RBCC Red Blood Cell Collection

BAX (BCL2L4) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Apoptosis regulator BAX (Bcl-2-like protein 4; Bcl2-L-4)

UniProt Q07812
ID BAX_HUMAN Reviewed; 192 AA.
AC Q07812; A8K4W1; P55269; Q07814; Q07815; Q8WZ49; Q9NR76; Q9NYG7;
read moreAC Q9UCZ6; Q9UCZ7; Q9UQD6;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Apoptosis regulator BAX;
DE AltName: Full=Bcl-2-like protein 4;
DE Short=Bcl2-L-4;
GN Name=BAX; Synonyms=BCL2L4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ALPHA; BETA AND GAMMA), FUNCTION,
RP SUBUNIT, AND SUBCELLULAR LOCATION.
RC TISSUE=B-cell;
RX PubMed=8358790; DOI=10.1016/0092-8674(93)90509-O;
RA Oltvai Z.N., Milliman C.L., Korsmeyer S.J.;
RT "Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that
RT accelerates programmed cell death.";
RL Cell 74:609-619(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM DELTA).
RX PubMed=7607685; DOI=10.1016/0888-7543(95)80180-T;
RA Apte S.S., Mattei M.-G., Olsen B.R.;
RT "Mapping of the human BAX gene to chromosome 19q13.3-q13.4 and
RT isolation of a novel alternatively spliced transcript, BAX delta.";
RL Genomics 26:592-594(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM EPSILON).
RC TISSUE=Brain;
RX PubMed=9920818; DOI=10.1006/bbrc.1998.0130;
RA Shi B., Triebe D., Kajiji S., Iwata K.K., Bruskin A., Mahajna J.;
RT "Identification and characterization of baxepsilon, a novel bax
RT variant missing the BH2 and the transmembrane domains.";
RL Biochem. Biophys. Res. Commun. 254:779-785(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ALPHA AND SIGMA), FUNCTION,
RP INTERACTION WITH BCL2A1 AND BCL2L1, AND TISSUE SPECIFICITY.
RX PubMed=10772918; DOI=10.1006/bbrc.2000.2537;
RA Schmitt E., Paquet C., Beauchemin M., Dever-Bertrand J., Bertrand R.;
RT "Characterization of Bax-sigma, a cell death-inducing isoform of
RT Bax.";
RL Biochem. Biophys. Res. Commun. 270:868-879(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSI), AND TISSUE SPECIFICITY.
RX PubMed=11912183; DOI=10.1093/hmg/11.6.675;
RA Cartron P.F., Oliver L., Martin S., Moreau C., LeCabellec M.T.,
RA Jezequel P., Meflah K., Vallette F.M.;
RT "The expression of a new variant of the pro-apoptotic molecule Bax,
RT Baxpsi, is correlated with an increased survival of glioblastoma
RT multiforme patients.";
RL Hum. Mol. Genet. 11:675-687(2002).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ZETA).
RC TISSUE=Ovarian carcinoma;
RA Perez R.P., Sanville H.;
RT "Bax mRNA splice variant lacking exons 2 and 3.";
RL Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA).
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 63-77 AND 98-118, AND VARIANTS ARG-67
RP AND VAL-108.
RX PubMed=7475270;
RA Meijerink J.P.P., Smetsers T.F.C.M., Sloetjes A.W., Linders E.H.P.,
RA Mensink E.J.B.M.;
RT "Bax mutations in cell lines derived from hematological
RT malignancies.";
RL Leukemia 9:1828-1832(1995).
RN [12]
RP MUTAGENESIS, AND FUNCTION OF BH3 MOTIF.
RX PubMed=8521816;
RA Chittenden T., Flemington C., Houghton A.B., Ebb R.G., Gallo G.J.,
RA Elangovan B., Chinnadurai G., Lutz R.J.;
RT "A conserved domain in Bak, distinct from BH1 and BH2, mediates cell
RT death and protein binding functions.";
RL EMBO J. 14:5589-5596(1995).
RN [13]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-184.
RX PubMed=10228148; DOI=10.1093/emboj/18.9.2330;
RA Nechushtan A., Smith C.L., Hsu Y.-T., Youle R.J.;
RT "Conformation of the Bax C-terminus regulates subcellular location and
RT cell death.";
RL EMBO J. 18:2330-2341(1999).
RN [14]
RP INTERACTION WITH SH3GLB1.
RX PubMed=11259440; DOI=10.1074/jbc.M101527200;
RA Cuddeback S.M., Yamaguchi H., Komatsu K., Miyashita T., Yamada M.,
RA Wu C., Singh S., Wang H.-G.;
RT "Molecular cloning and characterization of Bif-1. A novel Src homology
RT 3 domain-containing protein that associates with Bax.";
RL J. Biol. Chem. 276:20559-20565(2001).
RN [15]
RP INTERACTION WITH HN.
RX PubMed=12732850; DOI=10.1038/nature01627;
RA Guo B., Zhai D., Cabezas E., Welsh K., Nouraini S., Satterthwait A.C.,
RA Reed J.C.;
RT "Humanin peptide suppresses apoptosis by interfering with Bax
RT activation.";
RL Nature 423:456-461(2003).
RN [16]
RP INTERACTION WITH SFN AND YWHAZ, AND SUBCELLULAR LOCATION.
RX PubMed=15071501; DOI=10.1038/sj.emboj.7600194;
RA Tsuruta F., Sunayama J., Mori Y., Hattori S., Shimizu S.,
RA Tsujimoto Y., Yoshioka K., Masuyama N., Gotoh Y.;
RT "JNK promotes Bax translocation to mitochondria through
RT phosphorylation of 14-3-3 proteins.";
RL EMBO J. 23:1889-1899(2004).
RN [17]
RP INTERACTION WITH HHV-5 PROTEIN UL37.
RX PubMed=15004026; DOI=10.1074/jbc.M308408200;
RA Poncet D., Larochette N., Pauleau A.L., Boya P., Jalil A.A.,
RA Cartron P.F., Vallette F., Schnebelen C., Bartle L.M., Skaletskaya A.,
RA Boutolleau D., Martinou J.C., Goldmacher V.S., Kroemer G., Zamzami N.;
