From Wikipedia, the free encyclopedia
Mammalian protein found in Homo sapiens
The BCL2 associated agonist of cell death
[5] (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 ,
[6] 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 .
[7] 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.
[8]
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.
[9] 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.
[10]
Interactions
Overview of signal transduction pathways involved with
apoptosis .
Bcl-2-associated death promoter has been shown to
interact with:
See also
References
^
a
b
c
GRCh38: Ensembl release 89: ENSG00000002330 –
Ensembl , May 2017
^
a
b
c
GRCm38: Ensembl release 89: ENSMUSG00000024959 –
Ensembl , May 2017
^
"Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"BAD BCL2 associated agonist of cell death [Homo sapiens (Human)] - Gene - NCBI" .
^ Adachi M, Imai K (2002).
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^ Hsu SY, Kaipia A, Zhu L, Hsueh AJ (1997).
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^ Helmreich, E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 238-43
^ E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 242
^ Foster, T.C. et al. (2001) J. Neurosci. 21, 4066-4073, "Calcineurin Links Ca++ Dysregulation with Brain Aging"(
^
a
b
c
d
e
f Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (February 2005).
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^ 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.
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10.1074/jbc.M413488200 .
PMID
15705582 .
^ 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.
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PMID
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^ 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.
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^
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b Ayllón V, Cayla X, García A, Fleischer A, Rebollo A (July 2002).
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^ 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.
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S2CID
52847351 .
^
a
b 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.
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PMID
7834748 .
S2CID
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^ 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.
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PMID
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^ 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.
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11494146 .
^ 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.
Bibcode :
1997Natur.390..413I .
doi :
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PMID
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S2CID
1936633 .
^ Komatsu K, Wharton W, Hang H, Wu C, Singh S, Lieberman HB, Pledger WJ, Wang HG (November 2000).
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^
a
b
c 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.
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PMID
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S2CID
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^ 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.
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^
a
b 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/mend.11.12.0023 .
PMID
9369453 .
^ 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.
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PMID
11410287 .
Further reading
Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res . 2 (2): 141–51.
doi :
10.2174/1570162043484924 .
PMID
15078178 .
Jiang P, Du W, Wu M (2007).
"p53 and Bad: remote strangers become close friends" . Cell Res . 17 (4): 283–5.
doi :
10.1038/cr.2007.19 .
PMID
17404594 .
Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (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 .
S2CID
10343291 .
Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996).
"Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)" . Cell . 87 (4): 619–28.
doi :
10.1016/S0092-8674(00)81382-3 .
PMID
8929531 .
S2CID
860908 .
Wang HG, Rapp UR, Reed JC (1996).
"Bcl-2 targets the protein kinase Raf-1 to mitochondria" . Cell . 87 (4): 629–38.
doi :
10.1016/S0092-8674(00)81383-5 .
PMID
8929532 .
S2CID
16559750 .
Inohara N, Ding L, Chen S, Núñez G (1997).
"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)" . EMBO J . 16 (7): 1686–94.
doi :
10.1093/emboj/16.7.1686 .
PMC
1169772 .
PMID
9130713 .
Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ (1997).
"BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity" . J. Biol. Chem . 272 (39): 24101–4.
doi :
10.1074/jbc.272.39.24101 .
PMID
9305851 .
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/mend.11.12.0023 .
PMID
9369453 .
del Peso L, González-García M, Page C, Herrera R, Nuñez G (1997). "Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt". Science . 278 (5338): 687–9.
Bibcode :
1997Sci...278..687D .
doi :
10.1126/science.278.5338.687 .
PMID
9381178 .
Ottilie S, Diaz JL, Horne W, Chang J, Wang Y, Wilson G, Chang S, Weeks S, Fritz LC, Oltersdorf T (1997).
"Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins" . J. Biol. Chem . 272 (49): 30866–72.
doi :
10.1074/jbc.272.49.30866 .
PMID
9388232 .
Huang DC, Adams JM, Cory S (1998).
"The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4" . EMBO J . 17 (4): 1029–39.
doi :
10.1093/emboj/17.4.1029 .
PMC
1170452 .
PMID
9463381 .
Blume-Jensen P, Janknecht R, Hunter T (1998).
"The kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136" . Curr. Biol . 8 (13): 779–82.
Bibcode :
1998CBio....8..779B .
doi :
10.1016/S0960-9822(98)70302-1 .
PMID
9651683 .
S2CID
15596347 .
Strobel T, Tai YT, Korsmeyer S, Cannistra SA (1998).
"BAD partly reverses paclitaxel resistance in human ovarian cancer cells" . Oncogene . 17 (19): 2419–27.
doi :
10.1038/sj.onc.1202180 .
PMID
9824152 .
Song Q, Kuang Y, Dixit VM, Vincenz C (1999).
"Boo, a novel negative regulator of cell death, interacts with Apaf-1" . EMBO J . 18 (1): 167–78.
doi :
10.1093/emboj/18.1.167 .
PMC
1171112 .
PMID
9878060 .
Yasuda M, Han JW, Dionne CA, Boyd JM, Chinnadurai G (1999). "BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3". Cancer Res . 59 (3): 533–7.
PMID
9973195 .
Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC (1999). "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD". Science . 284 (5412): 339–43.
Bibcode :
1999Sci...284..339W .
doi :
10.1126/science.284.5412.339 .
PMID
10195903 .
Holmgreen SP, Huang DC, Adams JM, Cory S (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 .
Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J,
Wolozin B (1999).
"alpha-Synuclein shares physical and functional homology with 14-3-3 proteins" . J. Neurosci . 19 (14): 5782–91.
doi :
10.1523/JNEUROSCI.19-14-05782.1999 .
PMC
6783081 .
PMID
10407019 .
Scheid MP, Schubert KM, Duronio V (1999).
"Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase" . J. Biol. Chem . 274 (43): 31108–13.
doi :
10.1074/jbc.274.43.31108 .
PMID
10521512 .
Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999). "Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms". Science . 286 (5443): 1358–62.
doi :
10.1126/science.286.5443.1358 .
PMID
10558990 .
External links