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 [ edit ]
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 [ edit ]
Overview of signal transduction pathways involved with apoptosis .
Bcl-2-associated death promoter has been shown to interact with:
See also [ edit ]
References [ edit ]
^ 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). "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 .
^ 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 .
^ 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). "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 .
^ 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 .
^ 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 .
^ 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 .
^ a b 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 .
^ 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 . 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. doi :10.1016/0092-8674(95)90411-5 . PMID 7834748 . S2CID 10343291 .
^ 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 .
^ 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 .
^ 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 :10.1038/37144 . PMID 9389483 . S2CID 1936633 .
^ 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 .
^ 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. doi :10.1023/A:1011319901057 . PMID 11483855 . S2CID 23119757 .
^ 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 .
^ 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. doi :10.1016/S0167-4838(01)00202-3 . PMID 11410287 .
Further reading [ edit ]
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 [ edit ]