RT "An anti-apoptotic viral protein that recruits Bax to mitochondria.";
RL J. Biol. Chem. 279:22605-22614(2004).
RN [18]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CLU.
RX PubMed=16113678; DOI=10.1038/ncb1291;
RA Zhang H., Kim J.K., Edwards C.A., Xu Z., Taichman R., Wang C.Y.;
RT "Clusterin inhibits apoptosis by interacting with activated Bax.";
RL Nat. Cell Biol. 7:909-915(2005).
RN [19]
RP INTERACTION WITH FAIM2/LFG2.
RX PubMed=16964429;
RA Reimers K., Choi C.Y., Mau-Thek E., Vogt P.M.;
RT "Sequence analysis shows that Lifeguard belongs to a new
RT evolutionarily conserved cytoprotective family.";
RL Int. J. Mol. Med. 18:729-734(2006).
RN [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [21]
RP INTERACTION WITH RNF144B.
RX PubMed=20300062; DOI=10.1038/emboj.2010.39;
RA Benard G., Neutzner A., Peng G., Wang C., Livak F., Youle R.J.,
RA Karbowski M.;
RT "IBRDC2, an IBR-type E3 ubiquitin ligase, is a regulatory factor for
RT Bax and apoptosis activation.";
RL EMBO J. 29:1458-1471(2010).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [23]
RP INTERACTION WITH BOP/C22ORF29.
RX PubMed=23055042; DOI=10.1007/s13238-012-2069-7;
RA Zhang X., Weng C., Li Y., Wang X., Jiang C., Li X., Xu Y., Chen Q.,
RA Pan L., Tang H.;
RT "Human Bop is a novel BH3-only member of the Bcl-2 protein family.";
RL Protein Cell 3:790-801(2012).
RN [24]
RP STRUCTURE BY NMR, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=11106734; DOI=10.1016/S0092-8674(00)00167-7;
RA Suzuki M., Youle R.J., Tjandra N.;
RT "Structure of Bax: coregulation of dimer formation and intracellular
RT localization.";
RL Cell 103:645-654(2000).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 13-19 IN COMPLEX WITH
RP ANTIBODY FRAGMENT.
RX PubMed=16946732; DOI=10.1038/sj.cdd.4402025;
RA Peyerl F.W., Dai S., Murphy G.A., Crawford F., White J., Marrack P.,
RA Kappler J.W.;
RT "Elucidation of some Bax conformational changes through
RT crystallization of an antibody-peptide complex.";
RL Cell Death Differ. 14:447-452(2007).
RN [26]
RP STRUCTURE BY NMR IN COMPLEX WITH BCL2L11, FUNCTION, SUBUNIT,
RP MUTAGENESIS OF LYS-21, AND INTERACTION WITH BCL2L11.
RX PubMed=18948948; DOI=10.1038/nature07396;
RA Gavathiotis E., Suzuki M., Davis M.L., Pitter K., Bird G.H.,
RA Katz S.G., Tu H.C., Kim H., Cheng E.H., Tjandra N., Walensky L.D.;
RT "BAX activation is initiated at a novel interaction site.";
RL Nature 455:1076-1081(2008).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 48-81 IN COMPLEXES WITH
RP BCL2L1 AND MCL1, INTERACTION WITH MCL1; BCL2; BCL2L1 AND BCL2L2,
RP FUNCTION, AND MUTAGENESIS OF MET-74.
RX PubMed=21199865; DOI=10.1074/jbc.M110.161281;
RA Czabotar P.E., Lee E.F., Thompson G.V., Wardak A.Z., Fairlie W.D.,
RA Colman P.M.;
RT "Mutation to Bax beyond the BH3 domain disrupts interactions with pro-
RT survival proteins and promotes apoptosis.";
RL J. Biol. Chem. 286:7123-7131(2011).
RN [28]
RP VARIANTS GLU-11; ARG-67 AND VAL-108.
RX PubMed=9531611;
RA Meijerink J.P.P., Mensink E.J.B.M., Wang K., Sedlak T.W.,
RA Sloetjes A.W., de Witte T., Waksman G., Korsmeyer S.J.;
RT "Hematopoietic malignancies demonstrate loss-of-function mutations of
RT BAX.";
RL Blood 91:2991-2997(1998).
CC -!- FUNCTION: Accelerates programmed cell death by binding to, and
CC antagonizing the apoptosis repressor BCL2 or its adenovirus
CC homolog E1B 19k protein. Under stress conditions, undergoes a
CC conformation change that causes translocation to the mitochondrion
CC membrane, leading to the release of cytochrome c that then
CC triggers apoptosis. Promotes activation of CASP3, and thereby
CC apoptosis.
CC -!- SUBUNIT: Homodimer. Forms higher oligomers under stress
CC conditions. Interacts with BCL2L11. Interaction with BCL2L11
CC promotes BAX oligomerization and association with mitochondrial
CC membranes, with subsequent release of cytochrome c. Forms
CC heterodimers with BCL2, E1B 19K protein, BCL2L1 isoform Bcl-X(L),
CC BCL2L2, MCL1 and A1. Interacts with SH3GLB1 and HN. Interacts with
CC SFN and YWHAZ; the interaction occurs in the cytoplasm. Under
CC stress conditions, JNK-mediated phosphorylation of SFN and YWHAZ,
CC releases BAX to mitochondria. Isoform Sigma interacts with BCL2A1
CC and BCL2L1 isoform Bcl-X(L). Interacts with RNF144B, which
CC regulates the ubiquitin-dependent stability of BAX. Interacts with
CC CLU under stress conditions that cause a conformation change
CC leading to BAX oligomerization and association with mitochondria.
CC Does not interact with CLU in unstressed cells. Interacts with
CC FAIM2/LFG2. Interacts with human cytomegalovirus/HHV-5 protein
CC vMIA/UL37. Interacts with BOP/C22orf29.
CC -!- INTERACTION:
CC Self; NbExp=27; IntAct=EBI-516580, EBI-516580;
CC Q16611:BAK1; NbExp=5; IntAct=EBI-516580, EBI-519866;
CC P10415:BCL2; NbExp=9; IntAct=EBI-516580, EBI-77694;
CC Q07817:BCL2L1; NbExp=3; IntAct=EBI-516580, EBI-78035;
