| BCL2-associated X protein |
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| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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1F16, 2G5B, 2K7W, 2LR1, 3PK1, 3PL7, 4BD2, 4BD6, 4BD7, 4BD8, 4BDU
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| Identifiers |
| Symbols |
BAX; BCL2L4 |
| External IDs |
OMIM: 600040 MGI: 99702 HomoloGene: 7242 ChEMBL: 5318 GeneCards: BAX Gene |
| Gene Ontology |
| Molecular function |
• protein binding
• lipid binding
• channel activity
• identical protein binding
• protein homodimerization activity
• protein heterodimerization activity
• BH3 domain binding
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| Cellular component |
• nucleus
• mitochondrion
• mitochondrial outer membrane
• mitochondrial permeability transition pore complex
• endoplasmic reticulum
• endoplasmic reticulum membrane
• cytosol
• cytosolic part
• pore complex
• Bcl-2 family protein complex
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| Biological process |
• response to acid
• ovarian follicle development
• neuron migration
• T cell homeostatic proliferation
• B cell homeostasis
• B cell apoptotic process
• kidney development
• release of cytochrome c from mitochondria
• protein insertion into mitochondrial membrane involved in apoptotic signaling pathway
• blood vessel remodeling
• myeloid cell homeostasis
• B cell negative selection
• B cell homeostatic proliferation
• positive regulation of B cell apoptotic process
• apoptotic DNA fragmentation
• glycosphingolipid metabolic process
• regulation of nitrogen utilization
• apoptotic process
• induction of apoptosis
• activation of cysteine-type endopeptidase activity involved in apoptotic process
• cleavage of lamin involved in execution phase of apoptosis
• transformed cell apoptotic process
• response to DNA damage stimulus
• germ cell development
• mitochondrial fusion
• activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c
• apoptotic mitochondrial changes
• fertilization
• response to toxin
• response to salt stress
• establishment or maintenance of transmembrane electrochemical gradient
• response to gamma radiation
• virus-host interaction
• hypothalamus development
• cerebral cortex development
• nuclear fragmentation involved in apoptotic nuclear change
• negative regulation of protein binding
• positive regulation of protein oligomerization
• reduction of endoplasmic reticulum calcium ion concentration
• release of matrix enzymes from mitochondria
• negative regulation of peptidyl-serine phosphorylation
• regulation of mammary gland epithelial cell proliferation
• cellular response to UV
• limb morphogenesis
• germ cell programmed cell death
• odontogenesis of dentin-containing tooth
• positive regulation of apoptotic process
• regulation of protein homodimerization activity
• regulation of protein heterodimerization activity
• negative regulation of neuron apoptotic process
• positive regulation of neuron apoptotic process
• mitochondrial fragmentation involved in apoptotic process
• development of secondary sexual characteristics
• retinal cell programmed cell death
• positive regulation of developmental pigmentation
• negative regulation of fibroblast proliferation
• spermatid differentiation
• post-embryonic camera-type eye morphogenesis
• response to axon injury
• homeostasis of number of cells within a tissue
• protein oligomerization
• protein homooligomerization
• positive regulation of release of sequestered calcium ion into cytosol
• neuron apoptotic process
• regulation of cell cycle
• regulation of mitochondrial membrane potential
• Sertoli cell proliferation
• retina development in camera-type eye
• positive regulation of apoptotic process involved in mammary gland involution
• vagina development
• intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
• cellular response to organic substance
• positive regulation of release of cytochrome c from mitochondria
• apoptotic signaling pathway
• intrinsic apoptotic signaling pathway
• positive regulation of endoplasmic reticulum unfolded protein response
• retinal cell apoptotic process
• positive regulation of intrinsic apoptotic signaling pathway
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| Sources: Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
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| Entrez |
581 |
12028 |
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| Ensembl |
ENSG00000087088 |
ENSMUSG00000003873 |
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| UniProt |
Q07812 |
Q07813 |
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| RefSeq (mRNA) |
NM_004324 |
NM_007527 |
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| RefSeq (protein) |
NP_004315 |
NP_031553 |
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| Location (UCSC) |
Chr 19:
49.46 – 49.47 Mb |
Chr 7:
45.46 – 45.47 Mb |
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| PubMed search |
[1] |
[2] |
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The Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.[1][2]
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Contents
- 1 Background
- 2 Functions
- 3 Role in Cancer
- 4 Interactions
- 5 See also
- 6 References
- 7 Further reading
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Background
The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family [3][4]. 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.[5] 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 [6] 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.
