View source for Bcl-2-associated X protein

{{Use dmy dates|date=December 2016}}
{{Infobox_gene}}

'''Apoptosis regulator BAX''', also known as '''bcl-2-like protein 4''', is a [[protein]] that in humans is encoded by the ''BAX'' [[gene]]. ''BAX'' is a member of the [[Bcl-2 family|Bcl-2 gene family]]. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.<ref name="entrez">{{cite web | title = Entrez Gene: BCL2-associated X protein | url = https://www.ncbi.nlm.nih.gov/gene/581 }}</ref>

== Structure ==

The ''BAX'' gene was the first identified pro-[[Apoptosis|apoptotic]] member of the [[Bcl-2]] [[protein family]].<ref name="Oltvai_1993">{{cite journal |vauthors=Oltvai ZN, Milliman CL, Korsmeyer SJ | title = Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death | journal = Cell | volume = 74 | issue = 4 | pages = 609–19 |date=August 1993| pmid = 8358790 | doi = 10.1016/0092-8674(93)90509-O }}</ref> Bcl-2 family members share one or more of the four characteristic [[Domain (biology)|domain]]s of [[Homology (biology)|homology]] entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4), and can form hetero- or homodimers.<ref name="Oltvai_1993"/><ref name="1995 PNAS" /> These domains are composed of nine α-helices, with a hydrophobic α-helix core surrounded by amphipathic helices and a transmembrane C-terminal α-helix anchored to the [[Mitochondrion#Outer membrane|mitochondrial outer membrane]] (MOM). A hydrophobic groove formed along the C-terminal of α2 to the N-terminal of α5, and some residues from α8, binds the BH3 domain of other BAX or BCL-2 proteins in its active form. In the protein's inactive form, the groove binds its transmembrane domain, transitioning it from a membrane-bound to a cytosolic protein. A smaller hydrophobic groove formed by the α1 and α6 helices is located on the opposite side of the protein from the major groove, and may serve as a BAX activation site.<ref name="pmid24162660">{{cite journal|last1=Westphal|first1=D|last2=Kluck|first2=RM|last3=Dewson|first3=G|title=Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis.|journal=Cell death and differentiation|date=February 2014|volume=21|issue=2|pages=196–205|pmid=24162660|doi=10.1038/cdd.2013.139|pmc=3890949}}</ref>

[[Orthologs]] of the ''BAX'' gene have been identified in most [[mammals]] for which complete genome data are available.<ref name="OrthoMaM">{{cite web | title = OrthoMaM phylogenetic marker: BAX coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000087088_BAX.xml }}</ref>

== Function ==

In healthy mammalian cells, the majority of BAX is found in the [[cytosol]], but upon initiation of apoptotic [[cell signaling|signaling]], Bax undergoes a conformational shift.  Upon induction of apoptosis, BAX becomes organelle membrane-associated, and in particular, mitochondrial membrane associated.<ref name="pmid9670005">{{cite journal |vauthors=Gross A, Jockel J, Wei MC, Korsmeyer SJ | title = Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis | journal = EMBO J. | volume = 17 | issue = 14 | pages = 3878–85 |date=July 1998| pmid = 9670005 | pmc = 1170723 | doi = 10.1093/emboj/17.14.3878 }}</ref><ref name="pmid9108035">{{cite journal |vauthors=Hsu YT, Wolter KG, Youle RJ | title = Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 8 | pages = 3668–72 |date=April 1997| pmid = 9108035 | pmc = 20498 | doi =10.1073/pnas.94.8.3668 |bibcode = 1997PNAS...94.3668H }}</ref><ref name="pmid10228148">{{cite journal |vauthors=Nechushtan A, Smith CL, Hsu YT, Youle RJ | title = Conformation of the Bax C-terminus regulates subcellular location and cell death | journal = EMBO J. | volume = 18 | issue = 9 | pages = 2330–41 |date=May 1999| pmid = 10228148 | pmc = 1171316 | doi = 10.1093/emboj/18.9.2330 }}</ref><ref name="pmid11161816">{{cite journal |vauthors=Pierrat B, Simonen M, Cueto M, Mestan J, Ferrigno P, Heim J | title = SH3GLB, a new endophilin-related protein family featuring an SH3 domain | journal = Genomics | volume = 71 | issue = 2 | pages = 222–34 |date=January 2001| pmid = 11161816 | doi = 10.1006/geno.2000.6378 }}</ref><ref name="pmid9382873">{{cite journal |vauthors=Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ | title = Movement of Bax from the cytosol to mitochondria during apoptosis | journal = J. Cell Biol. | volume = 139 | issue = 5 | pages = 1281–92 |date=December 1997| pmid = 9382873 | pmc = 2140220 | doi = 10.1083/jcb.139.5.1281 }}</ref>