CC Q07817-1:BCL2L1; NbExp=13; IntAct=EBI-516580, EBI-287195;
CC O43521:BCL2L11; NbExp=19; IntAct=EBI-516580, EBI-526406;
CC Q92843:BCL2L2; NbExp=3; IntAct=EBI-516580, EBI-707714;
CC P55957:BID; NbExp=15; IntAct=EBI-516580, EBI-519672;
CC P70444:Bid (xeno); NbExp=2; IntAct=EBI-516580, EBI-2128640;
CC O75460:ERN1; NbExp=2; IntAct=EBI-516580, EBI-371750;
CC Q07820:MCL1; NbExp=6; IntAct=EBI-516580, EBI-1003422;
CC P97287:Mcl1 (xeno); NbExp=2; IntAct=EBI-516580, EBI-707292;
CC Q9ULZ3:PYCARD; NbExp=7; IntAct=EBI-516580, EBI-751215;
CC Q7Z419:RNF144B; NbExp=5; IntAct=EBI-516580, EBI-2129982;
CC Q9Y371-1:SH3GLB1; NbExp=2; IntAct=EBI-516580, EBI-5291808;
CC P24391:tom-40 (xeno); NbExp=2; IntAct=EBI-516580, EBI-1791540;
CC P49334:TOM22 (xeno); NbExp=3; IntAct=EBI-516580, EBI-12527;
CC P23644:TOM40 (xeno); NbExp=2; IntAct=EBI-516580, EBI-12539;
CC P07213:TOM70 (xeno); NbExp=2; IntAct=EBI-516580, EBI-12551;
CC Q9P2Y5:UVRAG; NbExp=6; IntAct=EBI-516580, EBI-2952704;
CC P17361:VACWR028 (xeno); NbExp=3; IntAct=EBI-516580, EBI-7115640;
CC P12956:XRCC6; NbExp=2; IntAct=EBI-516580, EBI-353208;
CC -!- SUBCELLULAR LOCATION: Isoform Alpha: Mitochondrion membrane;
CC Single-pass membrane protein. Cytoplasm. Note=Colocalizes with 14-
CC 3-3 proteins in the cytoplasm. Under stress conditions, undergoes
CC a conformation change that causes release from JNK-phosphorylated
CC 14-3-3 proteins and translocation to the mitochondrion membrane.
CC -!- SUBCELLULAR LOCATION: Isoform Beta: Cytoplasm.
CC -!- SUBCELLULAR LOCATION: Isoform Gamma: Cytoplasm.
CC -!- SUBCELLULAR LOCATION: Isoform Delta: Cytoplasm (Potential).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=Alpha;
CC IsoId=Q07812-1; Sequence=Displayed;
CC Name=Beta;
CC IsoId=Q07812-2, Q07814-1;
CC Sequence=VSP_031237;
CC Name=Gamma;
CC IsoId=Q07812-3, Q07815-1;
CC Sequence=VSP_031234, VSP_031236;
CC Name=Delta;
CC IsoId=Q07812-4, P55269-1;
CC Sequence=VSP_031235;
CC Name=Epsilon;
CC IsoId=Q07812-5; Sequence=VSP_031240;
CC Name=Zeta;
CC IsoId=Q07812-6; Sequence=VSP_031239;
CC Name=Psi;
CC IsoId=Q07812-7; Sequence=VSP_031238;
CC Name=Sigma;
CC IsoId=Q07812-8; Sequence=VSP_037475;
CC -!- TISSUE SPECIFICITY: Expressed in a wide variety of tissues.
CC Isoform Psi is found in glial tumors. Isoform Alpha is expressed
CC in spleen, breast, ovary, testis, colon and brain, and at low
CC levels in skin and lung. Isoform Sigma is expressed in spleen,
CC breast, ovary, testis, lung, colon, brain and at low levels in
CC skin. Isoform Alpha and isoform Sigma are expressed in pro-
CC myelocytic leukemia, histiocytic lymphoma, Burkitt's lymphoma, T-
CC cell lymphoma, lymphoblastic leukemia, breast adenocarcinoma,
CC ovary adenocarcinoma, prostate carcinoma, prostate adenocarcinoma,
CC lung carcinoma, epidermoid carcinoma, small cell lung carcinoma
CC and colon adenocarcinoma cell lines.
CC -!- DOMAIN: Intact BH3 motif is required by BIK, BID, BAK, BAD and BAX
CC for their pro-apoptotic activity and for their interaction with
CC anti-apoptotic members of the Bcl-2 family (By similarity).
CC -!- SIMILARITY: Belongs to the Bcl-2 family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/bax/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/BAXID128ch19q13.html";
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DR EMBL; L22473; AAA03619.1; -; mRNA.
DR EMBL; L22474; AAA03620.1; -; mRNA.
DR EMBL; L22475; AAA03621.1; -; mRNA.
DR EMBL; U19599; AAC50142.1; -; mRNA.
DR EMBL; AF007826; AAD22706.1; -; mRNA.
DR EMBL; AF247393; AAF71267.1; -; mRNA.
DR EMBL; AJ417988; CAD10744.1; -; mRNA.
DR EMBL; AF250190; AAF82094.1; -; mRNA.
DR EMBL; AK291076; BAF83765.1; -; mRNA.
DR EMBL; AY217036; AAO22992.1; -; Genomic_DNA.
DR EMBL; CH471177; EAW52418.1; -; Genomic_DNA.
DR EMBL; CH471177; EAW52417.1; -; Genomic_DNA.
DR EMBL; BC014175; AAH14175.1; -; mRNA.
DR PIR; A47538; A47538.
DR PIR; B47538; B47538.
DR PIR; C47538; C47538.
DR PIR; I38921; I38921.
DR PIR; JC7255; JC7255.
DR RefSeq; NP_004315.1; NM_004324.3.
DR RefSeq; NP_620116.1; NM_138761.3.
DR RefSeq; NP_620118.1; NM_138763.3.
DR RefSeq; NP_620119.2; NM_138764.4.
DR UniGene; Hs.624291; -.
DR PDB; 1F16; NMR; -; A=1-192.
DR PDB; 2G5B; X-ray; 2.30 A; I/J/K/L=13-19.
DR PDB; 2K7W; NMR; -; A=1-192.
DR PDB; 2LR1; NMR; -; A=1-192.
DR PDB; 3PK1; X-ray; 2.49 A; B/D=48-81.
DR PDB; 3PL7; X-ray; 2.61 A; C=48-81.
DR PDB; 4BD2; X-ray; 2.21 A; A=1-171.
DR PDB; 4BD6; X-ray; 2.49 A; A=1-171, C=48-81.
DR PDB; 4BD7; X-ray; 2.80 A; A/B/C/D=1-171.
DR PDB; 4BD8; X-ray; 2.22 A; A/B/C/D=1-171.
DR PDB; 4BDU; X-ray; 3.00 A; A/B/C/D=53-128.
DR PDBsum; 1F16; -.
DR PDBsum; 2G5B; -.
DR PDBsum; 2K7W; -.
DR PDBsum; 2LR1; -.
DR PDBsum; 3PK1; -.
DR PDBsum; 3PL7; -.
DR PDBsum; 4BD2; -.
DR PDBsum; 4BD6; -.
DR PDBsum; 4BD7; -.
DR PDBsum; 4BD8; -.
DR PDBsum; 4BDU; -.
DR ProteinModelPortal; Q07812; -.
DR SMR; Q07812; 1-192.
DR DIP; DIP-232N; -.
DR IntAct; Q07812; 32.
