to inhibit Bax-triggered apoptosis.<ref>E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 242</ref> BAD phosphorylation is thus anti-apoptotic, and BAD dephosphorylation (e.g., by Ca++-stimulated Calcineurin) is pro-apoptotic.  The latter may be involved in neural diseases such as schizophrenia.<ref>Foster, T.C. et al (2001) J. Neurosci. 21, 4066-4073, "Calcineurin Links Ca++ Dysregulation with Brain Aging"(</ref>
== Interactions ==
[[Image:Signal transduction pathways.svg|300px|thumb|left|Overview of signal transduction pathways involved with [[apoptosis]].]]
Bcl-2-associated death promoter has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[BCL2-like 1 (gene)|BCL2L1]],<ref name = pmid15694340>{{cite journal | vauthors = Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC | title = Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function | journal = Mol. Cell | volume = 17 | issue = 3 | pages = 393–403 | date = February 2005 | pmid = 15694340 | doi = 10.1016/j.molcel.2004.12.030 }}</ref><ref name = pmid15705582>{{cite journal | vauthors = Jin Z, Xin M, Deng X | title = Survival function of protein kinase C{iota} as a novel nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-activated bad kinase | journal = J. Biol. Chem. | volume = 280 | issue = 16 | pages = 16045–52 | date = April 2005 | pmid = 15705582 | doi = 10.1074/jbc.M413488200 }}</ref><ref name = pmid9824152>{{cite journal | vauthors = Strobel T, Tai YT, Korsmeyer S, Cannistra SA | title = BAD partly reverses paclitaxel resistance in human ovarian cancer cells | journal = Oncogene | volume = 17 | issue = 19 | pages = 2419–27  | date = November 1998 | pmid = 9824152 | doi = 10.1038/sj.onc.1202180 }}</ref><ref name = pmid12137781>{{cite journal | vauthors = Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M | title = Development of a high-throughput fluorescence polarization assay for Bcl-x(L) | journal = Anal. Biochem. | volume = 307 | issue = 1 | pages = 70–5  | date = August 2002 | pmid = 12137781 | doi = 10.1016/S0003-2697(02)00028-3 }}</ref><ref name = pmid12115603>{{cite journal | vauthors = Ayllón V, Cayla X, García A, Fleischer A, Rebollo A | title = The anti-apoptotic molecules Bcl-xL and Bcl-w target protein phosphatase 1alpha to Bad | journal = Eur. J. Immunol. | volume = 32 | issue = 7 | pages = 1847–55 | date = July 2002 | pmid = 12115603 | doi = 10.1002/1521-4141(200207)32:7<1847::AID-IMMU1847>3.0.CO;2-7 }}</ref><ref name = pmid10620799>{{cite journal | vauthors = Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG | title = Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis | journal = Nat. Cell Biol. | volume = 2 | issue = 1 | pages = 1–6  | date = January 2000 | pmid = 10620799 | doi = 10.1038/71316 }}</ref><ref name = pmid7834748>{{cite journal | vauthors = Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ | title = Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death | journal = Cell | volume = 80 | issue = 2 | pages = 285–91  | date = January 1995 | pmid = 7834748 | doi = 