Functions
In healthy mammalian cells, the majority of BAX is found in the cytosol, but upon initiation of apoptotic signaling, Bax undergoes a conformation shift. Upon induction of apoptosis, BAX becomes organelle membrane-associated, and in particular, mitochondrial membrane associated [7] [8] [9] [10] [11]. BAX is believed to interact with, and induce the opening of the mitochondrial voltage-dependent anion channel, VDAC. [12]. Alternatively, growing evidence also suggests that activated BAX and/or Bak form an oligomeric pore, MAC in the outer membrane [13]. 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 [14]. 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
The expression of BAX is upregulated by the tumor suppressor protein p53, and BAX has been shown to be involved in p53-mediated apoptosis. The p53 protein is a transcription factor[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 [16] . 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.[17]
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[18].
Interactions
Overview of signal transduction pathways involved with apoptosis.
Bcl-2-associated X protein has been shown to interact with SH3GLB1,[19][20] VDAC1,[21][22] BCL2-like 1,[23][24][25] Bcl-2,[26][27][28][29] SLC25A4,[30] BCL2-related protein A1[31] and YWHAQ.[32]
See also
- Apoptosis
- Apoptosome
- Bcl-2
- BH3 interacting domain death agonist (BID)
- Caspases
- Cytochrome c
- Noxa
- Mitochondrion
- p53 upregulated modulator of apoptosis (PUMA)
References
- ^ Lodish et al., Molecular Cell Biology (5th ed.) W.H. Freeman and Company, New York, 2003.
- ^ Molecular Human Reproduction, Vol 4, 1099 – 1109, Copyright © 1998 by Oxford University Press
- ^ Oltvai, Z. N.; Milliman, C. L. and Korsmeyer, S. J. (August 1993). "Bcl-2 Heterodimerizes In Vivo with a Conserved Homolog, Bax, That Accelerates Programed Cell Death". Cell 74 (4): 609–619. doi:10.1016/0092-8674(93)90509-O. PMID 8358790.
- ^ Oltvai, Z.; Milliman, C.; Korsmeyer, S. J. (1993). "Bcl-2 Heterodimerizes in vivo with a Conserved Homolog, Bax, that Accelerates Programmed Cell Death". Cell 74 (4): 609–619.
- ^ Oltvai, Z.; Milliman, C.; Korsmeyer, S. J. (1993). Bcl-2 Heterodimerizes in vivo with a Conserved Homolog, BAX, that Accelerates Programmed Cell Death. Cell 74 (4): 609–619.
- ^ "OrthoMaM phylogenetic marker: BAX coding sequence".
- ^ Gross, A., Jockel, J., Wei, M. C., and Korsmeyer, S. J. (1998). Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J. 17: 3878–3885.
- ^ Hsu, Y. T., Wolter, K. G., and Youle, R. J. (1997). Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc.Natl. Acad. Sci. USA 94: 3668–3672.
- ^ Nechushtan, A., Smith, C. L., Hsu, Y. T., and Youle, R. J. (1999). Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J. 18: 2330–2341.
- ^ 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 (United States) 71 (2): 222–34
- ^ Wolter, K. G.; Hsu, Y., Smith, C. L., Mechushtan, A., Xi, X., and Youle, R. J. (December 1997). "Movement of BAX from Cytosol to Mitochondria during Apoptosis". Journal of Cell Biology 139 (5): 1281–1292. doi:10.1083/jcb.139.5.1281. PMC 2140220. PMID 9382873.
- ^ Shi, Yong; Chen Jianjun, Weng Changjiang, Chen Rui, Zheng Yanhua, Chen Quan, Tang Hong (June 2003). "Identification of the protein-protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins". Biochem. Biophys. Res. Commun. (United States) 305 (4): 989–96.