DR MINT; MINT-134330; -.
DR BindingDB; Q07812; -.
DR ChEMBL; CHEMBL5318; -.
DR TCDB; 1.A.21.1.2; the bcl-2 (bcl-2) family.
DR PhosphoSite; Q07812; -.
DR DMDM; 728945; -.
DR PaxDb; Q07812; -.
DR PRIDE; Q07812; -.
DR DNASU; 581; -.
DR Ensembl; ENST00000293288; ENSP00000293288; ENSG00000087088.
DR Ensembl; ENST00000345358; ENSP00000263262; ENSG00000087088.
DR Ensembl; ENST00000354470; ENSP00000346461; ENSG00000087088.
DR Ensembl; ENST00000356483; ENSP00000348871; ENSG00000087088.
DR Ensembl; ENST00000391871; ENSP00000375744; ENSG00000087088.
DR Ensembl; ENST00000415969; ENSP00000389971; ENSG00000087088.
DR Ensembl; ENST00000515540; ENSP00000426328; ENSG00000087088.
DR Ensembl; ENST00000539787; ENSP00000441413; ENSG00000087088.
DR GeneID; 581; -.
DR KEGG; hsa:581; -.
DR UCSC; uc002plk.3; human.
DR CTD; 581; -.
DR GeneCards; GC19P049458; -.
DR HGNC; HGNC:959; BAX.
DR HPA; CAB004206; -.
DR HPA; HPA027878; -.
DR MIM; 600040; gene.
DR neXtProt; NX_Q07812; -.
DR PharmGKB; PA25269; -.
DR eggNOG; NOG46695; -.
DR HOVERGEN; HBG003606; -.
DR KO; K02159; -.
DR OMA; ADMFADG; -.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; BAX; human.
DR EvolutionaryTrace; Q07812; -.
DR GeneWiki; Bcl-2-associated_X_protein; -.
DR GenomeRNAi; 581; -.
DR NextBio; 2371; -.
DR PMAP-CutDB; Q07812; -.
DR PRO; PR:Q07812; -.
DR ArrayExpress; Q07812; -.
DR Bgee; Q07812; -.
DR CleanEx; HS_BAX; -.
DR Genevestigator; Q07812; -.
DR GO; GO:0097136; C:Bcl-2 family protein complex; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:HGNC.
DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR GO; GO:0005757; C:mitochondrial permeability transition pore complex; IDA:HGNC.
DR GO; GO:0005634; C:nucleus; IMP:UniProtKB.
DR GO; GO:0051434; F:BH3 domain binding; IDA:UniProtKB.
DR GO; GO:0015267; F:channel activity; IDA:BHF-UCL.
DR GO; GO:0008289; F:lipid binding; IDA:HGNC.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:HGNC.
DR GO; GO:0008635; P:activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c; IDA:HGNC.
DR GO; GO:0006309; P:apoptotic DNA fragmentation; IMP:HGNC.
DR GO; GO:0001782; P:B cell homeostasis; IEA:Ensembl.
DR GO; GO:0002358; P:B cell homeostatic proliferation; IEA:Ensembl.
DR GO; GO:0002352; P:B cell negative selection; IEA:Ensembl.
DR GO; GO:1990117; P:B cell receptor apoptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0001974; P:blood vessel remodeling; IEA:Ensembl.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:Ensembl.
DR GO; GO:0071310; P:cellular response to organic substance; IEA:Ensembl.
DR GO; GO:0034644; P:cellular response to UV; IEA:Ensembl.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0006922; P:cleavage of lamin involved in execution phase of apoptosis; IMP:HGNC.
DR GO; GO:0045136; P:development of secondary sexual characteristics; IEA:Ensembl.
DR GO; GO:0010248; P:establishment or maintenance of transmembrane electrochemical gradient; IDA:HGNC.
DR GO; GO:0009566; P:fertilization; IEA:Ensembl.
DR GO; GO:0007281; P:germ cell development; IEA:Ensembl.
DR GO; GO:0035234; P:germ cell programmed cell death; IEA:Ensembl.
DR GO; GO:0006687; P:glycosphingolipid metabolic process; IEA:Ensembl.
DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; IEA:Ensembl.
DR GO; GO:0021854; P:hypothalamus development; IEA:Ensembl.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; IMP:UniProtKB.
DR GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR GO; GO:0035108; P:limb morphogenesis; IEA:Ensembl.
DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IDA:HGNC.
DR GO; GO:0008053; P:mitochondrial fusion; IDA:HGNC.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0002262; P:myeloid cell homeostasis; IEA:Ensembl.
DR GO; GO:0032471; P:negative regulation of endoplasmic reticulum calcium ion concentration; IEA:Ensembl.
DR GO; GO:0048147; P:negative regulation of fibroblast proliferation; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; IEA:Ensembl.
DR GO; GO:0032091; P:negative regulation of protein binding; IDA:UniProtKB.
DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:0030264; P:nuclear fragmentation involved in apoptotic nuclear change; IMP:HGNC.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
DR GO; GO:0001541; P:ovarian follicle development; IEA:Ensembl.
DR GO; GO:0060058; P:positive regulation of apoptotic process involved in mammary gland involution; IEA:Ensembl.
DR GO; GO:0002904; P:positive regulation of B cell apoptotic process; IEA:Ensembl.
DR GO; GO:0048087; P:positive regulation of developmental pigmentation; IEA:Ensembl.
DR GO; GO:1900103; P:positive regulation of endoplasmic reticulum unfolded protein response; IMP:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization; TAS:Reactome.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IDA:HGNC.
DR GO; GO:0032461; P:positive regulation of protein oligomerization; IDA:UniProtKB.