10.1016/0092-8674(95)90411-5 }}</ref><ref name = pmid11206074>{{cite journal | vauthors = Petros AM, Nettesheim DG, Wang Y, Olejniczak ET, Meadows RP, Mack J, Swift K, Matayoshi ED, Zhang H, Thompson CB, Fesik SW | title = Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies | journal = Protein Sci. | volume = 9 | issue = 12 | pages = 2528–34  | date = Dec 2000 | pmid = 11206074 | pmc = 2144516 | doi = 10.1110/ps.9.12.2528 }}</ref><ref name = pmid11494146>{{cite journal | vauthors = Chattopadhyay A, Chiang CW, Yang E | title = BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest | journal = Oncogene | volume = 20 | issue = 33 | pages = 4507–18  | date = July 2001 | pmid = 11494146 | doi = 10.1038/sj.onc.1204584 }}</ref><ref name = pmid9389483>{{cite journal | vauthors = Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y | title = Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy | journal = Nature | volume = 390 | issue = 6658 | pages = 413–7  | date = November 1997 | pmid = 9389483 | doi = 10.1038/37144 }}</ref><ref name = pmid11077446>{{cite journal | vauthors = Komatsu K, Wharton W, Hang H, Wu C, Singh S, Lieberman HB, Pledger WJ, Wang HG | title = PCNA interacts with hHus1/hRad9 in response to DNA damage and replication inhibition | journal = Oncogene | volume = 19 | issue = 46 | pages = 5291–7  | date = November 2000 | pmid = 11077446 | doi = 10.1038/sj.onc.1203901 }}</ref>
* [[BCL2-related protein A1|BCL2A1]],<ref name = pmid15694340/><ref name = pmid11483855/>
* [[BCL2L2]],<ref name = pmid15694340/><ref name = pmid12115603/><ref name = pmid11483855>{{cite journal | vauthors = Bae J, Hsu SY, Leo CP, Zell K, Hsueh AJ | title = Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis | journal = Apoptosis | volume = 6 | issue = 5 | pages = 319–30  | date = October 2001 | pmid = 11483855 | doi = 10.1023/A:1011319901057 }}</ref><ref name = pmid10381646>{{cite journal | vauthors = Holmgreen SP, Huang DC, Adams JM, Cory S | title = Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members | journal = Cell Death Differ. | volume = 6 | issue = 6 | pages = 525–32 | date = June 1999 | pmid = 10381646 | doi = 10.1038/sj.cdd.4400519 }}</ref>
* [[Bcl-2]],<ref name = pmid15694340/><ref name = pmid7834748/>
* [[MCL1]]<ref name = pmid15694340/><ref name = pmid11483855/>
* [[S100A10]],<ref name = pmid9369453/>
* [[YWHAQ]],<ref name = pmid15694340/><ref name = pmid9369453>{{cite journal | vauthors = Hsu SY, Kaipia A, Zhu L, Hsueh AJ | title = Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11 | journal = Mol. Endocrinol. | volume = 11 | issue = 12 | pages = 1858–67  | date = November 1997 | pmid = 9369453 | doi = 10.1210/me.11.12.1858 }}</ref>  and
* [[YWHAZ]].<ref name = pmid11410287>{{cite journal | vauthors = Yang H, Masters SC, Wang H, Fu H | title = The proapoptotic protein Bad binds the amphipathic groove of 14-3-3zeta | journal = Biochim. Biophys. Acta | volume = 1547 | issue = 2 | pages = 313–9  | date = June 2001 | pmid = 11410287 | doi = 10.1016/S0167-4838(01)00202-3 }}</ref>  
{{Div col end}}