BAX is believed to interact with, and induce the opening of the mitochondrial voltage-dependent anion channel, [[voltage-dependent anion channel|VDAC]].<ref name="pmid12767928">{{cite journal |vauthors=Shi Y, Chen J, Weng C, Chen R, Zheng Y, Chen Q, Tang H | title = Identification of the protein–protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins | journal = Biochem. Biophys. Res. Commun. | volume = 305 | issue = 4 | pages = 989–96 |date=June 2003| pmid = 12767928 | doi = 10.1016/S0006-291X(03)00871-4 }}</ref> Alternatively, growing evidence also suggests that activated BAX and/or [[Bcl-2 homologous antagonist killer|Bak]] form an oligomeric pore, [[MAC, the Mitochondrial Apoptosis-Induced Channel|MAC]] in the MOM.<ref name="pmid16874066">{{cite journal|vauthors=Buytaert E, Callewaert G, Vandenheede JR, Agostinis P |title=Deficiency in apoptotic effectors Bax and Bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum |journal=Autophagy |volume=2 |issue=3 |pages=238–40 |year=2006 |pmid=16874066 |doi=10.4161/auto.2730 |url=https://www.landesbioscience.com/journals/autophagy/article/2730/?nocache=1168313207 }}{{dead link|date=October 2016 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> 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]].<ref name="pmid15637055">{{cite journal |vauthors=Weng C, Li Y, Xu D, Shi Y, Tang H | title = Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells | journal = J. Biol. Chem. | volume = 280 | issue = 11 | pages = 10491–500 |date=March 2005| pmid = 15637055 | doi = 10.1074/jbc.M412819200 }}</ref> This defines a direct role for BAX in mitochondrial outer membrane permeabilization. BAX activation is stimulated by various abiotic factors, including heat, hydrogen peroxide, low or high pH, and mitochondrial membrane remodeling. In addition, it can become activated by binding BCL-2, as well as non-BCL-2 proteins such as p53 and Bif-1. Conversely, BAX can become inactivated by interacting with VDAC2, Pin1, and IBRDC2.<ref name="pmid24162660"/>

== Clinical significance ==

The expression of ''BAX'' is upregulated by the [[tumor suppressor gene|tumor suppressor]] protein [[p53]], and BAX has been shown to be involved in p53-mediated apoptosis. The p53 protein is a [[transcription factor]] 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]]. 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.<ref name="Miyashita_1994">{{cite journal |vauthors=Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC | title = Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo | journal = Oncogene | volume = 9 | issue = 6 | pages = 1799–805 |date=June 1994| pmid = 8183579 | doi = }}</ref><ref name="Selvakumaran_1994">{{cite journal |vauthors=Selvakumaran M, Lin HK, Miyashita T, Wang HG, Krajewski S, Reed JC, Hoffman B, Liebermann D | title = Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways | journal = Oncogene | volume = 9 | issue = 6 | pages = 1791–8 |date=June 1994| pmid = 8183578 | doi = }}</ref><ref name="Miyashita_1995">{{cite journal |vauthors=Miyashita T, Reed JC | title = Tumor suppressor p53 is a direct transcriptional activator of the human bax gene | journal = Cell | volume = 80 | issue = 2 | pages = 293–9 |date=January 1995| pmid = 7834749 | doi = 10.1016/0092-8674(95)90412-3 }}</ref>