DR GO; GO:0090200; P:positive regulation of release of cytochrome c from mitochondria; IDA:UniProtKB.
DR GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IEA:Ensembl.
DR GO; GO:0048597; P:post-embryonic camera-type eye morphogenesis; IEA:Ensembl.
DR GO; GO:0051260; P:protein homooligomerization; IDA:HGNC.
DR GO; GO:0001844; P:protein insertion into mitochondrial membrane involved in apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0051726; P:regulation of cell cycle; IEA:Ensembl.
DR GO; GO:0033599; P:regulation of mammary gland epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0051881; P:regulation of mitochondrial membrane potential; IDA:HGNC.
DR GO; GO:0006808; P:regulation of nitrogen utilization; IEA:Ensembl.
DR GO; GO:0043497; P:regulation of protein heterodimerization activity; IPI:HGNC.
DR GO; GO:0043496; P:regulation of protein homodimerization activity; IDA:HGNC.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IDA:HGNC.
DR GO; GO:0032976; P:release of matrix enzymes from mitochondria; IDA:HGNC.
DR GO; GO:0001101; P:response to acid; IEA:Ensembl.
DR GO; GO:0048678; P:response to axon injury; IEA:Ensembl.
DR GO; GO:0010332; P:response to gamma radiation; IEA:Ensembl.
DR GO; GO:0009651; P:response to salt stress; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IDA:HGNC.
DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl.
DR GO; GO:1990009; P:retinal cell apoptotic process; IMP:HGNC.
DR GO; GO:0046666; P:retinal cell programmed cell death; IEA:Ensembl.
DR GO; GO:0060011; P:Sertoli cell proliferation; IEA:Ensembl.
DR GO; GO:0048515; P:spermatid differentiation; IEA:Ensembl.
DR GO; GO:0001777; P:T cell homeostatic proliferation; IEA:Ensembl.
DR GO; GO:0006927; P:transformed cell apoptotic process; IMP:HGNC.
DR GO; GO:0060068; P:vagina development; IEA:Ensembl.
DR InterPro; IPR026304; BAX.
DR InterPro; IPR002475; Bcl2-like.
DR InterPro; IPR020717; Bcl2_BH1_motif_CS.
DR InterPro; IPR020726; Bcl2_BH2_motif_CS.
DR InterPro; IPR020728; Bcl2_BH3_motif_CS.
DR InterPro; IPR026298; Blc2_fam.
DR PANTHER; PTHR11256; PTHR11256; 1.
DR PANTHER; PTHR11256:SF9; PTHR11256:SF9; 1.
DR Pfam; PF00452; Bcl-2; 1.
DR PRINTS; PR01862; BCL2FAMILY.
DR PROSITE; PS50062; BCL2_FAMILY; 1.
DR PROSITE; PS01080; BH1; 1.
DR PROSITE; PS01258; BH2; 1.
DR PROSITE; PS01259; BH3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Apoptosis;
KW Complete proteome; Cytoplasm; Host-virus interaction; Membrane;
KW Mitochondrion; Polymorphism; Reference proteome; Transmembrane;
KW Transmembrane helix; Tumor suppressor.
FT CHAIN 1 192 Apoptosis regulator BAX.
FT /FTId=PRO_0000143053.
FT TRANSMEM 172 192 Helical; (Potential).
FT MOTIF 59 73 BH3.
FT MOTIF 98 118 BH1.
FT MOTIF 150 165 BH2.
FT MOD_RES 1 1 N-acetylmethionine.
FT VAR_SEQ 1 78 Missing (in isoform Zeta).
FT /FTId=VSP_031239.
FT VAR_SEQ 1 19 Missing (in isoform Psi).
FT /FTId=VSP_031238.
FT VAR_SEQ 12 41 GPTSSEQIMKTGALLLQGFIQDRAGRMGGE -> VSSRIEQ
FT GEWGGRHPSWPWTRCLRMRPPRS (in isoform
FT Gamma).
FT /FTId=VSP_031234.
FT VAR_SEQ 30 78 Missing (in isoform Delta).
FT /FTId=VSP_031235.
FT VAR_SEQ 42 192 Missing (in isoform Gamma).
FT /FTId=VSP_031236.
FT VAR_SEQ 125 192 LCTKVPELIRTIMGWTLDFLRERLLGWIQDQGGWDGLLSYF
FT GTPTWQTVTIFVAGVLTASLTIWKKMG -> GVKWRDLGSL
FT QPLPPGFKRFTCLSIPRSWDYRPCAPRCRN (in
FT isoform Epsilon).
FT /FTId=VSP_031240.
FT VAR_SEQ 159 192 DGLLSYFGTPTWQTVTIFVAGVLTASLTIWKKMG -> VRL
FT LKPPHPHHRALTTAPAPPSLPPATPLGPWAFWSRSQWCPLP
FT IFRSSDVVYNAFSLRV (in isoform Beta).
FT /FTId=VSP_031237.
FT VAR_SEQ 159 171 Missing (in isoform Sigma).
FT /FTId=VSP_037475.
FT VARIANT 11 11 G -> E (in a plasmacytoma cell line).
FT /FTId=VAR_013575.
FT VARIANT 39 39 G -> R (in dbSNP:rs36017265).
FT /FTId=VAR_047053.
FT VARIANT 67 67 G -> R (in a T-cell acute lymphoblastic
FT leukemia cell line; loss of
FT heterodimerization with Bcl-2 or Bcl-
FT X(L)).
FT /FTId=VAR_007809.
FT VARIANT 108 108 G -> V (in a Burkitt lymphoma; loss of
FT homodimerization).
FT /FTId=VAR_013576.
FT MUTAGEN 21 21 K->E: Reduces interaction with BCL2L11,
FT homooligomerization and triggering of
FT apoptosis.
FT MUTAGEN 74 74 M->D,E: Strongly reduced interaction with
FT MCL1, BCL2, BCL2L1 and BCL2L2. No effect
FT on cytochrome c release and subsequent
FT apoptosis triggered by etoposide.
FT MUTAGEN 184 184 S->D,E,H,K: Constitutive cytoplasmic
FT location.
FT MUTAGEN 184 184 S->V: Constitutive mitochondrial
FT location.
FT TURN 2 4
FT STRAND 10 14
FT HELIX 16 36
FT STRAND 43 45
FT HELIX 54 72
FT HELIX 74 82
FT HELIX 88 99
FT TURN 100 102
FT HELIX 107 147
FT HELIX 149 154
FT TURN 155 158
FT HELIX 159 164
FT HELIX 171 188
SQ SEQUENCE 192 AA; 21184 MW; 6C0CDB0A7DEE4994 CRC64;
MDGSGEQPRG GGPTSSEQIM KTGALLLQGF IQDRAGRMGG EAPELALDPV PQDASTKKLS
ECLKRIGDEL DSNMELQRMI AAVDTDSPRE VFFRVAADMF SDGNFNWGRV VALFYFASKL
VLKALCTKVP ELIRTIMGWT LDFLRERLLG WIQDQGGWDG LLSYFGTPTW QTVTIFVAGV
LTASLTIWKK MG
//