== See also ==
== See also ==
*[[Programmed cell death]]
*[[Programmed cell death]]
{{Clear}}


== References ==
== References ==
{{reflist|2}}
{{Reflist|35em}}
 
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Tolstrup M, Ostergaard L, Laursen AL, ''et al.'' |title=HIV/SIV escape from immune surveillance: focus on Nef. |journal=Curr. HIV Res. |volume=2 |issue= 2 |pages= 141-51 |year= 2004 |pmid= 15078178 |doi=  }}
*{{cite journal  | author=Jiang P, Du W, Wu M |title=p53 and Bad: remote strangers become close friends. |journal=Cell Res. |volume=17 |issue= 4 |pages= 283-5 |year= 2007 |pmid= 17404594 |doi= 10.1038/cr.2007.19 }}
*{{cite journal  | author=Yang E, Zha J, Jockel J, ''et al.'' |title=Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. |journal=Cell |volume=80 |issue= 2 |pages= 285-91 |year= 1995 |pmid= 7834748 |doi=  }}
*{{cite journal  | author=Zha J, Harada H, Yang E, ''et al.'' |title=Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L) |journal=Cell |volume=87 |issue= 4 |pages= 619-28 |year= 1997 |pmid= 8929531 |doi=  }}
*{{cite journal  | author=Wang HG, Rapp UR, Reed JC |title=Bcl-2 targets the protein kinase Raf-1 to mitochondria. |journal=Cell |volume=87 |issue= 4 |pages= 629-38 |year= 1997 |pmid= 8929532 |doi=  }}
*{{cite journal  | author=Inohara N, Ding L, Chen S, Núñez G |title=harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). |journal=EMBO J. |volume=16 |issue= 7 |pages= 1686-94 |year= 1997 |pmid= 9130713 |doi= 10.1093/emboj/16.7.1686 }}
*{{cite journal  | author=Zha J, Harada H, Osipov K, ''et al.'' |title=BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. |journal=J. Biol. Chem. |volume=272 |issue= 39 |pages= 24101-4 |year= 1997 |pmid= 9305851 |doi=  }}
*{{cite journal  | author=Hsu SY, Kaipia A, Zhu L, Hsueh AJ |title=Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11. |journal=Mol. Endocrinol. |volume=11 |issue= 12 |pages= 1858-67 |year= 1997 |pmid= 9369453 |doi=  }}
*{{cite journal  | author=del Peso L, González-García M, Page C, ''et al.'' |title=Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. |journal=Science |volume=278 |issue= 5338 |pages= 687-9 |year= 1997 |pmid= 9381178 |doi=  }}
*{{cite journal  | author=Ottilie S, Diaz JL, Horne W, ''et al.'' |title=Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins. |journal=J. Biol. Chem. |volume=272 |issue= 49 |pages= 30866-72 |year= 1998 |pmid= 9388232 |doi=  }}
*{{cite journal  | author=Huang DC, Adams JM, Cory S |title=The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4. |journal=EMBO J. |volume=17 |issue= 4 |pages= 1029-39 |year= 1998 |pmid= 9463381 |doi= 10.1093/emboj/17.4.1029 }}
*{{cite journal  | author=Blume-Jensen P, Janknecht R, Hunter T |title=The kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136. |journal=Curr. Biol. |volume=8 |issue= 13 |pages= 779-82 |year= 1998 |pmid= 9651683 |doi=  }}
*{{cite journal  | author=Strobel T, Tai YT, Korsmeyer S, Cannistra SA |title=BAD partly reverses paclitaxel resistance in human ovarian cancer cells. |journal=Oncogene |volume=17 |issue= 19 |pages= 2419-27 |year= 1998 |pmid= 9824152 |doi= 10.1038/sj.onc.1202180 }}
*{{cite journal  | author=Song Q, Kuang Y, Dixit VM, Vincenz C |title=Boo, a novel negative regulator of cell death, interacts with Apaf-1. |journal=EMBO J. |volume=18 |issue= 1 |pages= 167-78 |year= 1999 |pmid= 9878060 |doi= 10.1093/emboj/18.1.167 }}
*{{cite journal  | author=Yasuda M, Han JW, Dionne CA, ''et al.'' |title=BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3. |journal=Cancer Res. |volume=59 |issue= 3 |pages= 533-7 |year= 1999 |pmid= 9973195 |doi=  }}
*{{cite journal  | author=Wang HG, Pathan N, Ethell IM, ''et al.'' |title=Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. |journal=Science |volume=284 |issue= 5412 |pages= 339-43 |year= 1999 |pmid= 10195903 |doi=  }}
*{{cite journal  | author=Holmgreen SP, Huang DC, Adams JM, Cory S |title=Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members. |journal=Cell Death Differ. |volume=6 |issue= 6 |pages= 525-32 |year= 1999 |pmid= 10381646 |doi= 10.1038/sj.cdd.4400519 }}
*{{cite journal  | author=Ostrerova N, Petrucelli L, Farrer M, ''et al.'' |title=alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. |journal=J. Neurosci. |volume=19 |issue= 14 |pages= 5782-91 |year= 1999 |pmid= 10407019 |doi=  }}
*{{cite journal  | author=Scheid MP, Schubert KM, Duronio V |title=Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase. |journal=J. Biol. Chem. |volume=274 |issue= 43 |pages= 31108-13 |year= 1999 |pmid= 10521512 |doi=  }}
*{{cite journal  | author=Bonni A, Brunet A, West AE, ''et al.'' |title=Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. |journal=Science |volume=286 |issue= 5443 |pages= 1358-62 |year= 1999 |pmid= 10558990 |doi=  }}
}}
{{refend}}