Drugs that activate BAX, such as ABT737, a BH3 mimetic, hold promise as anticancer treatments by inducing apoptosis in cancer cells.<ref name="pmid24162660"/> For instance, 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.<ref name="pmid9824152">{{cite journal |vauthors=Strobel T, Tai YT, Korsmeyer S, Cannistra SA | title = BAD partly reverses paclitaxel resistance in human ovarian cancer cells | journal = Oncogene | volume = 17 | issue = 19 | pages = 2419–27 |date=November 1998| pmid = 9824152 | doi = 10.1038/sj.onc.1202180 }}</ref> Meanwhile, excessive apoptosis in such conditions as ischemia reperfusion injury and amyotrophic lateral sclerosis may benefit from drug inhibitors of BAX.<ref name="pmid24162660"/>

== Interactions ==
[[Image:Signal transduction pathways.svg|thumb|right|Overview of signal transduction pathways involved with [[apoptosis]].]]
Bcl-2-associated X protein has been shown to [[Protein–protein interaction|interact]] with:
* [[Bcl-2]],<ref name="Oltvai_1993" /><ref name="1995 PNAS">{{cite journal |vauthors=Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ |title=Multiple Bcl-2 family members demonstrate selective dimerizations with Bax |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=17 |pages=7834–8 |date=August 1995 |pmid=7644501 |pmc=41240 |doi=10.1073/pnas.92.17.7834 |bibcode=1995PNAS...92.7834S }}</ref><ref name="pmid15231068">{{cite journal |author=Hoetelmans RW |title=Nuclear partners of Bcl-2: Bax and PML |journal=DNA Cell Biol. |volume=23 |issue=6 |pages=351–4 |year=2004 |pmid=15231068 |doi=10.1089/104454904323145236 }}</ref><ref name="pmid14980220">{{cite journal |vauthors=Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK |title=Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 |journal=Cell |volume=116 |issue=4 |pages=527–40 |year=2004 |pmid=14980220 |doi =10.1016/S0092-8674(04)00162-X }}</ref><ref name="pmid10620799">{{cite journal |vauthors=Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG |title=Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis |journal=Nat. Cell Biol. |volume=2 |issue=1 |pages=1–6 |year=2000 |pmid=10620799 |doi=10.1038/71316 }}</ref> 
* [[BCL2-like 1 (gene)|BCL2L1]],<ref name="1995 PNAS" /><ref name="pmid9824152" /><ref name="pmid12137781">{{cite journal |vauthors=Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M |title=Development of a high-throughput fluorescence polarization assay for Bcl-x(L) |journal=Anal. Biochem. |volume=307 |issue=1 |pages=70–5 |year=2002 |pmid=12137781 |doi =10.1016/S0003-2697(02)00028-3 }}</ref><ref name="pmid12853473">{{cite journal |vauthors=Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken B, Schulze-Osthoff K, Daniel PT |title=Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway |journal=EMBO J. |volume=22 |issue=14 |pages=3580–90 |year=2003 |pmid=12853473 |pmc=165613 |doi=10.1093/emboj/cdg343 }}</ref> 
* [[BCL2-related protein A1|BCL2A1]]<ref name="1995 PNAS" /><ref name="pmid10753914">{{cite journal |vauthors=Zhang H, Cowan-Jacob SW, Simonen M, Greenhalf W, Heim J, Meyhack B |title=Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells |journal=J. Biol. Chem. |volume=275 |issue=15 |pages=11092–9 |year=2000 |pmid=10753914 |doi =10.1074/jbc.275.15.11092 }}</ref> 