MIM 600040
*RECORD*
*FIELD* NO
600040
*FIELD* TI
*600040 BCL2-ASSOCIATED X PROTEIN; BAX
*FIELD* TX

DESCRIPTION

The proapoptotic BAX protein induces cell death by acting on
read moremitochondria.

CLONING

Oltvai et al. (1993) identified BAX as a protein partner of BCL2
(151430).

GENE FUNCTION

Development as well as maintenance of many adult tissues is achieved by
several dynamically regulated processes that include cell proliferation,
differentiation, and programmed cell death. Oltvai et al. (1993) noted
that, in the latter process, cells are eliminated by a highly
characteristic suicide program called apoptosis. The best-defined
genetic pathway of cell death exists in the nematode Caenorhabditis
elegans. Two autosomal recessive death effector genes, ced-3 and ced-4,
are required for the death of all 131 cells destined to die during worm
development. One autosomal dominant death repressor gene, ced-9, can
save those cells in its gain-of-function form. This implies that both
effector and repressor genes also exist within each mammalian cell death
pathway. BCL2 is one such mammalian gene that has been identified; it
functions as a repressor of programmed cell death.

Oltvai et al. (1993) showed that BCL2 associates in vivo with a 21-kD
program partner, BAX. BAX shows extensive amino acid homology with BCL2
and forms homodimers and heterodimers with BCL2 in vivo. When BAX
predominates, programmed cell death is accelerated, and the death
repressor activity of BCL2 is countered. Their findings suggested to
Oltvai et al. (1993) a model in which the ratio of BCL2 to BAX
determines survival or death following an apoptotic stimulus.

The BAX gene promoter region contains 4 motifs with homology to
consensus p53-binding sites. In cotransfection assays using
p53-deficient tumor cell lines, Miyashita and Reed (1995) found that
wildtype but not mutant p53 expression plasmids transactivated a
reporter gene plasmid that utilized the BAX gene promoter to drive
transcription of chloramphenicol acetyltransferase. Introduction of
mutations into the consensus p53-binding site sequences abolished p53
responsiveness of the reporter gene plasmids. Taken together, the
results suggested that BAX is a primary-response gene for p53 (191170)
and is involved in a p53-regulated pathway for induction of apoptosis.

Apte et al. (1995) isolated a BAX cDNA clone in which the mRNA encoded
by exon 3 was absent. The skipping of exon 3 predicted the existence of
an interstitially truncated form of the major BAX protein (BAX-alpha),
termed BAX-delta. Unlike 2 previously described variant forms, BAX-delta
retains the functionally critical C-terminal membrane anchor region, as
well as the BCL2 homology 1 and 2 (BH1 and BH2) domains.

Cartron et al. (2002) examined the expression of BAX in 55 patients with
glioblastoma multiforme (see 137800), the most common and aggressive
form of brain tumors. The authors identified a novel form of BAX,
designated BAX-psi, which was present in 24% of the patients. BAX-psi is
an N-terminal truncated form of BAX which results from a partial
deletion of exon 1 of the BAX gene. BAX-psi and the wildtype form,
BAX-alpha, are encoded by distinct mRNAs, both of which are present in
normal tissues. Glial tumors expressed either BAX-alpha or BAX-psi
proteins, an apparent consequence of an exclusive transcription of the
corresponding mRNAs. The BAX-psi protein was preferentially localized to
mitochondria and was a more powerful inducer of apoptosis than
BAX-alpha. BAX-psi tumors exhibited slower proliferation in Swiss nude
mice, and this feature could be circumvented by the coexpression of the
BCL2 (151430) transgene, the functional antagonist of BAX. The
expression of BAX-psi correlated with a longer survival in patients (18
months versus 10 months for BAX-alpha patients). The authors
hypothesized a beneficial involvement of the psi variant of BAX in tumor
progression.

During transduction of an apoptotic signal into the cell, there is an
alteration in the permeability of the membranes of the cell's
mitochondria, which causes the translocation of the apoptogenic protein
cytochrome c into the cytoplasm, which in turn activates death-driving
proteolytic proteins known as caspases (see 147678). The BCL2 family of
proteins, whose members may be antiapoptotic or proapoptotic, regulates
cell death by controlling this mitochondrial membrane permeability
during apoptosis. Shimizu et al. (1999) created liposomes that carried
the mitochondrial porin channel VDAC (604492) to show that the
recombinant proapoptotic proteins Bax and Bak (600516) accelerate the
opening of VDAC, whereas the antiapoptotic protein BCLXL (600039) closes
VDAC by binding to it directly. Bax and Bak allow cytochrome c to pass
through VDAC out of liposomes, but passage is prevented by BCLXL. In
agreement with this, VDAC1-deficient mitochondria from a mutant yeast
did not exhibit a Bax/Bak-induced loss in membrane potential and
cytochrome c release, both of which were inhibited by BCLXL. Shimizu et
al. (1999) concluded that the BCL2 family of proteins bind to the VDAC
in order to regulate the mitochondrial membrane potential and the
release of cytochrome c during apoptosis.

Since the BAX protein regulates apoptosis in a cellular pathway that
involves both BCL2 and p53, 2 molecules associated with human glioma
agenesis, Chou et al. (1996) evaluated the possibility that BAX
functions as a glioma tumor suppressor gene. Somatic cell hybrid panels,
fluorescence in situ hybridization, and cosmid mapping localized the BAX
gene to 19q13.3 at the telomeric end of the glioma candidate region
frequently deleted in gliomas. However, routine and pulsed field gel
electrophoresis/Southern blotting studies failed to reveal large scale
deletions or rearrangements of the BAX gene in gliomas. In addition,
SSCP analysis of 6 BAX exons and flanking intronic sequences did not
disclose mutations in 20 gliomas with allelic loss of the other copy of
19q. Thus, BAX is probably not the 19q glioma tumor suppressor gene.

To assess the role of BAX in drug-induced apoptosis in human colorectal
cancer cells (HCT116 cells), Zhang et al. (2000) generated cells that
lacked functional BAX genes. Such cells were partially resistant to the
apoptotic effects of the chemotherapeutic agent 5-fluorouracil, but
apoptosis was not abolished. In contrast, the absence of BAX completely
abolished the apoptotic response to the chemopreventive agent sulindac
and other nonsteroidal antiinflammatory drugs (NSAIDs). NSAIDs inhibited
the expression of the antiapoptotic protein BCLXL, resulting in an
altered ratio of BAX to BCLXL and subsequent mitochondria-mediated cell
death. Zhang et al. (2000) concluded that their results establish an
unambiguous role for BAX in apoptotic processes in human epithelial
cancers and may have implications for cancer chemoprevention strategies.

Studies of Bax-deficient mice indicated that the proapoptotic BAX
molecule can function as a tumor suppressor. For that reason, Meijerink
et al. (1998) examined human hematopoietic malignancies and found that
approximately 21% of cell lines possessed mutations in BAX, perhaps most
commonly in the acute lymphoblastic leukemia (ALL; 613065) subset. Both
T-cell and B-cell lines contained BAX somatic mutations. Approximately
half were nucleotide insertions or deletions within a deoxyguanosine
(G8) tract, resulting in a proximal frameshift and loss of
immunodetectable BAX protein. Other BAX mutants bore single amino acid
substitutions within BH1 or BH3 domains, demonstrated altered patterns
of protein dimerization, and had lost death-promoting activity.