== Further reading ==
{{Refbegin|35em}}
* {{cite journal | vauthors = Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M | title = HIV/SIV escape from immune surveillance: focus on Nef | journal = Curr. HIV Res. | volume = 2 | issue = 2 | pages = 141–51 | year = 2004 | pmid = 15078178 | doi = 10.2174/1570162043484924 }}
* {{cite journal | vauthors = Jiang P, Du W, Wu M | title = p53 and Bad: remote strangers become close friends | journal = Cell Res. | volume = 17 | issue = 4 | pages = 283–5 | year = 2007 | pmid = 17404594 | doi = 10.1038/cr.2007.19 }}
* {{cite journal | vauthors = Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ | title = Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death | journal = Cell | volume = 80 | issue = 2 | pages = 285–91 | year = 1995 | pmid = 7834748 | doi = 10.1016/0092-8674(95)90411-5 }}
* {{cite journal | vauthors = Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ | title = Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L) | journal = Cell | volume = 87 | issue = 4 | pages = 619–28 | year = 1996 | pmid = 8929531 | doi = 10.1016/S0092-8674(00)81382-3 }}
* {{cite journal | vauthors = Wang HG, Rapp UR, Reed JC | title = Bcl-2 targets the protein kinase Raf-1 to mitochondria | journal = Cell | volume = 87 | issue = 4 | pages = 629–38 | year = 1996 | pmid = 8929532 | doi = 10.1016/S0092-8674(00)81383-5 }}
* {{cite journal | vauthors = Inohara N, Ding L, Chen S, Núñez G | title = harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L) | journal = EMBO J. | volume = 16 | issue = 7 | pages = 1686–94 | year = 1997 | pmid = 9130713 | pmc = 1169772 | doi = 10.1093/emboj/16.7.1686 }}
* {{cite journal | vauthors = Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ | title = BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity | journal = J. Biol. Chem. | volume = 272 | issue = 39 | pages = 24101–4 | year = 1997 | pmid = 9305851 | doi = 10.1074/jbc.272.39.24101 }}
* {{cite journal | vauthors = Hsu SY, Kaipia A, Zhu L, Hsueh AJ | title = Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11 | journal = Mol. Endocrinol. | volume = 11 | issue = 12 | pages = 1858–67 | year = 1997 | pmid = 9369453 | doi = 10.1210/me.11.12.1858 }}
* {{cite journal | vauthors = del Peso L, González-García M, Page C, Herrera R, Nuñez G | title = Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt | journal = Science | volume = 278 | issue = 5338 | pages = 687–9 | year = 1997 | pmid = 9381178 | doi = 10.1126/science.278.5338.687 }}
* {{cite journal | vauthors = Ottilie S, Diaz JL, Horne W, Chang J, Wang Y, Wilson G, Chang S, Weeks S, Fritz LC, Oltersdorf T | title = Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins | journal = J. Biol. Chem. | volume = 272 | issue = 49 | pages = 30866–72 | year = 1997 | pmid = 9388232 | doi = 10.1074/jbc.272.49.30866 }}
* {{cite journal | vauthors = Huang DC, Adams JM, Cory S | title = The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4 | journal = EMBO J. | volume = 17 | issue = 4 | pages = 1029–39 | year = 1998 | pmid = 9463381 | pmc = 1170452 | doi = 10.1093/emboj/17.4.1029 }}
* {{cite journal | vauthors = Blume-Jensen P, Janknecht R, Hunter T | title = The kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136 | journal = Curr. Biol. | volume = 8 | issue = 13 | pages = 779–82 | year = 1998 | pmid = 9651683 | doi = 10.1016/S0960-9822(98)70302-1 }}
* {{cite journal | vauthors = Strobel T, Tai YT, Korsmeyer S, Cannistra SA | title = BAD partly reverses paclitaxel resistance in human ovarian cancer cells | journal = Oncogene | volume = 17 | issue = 19 | pages = 2419–27 | year = 1998 | pmid = 9824152 | doi = 10.1038/sj.onc.1202180 }}
* {{cite journal | vauthors = Song Q, Kuang Y, Dixit VM, Vincenz C | title = Boo, a novel negative regulator of cell death, interacts with Apaf-1 | journal = EMBO J. | volume = 18 | issue = 1 | pages = 167–78 | year = 1999 | pmid = 9878060 | pmc = 1171112 | doi = 10.1093/emboj/18.1.167 }}
* {{cite journal | vauthors = Yasuda M, Han JW, Dionne CA, Boyd JM, Chinnadurai G | title = BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3 | journal = Cancer Res. | volume = 59 | issue = 3 | pages = 533–7 | year = 1999 | pmid = 9973195 | doi =  }}
* {{cite journal | vauthors = Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC | title = Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD | journal = Science | volume = 284 | issue = 5412 | pages = 339–43 | year = 1999 | pmid = 10195903 | doi = 10.1126/science.284.5412.339 }}
* {{cite journal | vauthors = Holmgreen SP, Huang DC, Adams JM, Cory S | title = Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members | journal = Cell Death Differ. | volume = 6 | issue = 6 | pages = 525–32 | year = 1999 | pmid = 10381646 | doi = 10.1038/sj.cdd.4400519 }}
* {{cite journal | vauthors = Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B | author7link=Benjamin Wolozin | title = alpha-Synuclein shares physical and functional homology with 14-3-3 proteins | journal = J. Neurosci. | volume = 19 | issue = 14 | pages = 5782–91 | year = 1999 | pmid = 10407019 | doi =  }}
* {{cite journal | vauthors = Scheid MP, Schubert KM, Duronio V | title = Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase | journal = J. Biol. Chem. | volume = 274 | issue = 43 | pages = 31108–13 | year = 1999 | pmid = 10521512 | doi = 10.1074/jbc.274.43.31108 }}
* {{cite journal | vauthors = Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME | title = Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms | journal = Science | volume = 286 | issue = 5443 | pages = 1358–62 | year = 1999 | pmid = 10558990 | doi = 10.1126/science.286.5443.1358 }}
{{Refend}}


