Bcl-2-associated death promoter

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BCL2-associated agonist of cell death
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BAD ; BBC2; BCL2L8
External IDs OMIM603167 MGI1096330 HomoloGene3189 ChEMBL: 3817 GeneCards: BAD Gene
RNA expression pattern
PBB GE BAD 1861 at tn.png
PBB GE BAD 209364 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 572 12015
Ensembl ENSG00000002330 ENSMUSG00000024959
UniProt Q92934 Q61337
RefSeq (mRNA) NM_004322 NM_001285453
RefSeq (protein) NP_004313 NP_001272382
Location (UCSC) Chr 11:
64.04 – 64.05 Mb
Chr 19:
6.94 – 6.95 Mb
PubMed search [1] [2]
Pro-apoptotic Bcl-2 protein, BAD
PDB 1g5j EBI.jpg
complex of bcl-xl with peptide from bad
Identifiers
Symbol Bcl-2_BAD
Pfam PF10514
InterPro IPR018868

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[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.[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[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]

  1. ^ Adachi M. and Imai K. (2002). "The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2". Cell death and differentiation 9 (11): 1240–1247. doi:10.1038/sj.cdd.4401097. PMID 12404123. 
  2. ^ Sheau Yu Hsu et al. (1997). "Interference of BAD (Bcl-xL/Bcl-2-Associated Death Promoter)-Induced Apoptosis in Mammalian Cells by 14–3-3 Isoforms and P11". Molecular Endocrinology 11 (12): 1858–1867. 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. ^ 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. 
  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. ^ 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. 
  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. ^ 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. 
  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. ^ 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. 
  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. ^ 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/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[edit]

External links[edit]