The proapoptotic BAX protein induces cell death by acting on the
mitochondria. BAX binds to the permeability transition pore complex
(PTPC), a composite proteaceous channel that is involved in the
regulation of mitochondrial membrane permeability. Marzo et al. (1998)
found that immunodepletion of Bax from PTPC or purification of PTPC from
Bax-deficient mice yielded a PTPC that could not permeabilize membranes
in response to atractyloside, a proapoptotic ligand of the adenine
nucleotide translocator (ANT; 103220). Bax and ANT coimmunoprecipitated
and interacted in the yeast 2-hybrid system. Ectopic expression of Bax
induced cell death in wildtype but not in ANT-deficient yeast.
Recombinant Bax and purified ANT, but neither of them alone, efficiently
formed atractyloside-responsive channels in artificial membranes. Hence,
the proapoptotic molecule Bax and the constitutive mitochondrial protein
ANT cooperate within the PTPC to increase mitochondrial membrane
permeability and to trigger cell death.

The caspase-activated form of BID (601997), tBID, triggers the
homooligomerization of multidomain conserved proapoptotic family members
BAK or BAX, resulting in the release of cytochrome c from mitochondria.
Wei et al. (2001) found that cells lacking both BAK and BAX, but not
cells lacking only one of these components, are completely resistant to
tBID-induced cytochrome c release and apoptosis. Moreover, doubly
deficient cells are resistant to multiple apoptotic stimuli that act
through disruption of mitochondrial function: staurosporine, ultraviolet
radiation, growth factor deprivation, etoposide, and the endoplasmic
reticulum stress stimuli thapsigargin and tunicamycin. Thus, Wei et al.
(2001) concluded that activation of a 'multidomain' proapoptotic member,
BAK or BAX, appears to be an essential gateway to mitochondrial
dysfunction required for cell death in response to diverse stimuli.

Polycyclic aromatic hydrocarbons (PAHs) are toxic chemicals released
into the environment by fossil fuel combustion. Oocyte destruction and
ovarian failure occur in PAH-treated mice, and cigarette smoking causes
early menopause in women. In many cells, PAHs activate the aromatic
hydrocarbon receptor (AHR; 600253), a member of the Per-Arnt-Sim family
of transcription factors. The AHR is also activated by dioxin, one of
the most intensively studied environmental contaminants. Matikainen et
al. (2001) demonstrated that exposure of mice to PAHs induces the
expression of Bax in oocytes, followed by apoptosis. Ovarian damage
caused by PAHs is prevented by Ahr or Bax inactivation. Oocytes
microinjected with a Bax promoter-reporter construct show Ahr-dependent
transcriptional activation after PAH, but not dioxin, treatment,
consistent with findings that dioxin is not cytotoxic to oocytes. This
difference in the action of PAHs versus dioxin is conveyed by a single
basepair flanking each Ahr response element in the Bax promoter. Oocytes
in human ovarian biopsies grafted into immunodeficient mice also
accumulated Bax and underwent apoptosis after PAH exposure in vivo.
Thus, Matikainen et al. (2001) concluded that AHR-driven BAX
transcription is a novel and evolutionarily conserved cell-death
signaling pathway responsible for environmental toxicant-induced ovarian
failure.

To investigate the relationship between apoptosis and the BCL2/BAX
system in the human corpus luteum, Sugino et al. (2000) examined the
frequency of apoptosis and expression of BCL2 and BAX in the corpus
luteum during the menstrual cycle and in early pregnancy.
Immunohistochemistry revealed BCL2 expression in the luteal cells in the
midluteal phase and early pregnancy, but not in the regressing corpus
luteum. In contrast, BAX immunostaining was observed in the regressing
corpus luteum, but not in the midluteal phase or early pregnancy. The
BCL2 mRNA levels in the corpus luteum during the menstrual cycle were
highest in the midluteal phase and lowest in the regressing corpus
luteum. In the corpus luteum of early pregnancy, BCL2 mRNA levels were
significantly higher than those in the midluteal phase. In contrast, BAX
mRNA levels were highest in the regressing corpus luteum and remarkably
low in the corpus luteum of early pregnancy. When corpora lutea of the
midluteal phase were incubated with CG (see 118850), CG significantly
increased the mRNA and protein levels of BCL2 and significantly
decreased those of BAX. Sugino et al. (2000) concluded that BCL2 and BAX
may play important roles in the regulation of the life span of the human
corpus luteum by controlling the rate of apoptosis. CG may act to
prolong the life span of the corpus luteum by increasing BCL2 expression
and decreasing BAX expression when pregnancy occurs.

Li et al. (2001) found increased levels of BAX and its mRNA in the
stroma but not in the endothelium of Fuchs dystrophy (see 136800)
corneas. Following exposure to camptothecin (a DNA synthesis inhibitor
known to induce apoptosis in vitro), keratocytes from patients produced
an increased level of BAX and a low level of BCL2 distinctly different
from the response of normal keratocytes. The authors concluded that
their results point to a disease-related disturbance in the regulation
of apoptosis in Fuchs dystrophy. They proposed that excessive apoptosis
might be an important mechanism in the pathogenesis of Fuchs dystrophy.

Vaskivuo et al. (2001) investigated the extent and localization of
apoptosis in human fetal (aged 13 to 40 weeks) and adult ovaries. They
also studied the expression of apoptosis-regulating proteins BCL2 and
BAX. Expression of BCL2 was observed only in the youngest fetal ovaries
(weeks 13 to 14), and BAX was present in the ovaries throughout the
entire fetal period. In adult ovaries, apoptosis was detected in
granulosa cells of secondary and antral follicles, and BCL2 and BAX were
expressed from primary follicles onwards. Apoptosis was found in ovarian
follicles throughout fetal and adult life. During fetal development,
apoptosis was localized mainly to primary oocytes and was highest
between weeks 14 and 28, decreasing thereafter toward term.