==External links==
== External links ==
* {{MeshName|bcl-Associated+Death+Protein}}
* {{MeshName|bcl-Associated+Death+Protein}}
* {{UCSC gene info|BAD}}
{{Fas apoptosis signaling pathway}}


{{DEFAULTSORT:Bcl-2-Associated Death Promoter}}
[[Category:Programmed cell death]]
[[Category:Programmed cell death]]
[[Category:Proteins]]
[[Category:Proteins]]
{{molecular-biology-stub}}
[[de:Bcl-2-Antagonist-of-Cell-Death]]
{{WikiDoc Sources}}

Revision as of 09:56, 8 June 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human
Pro-apoptotic Bcl-2 protein, BAD
File:PDB 1g5j EBI.jpg
complex of bcl-xl with peptide from bad
Identifiers
SymbolBcl-2_BAD
PfamPF10514
InterProIPR018868

The Bcl-2-associated death promoter (BAD) protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family ,[1] a subfamily of the Bcl-2 family. It does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2 family.[2] After activation, it is able to form a heterodimer with anti-apoptotic proteins and prevent them from stopping apoptosis.

Mechanism of action

Bax/Bak are believed to initiate apoptosis by forming a pore in the mitochondrial outer membrane that allows cytochrome c to escape into the cytoplasm and activate the pro-apoptotic caspase cascade. The anti-apoptotic Bcl-2 and Bcl-xL proteins inhibit cytochrome c release through the mitochondrial pore and also inhibit activation of the cytoplasmic caspase cascade by cytochrome c.[3]

Dephosphorylated BAD forms a heterodimer with Bcl-2 and Bcl-xL, inactivating them and thus allowing Bax/Bak-triggered apoptosis. When BAD is phosphorylated by Akt/protein kinase B (triggered by PIP3), it forms the BAD-(14-3-3)protein heterodimer. This leaves Bcl-2 free to inhibit Bax-triggered apoptosis.[4] BAD phosphorylation is thus anti-apoptotic, and BAD dephosphorylation (e.g., by Ca2+-stimulated Calcineurin) is pro-apoptotic. The latter may be involved in neural diseases such as schizophrenia.[5]

Interactions

File:Signal transduction pathways.svg
Overview of signal transduction pathways involved with apoptosis.

