Bcl-2-associated X protein

From Wikipedia, the free encyclopedia
  (Redirected from Bax (biochemistry))
Jump to: navigation, search
BCL2-associated X protein
BAX protein 1F16.png
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BAX ; BCL2L4
External IDs OMIM600040 MGI99702 HomoloGene7242 ChEMBL: 5318 GeneCards: BAX Gene
RNA expression pattern
PBB GE BAX 208478 s at tn.png
PBB GE BAX 211833 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 581 12028
Ensembl ENSG00000087088 ENSMUSG00000003873
UniProt Q07812 Q07813
RefSeq (mRNA) NM_004324 NM_007527
RefSeq (protein) NP_004315 NP_031553
Location (UCSC) Chr 19:
49.46 – 49.47 Mb
Chr 7:
45.46 – 45.47 Mb
PubMed search [1] [2]

Apoptosis regulator BAX also known as bcl-2-like protein 4 is a protein that in humans is encoded by the BAX gene.[1]

BAX is a member of the Bcl-2 gene family. Apoptosis regulator BAX promotes apoptosis by binding to and antagonizing the Bcl-2 protein.[1]

The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family.[2] Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4), and can form hetero- or homodimers.[2][3] Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

Orthologs of the BAX gene [4] have been identified in most mammals for which complete genome data are available. Certain members of BAX, such as Bcl-2, Bcl-xl and Mcl1 are anti-apoptotic, whilst others are pro-apoptotic. BAX is a pro-apoptotic Bcl-2 protein containing BH1, BH2 and BH3 domains.

Function[edit]

In healthy mammalian cells, the majority of BAX is found in the cytosol, but upon initiation of apoptotic signaling, Bax undergoes a conformational shift. Upon induction of apoptosis, BAX becomes organelle membrane-associated, and in particular, mitochondrial membrane associated.[5][6][7][8][9]

BAX is believed to interact with, and induce the opening of the mitochondrial voltage-dependent anion channel, VDAC.[10] Alternatively, growing evidence also suggests that activated BAX and/or Bak form an oligomeric pore, MAC in the outer membrane.[11] This results in the release of cytochrome c and other pro-apoptotic factors from the mitochondria, often referred to as mitochondrial outer membrane permeabilization, leading to activation of caspases.[12] This defines a direct role for BAX in mitochondrial outer membrane permeabilization, a role common to the Bcl-2 proteins containing the BH1, BH2 and BH3 domains.

Role in Cancer[edit]

The expression of BAX is upregulated by the tumor suppressor protein p53, and BAX has been shown to be involved in p53-mediated apoptosis.[13][14][15] The p53 protein is a transcription factor[13][14][15] that, when activated as part of the cell's response to stress, regulates many downstream target genes, including BAX. Wild-type p53 has been demonstrated to upregulate the transcription of a chimeric reporter plasmid utilizing the consensus promoter sequence of BAX approximately 50-fold over mutant p53.[13][14][15] Thus it is likely that p53 promotes BAX's apoptotic faculties in vivo as a primary transcription factor. However, p53 also has a transcription-independent role in apoptosis. In particular, p53 interacts with Bax, promoting its activation as well as its insertion into the mitochondrial membrane.[13][14][15]

Binding of HA-BAD to BCL-xL and concomitant disruption of BAX:BCL-xL interaction was found to partly reverse paclitaxel resistance in human ovarian cancer cells.[16]

Interactions[edit]

Overview of signal transduction pathways involved with apoptosis.

Bcl-2-associated X protein has been shown to interact with:

See also[edit]


References[edit]