- ^ Buytaert E, Callewaert G, Vandenheede JR, Agostinis P (2007). "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
- ^ Weng, Changjiang; Li Yuan, Xu Dan, Shi Yong, Tang Hong (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. (United States) 280 (11): 10491–500.
- ^ Miyashita, Toshiyuki; Reed, John C. (1995). "Tumor Suppressor p53 Is a Direct Transcriptional Activator of the Human bax Gene". Cell 80 (2): 293–299.
- ^ Miyashita, Toshiyuki; Reed, John C. (1995). "Tumor Suppressor p53 Is a Direct Transcriptional Activator of the Human bax Gene". Cell 80 (2): 293–299.
- ^ Miyashita, Toshiyuki; Reed, John C. (1995). "Tumor Suppressor p53 Is a Direct Transcriptional Activator of the Human bax Gene". Cell 80 (2): 293–299.
- ^ Strobel, T; Tai Y T, Korsmeyer S, Cannistra S A (November 1998). "BAD partly reverses paclitaxel resistance in human ovarian cancer cells". Oncogene (ENGLAND) 17 (19): 2419–27.
- ^ 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 (United States) 71 (2): 222–34. doi:10.1006/geno.2000.6378. ISSN 0888-7543. PMID 11161816.
- ^ Cuddeback, S M; Yamaguchi H, Komatsu K, Miyashita T, Yamada M, Wu C, Singh S, Wang H G (June 2001). "Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax". J. Biol. Chem. (United States) 276 (23): 20559–65. doi:10.1074/jbc.M101527200. ISSN 0021-9258. PMID 11259440.
- ^ Weng, Changjiang; Li Yuan, Xu Dan, Shi Yong, Tang Hong (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. (United States) 280 (11): 10491–500. doi:10.1074/jbc.M412819200. ISSN 0021-9258. PMID 15637055.
- ^ Shi, Yong; Chen Jianjun, Weng Changjiang, Chen Rui, Zheng Yanhua, Chen Quan, Tang Hong (June 2003). "Identification of the protein-protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins". Biochem. Biophys. Res. Commun. (United States) 305 (4): 989–96. doi:10.1016/S0006-291X(03)00871-4. ISSN 0006-291X. PMID 12767928.
- ^ Strobel, T; Tai Y T, Korsmeyer S, Cannistra S A (November 1998). "BAD partly reverses paclitaxel resistance in human ovarian cancer cells". Oncogene (ENGLAND) 17 (19): 2419–27. doi:10.1038/sj.onc.1202180. ISSN 0950-9232. PMID 9824152.
- ^ Zhang, Haichao; Nimmer Paul, Rosenberg Saul H, Ng Shi-Chung, Joseph Mary (August 2002). "Development of a high-throughput fluorescence polarization assay for Bcl-x(L)". Anal. Biochem. (United States) 307 (1): 70–5. doi:10.1016/S0003-2697(02)00028-3. ISSN 0003-2697. PMID 12137781.
- ^ Gillissen, Bernhard; Essmann Frank, Graupner Vilma, Stärck Lilian, Radetzki Silke, Dörken Bernd, Schulze-Osthoff Klaus, Daniel Peter T (July 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. (England) 22 (14): 3580–90. doi:10.1093/emboj/cdg343. ISSN 0261-4189. PMC 165613. PMID 12853473.
- ^ Hoetelmans, R W M (June 2004). "Nuclear partners of Bcl-2: Bax and PML". DNA Cell Biol. (United States) 23 (6): 351–4. doi:10.1089/104454904323145236. ISSN 1044-5498. PMID 15231068.
- ^ Lin, Bingzhen; Kolluri Siva Kumar, Lin Feng, Liu Wen, Han Young-Hoon, Cao Xihua, Dawson Marcia I, Reed John C, Zhang Xiao-kun (February 2004). "Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3". Cell (United States) 116 (4): 527–40. doi:10.1016/S0092-8674(04)00162-X. ISSN 0092-8674. PMID 14980220.
- ^ Oltvai, Z N; Milliman C L, Korsmeyer S J (August 1993). "Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death". Cell (UNITED STATES) 74 (4): 609–19. doi:10.1016/0092-8674(93)90509-O. ISSN 0092-8674. PMID 8358790.