* [[SH3GLB1]],<ref name="pmid11161816" /><ref name="pmid11259440">{{cite journal |vauthors=Cuddeback SM, Yamaguchi H, Komatsu K, Miyashita T, Yamada M, Wu C, Singh S, Wang HG |title=Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax |journal=J. Biol. Chem. |volume=276 |issue=23 |pages=20559–65 |year=2001 |pmid=11259440 |doi=10.1074/jbc.M101527200 }}</ref> 
* [[SLC25A4]],<ref name="pmid9748162">{{cite journal |vauthors=Marzo I, Brenner C, Zamzami N, Jürgensmeier JM, Susin SA, Vieira HL, Prévost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G |title=Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis |journal=Science |volume=281 |issue=5385 |pages=2027–31 |year=1998 |pmid=9748162 |doi =10.1126/science.281.5385.2027 |bibcode=1998Sci...281.2027M }}</ref> 
* [[VDAC1]],<ref name="pmid12767928" /><ref name="pmid15637055" />
* [[TCTP]],<ref name="pmid18274553">{{cite journal |author =Susini L |title =TCTP protects from apoptotic cell death by antagonizing bax function |journal =Cell Death Differ |volume= 15|pages=1211–20 |date=August 2008 |pmid=18274553 |doi=10.1038/cdd.2008.18 |url= |display-authors=etal}}</ref>
* [[YWHAQ]],<ref name="pmid12426317">{{cite journal |vauthors=Nomura M, Shimizu S, Sugiyama T, Narita M, Ito T, Matsuda H, Tsujimoto Y |title=14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax |journal=J. Biol. Chem. |volume=278 |issue=3 |pages=2058–65 |year=2003 |pmid=12426317 |doi=10.1074/jbc.M207880200 }}</ref>
*Bid,<ref name="pmid24162660" />
*Bim,<ref name="pmid24162660" />
*Puma,<ref name="pmid24162660" />
*Noxa,<ref name="pmid24162660" />
*[[MFN2|Mfn2]],<ref>{{Cite journal |last=Hoppins |first=Suzanne |last2=Edlich |first2=Frank |last3=Cleland |first3=Megan M. |last4=Banerjee |first4=Soojay |last5=McCaffery |first5=J. Michael |last6=Youle |first6=Richard J. |last7=Nunnari |first7=Jodi |title=The Soluble Form of Bax Regulates Mitochondrial Fusion via MFN2 Homotypic Complexes |url=http://linkinghub.elsevier.com/retrieve/pii/S1097276510009160 |journal=Molecular Cell |volume=41 |issue=2 |pages=150–160 |doi=10.1016/j.molcel.2010.11.030 |pmc=3072068 |pmid=21255726}}</ref>
*[[cholesterol]],<ref name="pmid24874738">{{cite journal |last1=Mignard |first1=V |last2=Lalier |first2=L |last3=Paris |first3=F |last4=Vallette |first4=FM |title=Bioactive lipids and the control of Bax pro-apoptotic activity. |journal=Cell death & disease |date=29 May 2014 |volume=5 |pages=e1266 |pmid=24874738 |doi=10.1038/cddis.2014.226 |pmc=4047880}}</ref> and
*[[cardiolipin]].<ref name="pmid24874738" />

==See also==
* [[Apoptosis]]
* [[Apoptosome]]
* [[Bcl-2]]
* [[BH3 interacting domain death agonist]] (BID)
* [[Caspases]]
* [[Cytochrome c]]
* [[Noxa]]
* [[Mitochondrion]]
* [[p53 upregulated modulator of apoptosis]] (PUMA)
{{Clear}}

==References==
{{Reflist|35em}}

{{PDB Gallery|geneid=581}}
{{Fas apoptosis signaling pathway}}

==External links==
* {{UCSC gene info|BAX}}

[[Category:Apoptosis]]
[[Category:Programmed cell death]]
[[Category:Proteins]]