Bcl-2-associated death promoter has been shown to interact with:

See also

References

  1. ↑ Adachi M, Imai K (2002). "The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2". Cell Death Differ. 9 (11): 1240–7. doi:10.1038/sj.cdd.4401097. PMID 12404123.
  2. ↑ Hsu SY, Kaipia A, Zhu L, Hsueh AJ (1997). "Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11". Mol. Endocrinol. 11 (12): 1858–67. doi:10.1210/me.11.12.1858. PMID 9369453.
  3. ↑ Helmreich, E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 238-43
  4. ↑ E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 242
  5. ↑ Foster, T.C. et al. (2001) J. Neurosci. 21, 4066-4073, "Calcineurin Links Ca++ Dysregulation with Brain Aging"(
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (February 2005). "Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function". Mol. Cell. 17 (3): 393–403. doi:10.1016/j.molcel.2004.12.030. PMID 15694340.
  7. ↑ Jin Z, Xin M, Deng X (April 2005). "Survival function of protein kinase C{iota} as a novel nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-activated bad kinase". J. Biol. Chem. 280 (16): 16045–52. doi:10.1074/jbc.M413488200. PMID 15705582.
  8. ↑ Strobel T, Tai YT, Korsmeyer S, Cannistra SA (November 1998). "BAD partly reverses paclitaxel resistance in human ovarian cancer cells". Oncogene. 17 (19): 2419–27. doi:10.1038/sj.onc.1202180. PMID 9824152.
  9. ↑ Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M (August 2002). "Development of a high-throughput fluorescence polarization assay for Bcl-x(L)". Anal. Biochem. 307 (1): 70–5. doi:10.1016/S0003-2697(02)00028-3. PMID 12137781.
  10. ↑ 10.0 10.1 Ayllón V, Cayla X, García A, Fleischer A, Rebollo A (July 2002). "The anti-apoptotic molecules Bcl-xL and Bcl-w target protein phosphatase 1alpha to Bad". Eur. J. Immunol. 32 (7): 1847–55. doi:10.1002/1521-4141(200207)32:7<1847::AID-IMMU1847>3.0.CO;2-7. PMID 12115603.
  11. ↑ Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG (January 2000). "Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis". Nat. Cell Biol. 2 (1): 1–6. doi:10.1038/71316. PMID 10620799.
  12. ↑ 12.0 12.1 Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (January 1995). "Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death". Cell. 80 (2): 285–91. doi:10.1016/0092-8674(95)90411-5. PMID 7834748.
  13. ↑ Petros AM, Nettesheim DG, Wang Y, Olejniczak ET, Meadows RP, Mack J, Swift K, Matayoshi ED, Zhang H, Thompson CB, Fesik SW (Dec 2000). "Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies". Protein Sci. 9 (12): 2528–34. doi:10.1110/ps.9.12.2528. PMC 2144516. PMID 11206074.
  14. ↑ Chattopadhyay A, Chiang CW, Yang E (July 2001). "BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest". Oncogene. 20 (33): 4507–18. doi:10.1038/sj.onc.1204584. PMID 11494146.
  15. ↑ Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y (November 1997). "Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy". Nature. 390 (6658): 413–7. doi:10.1038/37144. PMID 9389483.
  16. ↑ Komatsu K, Wharton W, Hang H, Wu C, Singh S, Lieberman HB, Pledger WJ, Wang HG (November 2000). "PCNA interacts with hHus1/hRad9 in response to DNA damage and replication inhibition". Oncogene. 19 (46): 5291–7. doi:10.1038/sj.onc.1203901. PMID 11077446.
  17. ↑ 17.0 17.1 17.2 Bae J, Hsu SY, Leo CP, Zell K, Hsueh AJ (October 2001). "Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis". Apoptosis. 6 (5): 319–30. doi:10.1023/A:1011319901057. PMID 11483855.
  18. ↑ Holmgreen SP, Huang DC, Adams JM, Cory S (June 1999). "Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members". Cell Death Differ. 6 (6): 525–32. doi:10.1038/sj.cdd.4400519. PMID 10381646.
  19. ↑ 19.0 19.1 Hsu SY, Kaipia A, Zhu L, Hsueh AJ (November 1997). "Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11". Mol. Endocrinol. 11 (12): 1858–67. doi:10.1210/me.11.12.1858. PMID 9369453.
  20. ↑ Yang H, Masters SC, Wang H, Fu H (June 2001). "The proapoptotic protein Bad binds the amphipathic groove of 14-3-3zeta". Biochim. Biophys. Acta. 1547 (2): 313–9. doi:10.1016/S0167-4838(01)00202-3. PMID 11410287.

Further reading

External links

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