  1. ^ a b "Entrez Gene: BCL2-associated X protein". 
  2. ^ a b c Oltvai ZN, Milliman CL, Korsmeyer SJ (August 1993). "Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death". Cell 74 (4): 609–19. doi:10.1016/0092-8674(93)90509-O. PMID 8358790. 
  3. ^ a b c d Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ (August 1995). "Multiple Bcl-2 family members demonstrate selective dimerizations with Bax". Proc. Natl. Acad. Sci. U.S.A. 92 (17): 7834–8. doi:10.1073/pnas.92.17.7834. PMC 41240. PMID 7644501. 
  4. ^ "OrthoMaM phylogenetic marker: BAX coding sequence". 
  5. ^ Gross A, Jockel J, Wei MC, Korsmeyer SJ (July 1998). "Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis". EMBO J. 17 (14): 3878–85. doi:10.1093/emboj/17.14.3878. PMC 1170723. PMID 9670005. 
  6. ^ Hsu YT, Wolter KG, Youle RJ (April 1997). "Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis". Proc. Natl. Acad. Sci. U.S.A. 94 (8): 3668–72. doi:10.1073/pnas.94.8.3668. PMC 20498. PMID 9108035. 
  7. ^ Nechushtan A, Smith CL, Hsu YT, Youle RJ (May 1999). "Conformation of the Bax C-terminus regulates subcellular location and cell death". EMBO J. 18 (9): 2330–41. doi:10.1093/emboj/18.9.2330. PMC 1171316. PMID 10228148. 
  8. ^ a b Pierrat B, Simonen M, Cueto M, Mestan J, Ferrigno P, Heim J (January 2001). "SH3GLB, a new endophilin-related protein family featuring an SH3 domain". Genomics 71 (2): 222–34. doi:10.1006/geno.2000.6378. PMID 11161816. 
  9. ^ Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ (December 1997). "Movement of Bax from the cytosol to mitochondria during apoptosis". J. Cell Biol. 139 (5): 1281–92. doi:10.1083/jcb.139.5.1281. PMC 2140220. PMID 9382873. 
  10. ^ a b Shi Y, Chen J, Weng C, Chen R, Zheng Y, Chen Q, Tang H (June 2003). "Identification of the protein-protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins". Biochem. Biophys. Res. Commun. 305 (4): 989–96. doi:10.1016/S0006-291X(03)00871-4. PMID 12767928. 
  11. ^ Buytaert E, Callewaert G, Vandenheede JR, Agostinis P (2006). "Deficiency in apoptotic effectors Bax and Bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum". Autophagy 2 (3): 238–40. PMID 16874066. 
  12. ^ a b Weng C, Li Y, Xu D, Shi Y, Tang H (March 2005). "Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells". J. Biol. Chem. 280 (11): 10491–500. doi:10.1074/jbc.M412819200. PMID 15637055. 
  13. ^ a b c d Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC (June 1994). "Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo". Oncogene 9 (6): 1799–805. PMID 8183579. 
  14. ^ a b c d Selvakumaran M, Lin HK, Miyashita T, Wang HG, Krajewski S, Reed JC, Hoffman B, Liebermann D (June 1994). "Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways". Oncogene 9 (6): 1791–8. PMID 8183578. 
  15. ^ a b c d Miyashita T, Reed JC (January 1995). "Tumor suppressor p53 is a direct transcriptional activator of the human bax gene". Cell 80 (2): 293–9. doi:10.1016/0092-8674(95)90412-3. PMID 7834749. 
  16. ^ a b 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. 
  17. ^ Hoetelmans RW (2004). "Nuclear partners of Bcl-2: Bax and PML". DNA Cell Biol. 23 (6): 351–4. doi:10.1089/104454904323145236. PMID 15231068. 
  18. ^ Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK (2004). "Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3". Cell 116 (4): 527–40. doi:10.1016/S0092-8674(04)00162-X. PMID 14980220. 
  19. ^ Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG (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. 
  20. ^ Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M (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. 
  21. ^ Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken B, Schulze-Osthoff K, Daniel PT (2003). "Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway". EMBO J. 22 (14): 3580–90. doi:10.1093/emboj/cdg343. PMC 165613. PMID 12853473. 
  22. ^ Zhang H, Cowan-Jacob SW, Simonen M, Greenhalf W, Heim J, Meyhack B (2000). "Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells". J. Biol. Chem. 275 (15): 11092–9. doi:10.1074/jbc.275.15.11092. PMID 10753914. 
  23. ^ Cuddeback SM, Yamaguchi H, Komatsu K, Miyashita T, Yamada M, Wu C, Singh S, Wang HG (2001). "Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax". J. Biol. Chem. 276 (23): 20559–65. doi:10.1074/jbc.M101527200. PMID 11259440. 
  24. ^ Marzo I, Brenner C, Zamzami N, Jürgensmeier JM, Susin SA, Vieira HL, Prévost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G (1998). "Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis". Science 281 (5385): 2027–31. Bibcode:1998Sci...281.2027M. doi:10.1126/science.281.5385.2027. PMID 9748162. 
  25. ^ Nomura M, Shimizu S, Sugiyama T, Narita M, Ito T, Matsuda H, Tsujimoto Y (2003). "14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax". J. Biol. Chem. 278 (3): 2058–65. doi:10.1074/jbc.M207880200. PMID 12426317.