- ^ Komatsu, K; Miyashita T, Hang H, Hopkins K M, Zheng W, Cuddeback S, Yamada M, Lieberman H B, Wang H G (January 2000). "Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis". Nat. Cell Biol. (ENGLAND) 2 (1): 1–6. doi:10.1038/71316. ISSN 1465-7392. PMID 10620799.
- ^ Marzo, I; Brenner C, Zamzami N, Jürgensmeier J M, Susin S A, Vieira H L, Prévost M C, Xie Z, Matsuyama S, Reed J C, Kroemer G (September 1998). "Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis". Science (UNITED STATES) 281 (5385): 2027–31. doi:10.1126/science.281.5385.2027. ISSN 0036-8075. PMID 9748162.
- ^ Zhang, H; Cowan-Jacob S W, Simonen M, Greenhalf W, Heim J, Meyhack B (April 2000). "Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells". J. Biol. Chem. (UNITED STATES) 275 (15): 11092–9. doi:10.1074/jbc.275.15.11092. ISSN 0021-9258. PMID 10753914.
- ^ Nomura, Masaya; Shimizu Shigeomi, Sugiyama Tomoyasu, Narita Masashi, Ito Toshinori, Matsuda Hikaru, Tsujimoto Yoshihide (January 2003). "14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax". J. Biol. Chem. (United States) 278 (3): 2058–65. doi:10.1074/jbc.M207880200. ISSN 0021-9258. PMID 12426317.
- Molecular Human Reproduction, Vol 4, 1099 – 1109, Copyright © 1998 by Oxford University Press
- Lodish et al., Molecular Cell Biology (5th ed.) W.H. Freeman and Company, New York, 2003.
- Miyashita, Toshiyuki; Reed, John C. (1995). "Tumor Suppressor p53 Is a Direct Transcriptional Activator of the Human bax Gene". Cell 80 (2): 293–299. doi:10.1016/0092-8674(95)90412-3. PMID 7834749.
- Oltvai, Z.; Milliman, C.; Korsmeyer, S. J. (1993). "Bcl-2 Heterodimerizes in vivo with a Conserved Homolog, Bax, that Accelerates Programmed Cell Death". Cell 74 (4): 609–619. doi:10.1016/0092-8674(93)90509-O. PMID 8358790.
Further reading
- Kumarswamy R and Chandna S (2009). "Putative partners in Bax mediated cytochrome-c release: ANT, CypD, VDAC or none of them?". Mitochondrion. 9 (1): 1–8. doi:10.1016/j.mito.2008.10.003. PMID 18992370.
- Vieira HL, Haouzi D, El Hamel C, et al. (2001). "Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator.". Cell Death Differ. 7 (12): 1146–54. doi:10.1038/sj.cdd.4400778. PMID 11175251.
- Buytaert E, Callewaert G, Vandenheede JR, Agostinis P (2007). "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.
- Steele AD, Yi CH (2007). "Neuromuscular denervation: Bax up against the wall in amyotrophic lateral sclerosis.". J. Neurosci. 26 (50): 12849–51. doi:10.1523/JNEUROSCI.4086-06.2006. PMID 17171827.
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PDB gallery
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1f16: SOLUTION STRUCTURE OF A PRO-APOPTOTIC PROTEIN BAX
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Apoptosis signaling pathway
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| Fas path |
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Ligand
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Receptor
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Intracellular
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- Death-inducing signaling complex
- Cytochrome c
- Caspase 9
- Caspase 3
- Pro-apoptotic:
- BAX
- BAK1/Bcl-2 homologous antagonist killer
- Bcl-2-associated death promoter
- Anti-apoptotic:
- Bcl-2
- Bcl-xL
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| TNF path |
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Ligand
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Receptor
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- Tumor necrosis factor receptor
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Intracellular
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- FADD
- Caspase 8
- Caspase 3
- BID
- TRAF2
- ASK-1
- MEKK1
- IKK
- IκBα
- MKK7
- JNK
- NF-κB
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| Other |
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Intracellular
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- IAPs
- XIAP
- NAIP
- Survivin
- c-IAP-1
- c-IAP-2
- Apoptosis-inducing factor
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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