LeBlanc et al. (2002) demonstrated that BAX can be essential for death
receptor-mediated apoptosis in cancer cells. BAX-deficient human colon
carcinoma cells were resistant to death-receptor ligands, whereas
BAX-expressing sister clones were sensitive. BAX was dispensable for
apical death-receptor signaling events including caspase-8 (601763)
activation, but crucial for mitochondrial changes and downstream caspase
activation. Treatment of colon cancer cells deficient in DNA mismatch
repair with the TRAIL (603598) selected in vitro or in vivo for
refractory subclones with BAX frameshift mutations including deletions
at a novel site. Chemotherapeutic agents upregulated expression of the
TRAIL receptor DR5 (603612) and the BAX homolog BAK (600516) in BAX -/-
cells, and restored TRAIL sensitivity in vitro and in vivo. Thus,
LeBlanc et al. (2002) concluded that BAX mutation in mismatch
repair-deficient tumors can cause resistance to death receptor-targeted
therapy, but pre-exposure to chemotherapy rescues tumor sensitivity.

Guo et al. (2003) found that Bax coimmunoprecipitated with humanin
(606120), a peptide with neuroprotective activities against Alzheimer
disease (104300)-associated insults, and that humanin rescued rat
hippocampal neurons from Bax-induced lethality. Humanin prevented the
translocation of Bax from the cytosol to the mitochondria and suppressed
cytochrome c release. Guo et al. (2003) noted that the predicted humanin
peptides from the nuclear-encoded peptide and the mitochondrial-encoded
peptide were both able to bind Bax and prevent apoptosis. The authors
suggested that the HN gene arose from mitochondria and transferred to
the nuclear genome, providing a protective mechanism for additional
organelles.

Chipuk et al. (2004) found that cytosolic localization of endogenous
wildtype or trans-activation-deficient p53 (191170) was necessary and
sufficient for apoptosis. p53 directly activated the proapoptotic BCL2
protein BAX in the absence of other proteins to permeabilize
mitochondria and engage the apoptotic program. p53 also released both
proapoptotic multidomain proteins and BH3-only proteins that were
sequestered by BCL-XL (see 600039). The transcription-independent
activation of BAX by p53 occurred with similar kinetics and
concentrations to those produced by activated BID (601997). Chipuk et
al. (2004) proposed that when p53 accumulates in the cytosol, it can
function analogously to the BH3-only subset of proapoptotic BCL2
proteins to activate BAX and trigger apoptosis.

Clusterin (CLU; 185430) is overexpressed in human prostate and breast
cancers and in squamous cell carcinomas, and suppression of CLU renders
these cells sensitive to chemotherapeutic drug-mediated apoptosis. Zhang
et al. (2005) found that intracellular CLU inhibited apoptosis by
interfering with BAX activation in mitochondria. CLU specifically
interacted with BAX that was conformationally altered by
chemotherapeutic drugs, and the interaction inhibited BAX-mediated
apoptosis. Zhang et al. (2005) concluded that elevated CLU levels in
human cancers may promote oncogenic transformation and tumor progression
by interfering with BAX proapoptotic activities.

Perier et al. (2005) presented evidence suggesting that mitochondrial
complex I deficiency (252010) does not autonomously kill cells but
rather sensitizes neurons to the action of Bax through mitochondrial
oxidative damage. In isolated brain cell mitochondria, inhibition of
complex I activity resulted in increased levels of reactive oxygen
species and promoted Bax-dependent cytochrome c release. Perier et al.
(2005) proposed a model in which complex I defects lower the threshold
for activation of mitochondrial-dependent apoptosis by Bax, thus
rendering compromised neurons more prone to degeneration.

Hetz et al. (2006) investigated the unfolded protein response signaling
events in mice in the absence of proapoptotic BCL2 family members Bax
and Bak (600516) using double-knockout mice. Double-knockout mice
responded abnormally to tunicamycin-induced endoplasmic reticulum (ER)
stress in the liver, with extensive tissue damage and decreased
expression of the IRE1 substrate X box-binding protein-1 (Xbp1; 194355)
and its target genes. ER-stressed double knockout cells showed deficient
IRE1-alpha (604033) signaling. BAX and BAK formed a protein complex with
the cytosolic domain of IRE1-alpha that was essential for IRE1-alpha
activation. Thus, Hetz et al. (2006) concluded that BAX and BAK function
at the ER membrane to activate IRE1-alpha signaling and to provide a
physical link between members of the core apoptotic pathway and the
unfolded protein response.

Two members of the BCL2 family, BAX and BAK (600516), change
intracellular location early in the promotion of apoptosis to
concentrate in focal clusters at sites of mitochondrial division.
Karbowski et al. (2006) reported that in healthy cells, BAX or BAK is
required for normal fusion of mitochondria into elongated tubules. BAX
seems to induce mitochondrial fusion by activating assembly of the large
GTPase MFN2 (608507) and changing its submitochondrial distribution and
membrane mobility--properties that correlate with different GTP-bound
states of MFN2. Karbowski et al. (2006) concluded that BAX and BAK
regulate mitochondrial dynamics in healthy cells and that BCL2 family
members may also regulate apoptosis through organelle morphogenesis
machineries.

A central issue in the regulation of apoptosis by the BCL2 family is
whether its BH3-only members initiate apoptosis by directly binding to
the essential cell death mediators BAX and BAK, or whether they can act
indirectly, by engaging their prosurvival BCL2-like relatives. Contrary
to the direct-activation model, Willis et al. (2007) showed that BAX and
BAK can mediate apoptosis without discernable association with the
putative BH3-only activators (BIM, 603827; BID, 601997; and PUMA,
605854), even in cells with no BIM or BID and reduced PUMA. Willis et
al. (2007) concluded that BH3-only proteins induce apoptosis at least
primarily by engaging with multiple prosurvival relatives guarding BAX
and BAK.

Congenital muscular dystrophy type 1A (MDC1A; 607855) is caused by
mutations in the gene encoding laminin-alpha-2 (LAMA2; 156225).
Bax-mediated muscle cell death is a significant contributor to the
severe neuromuscular pathology seen in the Lama2-null mouse model of
MDC1A. Vishnudas and Miller (2009) analyzed molecular mechanisms of Bax
regulation in normal and LAMA2-deficient muscles and cells, including
myogenic cells from MDC1A patients. In mouse myogenic cells, Bax
coimmunoprecipitated with the multifunctional protein Ku70 (XRCC6;
152690). In addition, cell-permeable pentapeptides designed from Ku70,
termed Bax-inhibiting peptides (BIPs), inhibited staurosporine-induced
Bax translocation and cell death in mouse myogenic cells. Acetylation of
Ku70, which can inhibit binding to Bax and can be an indicator of
increased susceptibility to cell death, was more abundant in Lama2-null
mouse muscles than in normal mouse muscles. Myotubes formed in culture
from human LAMA2-deficient patient myoblasts produced high levels of
activated caspase-3 (CASP3; 600636) when grown on poly-L-lysine, but not
when grown on a LAMA2-containing substrate or when treated with BIPs.
Cytoplasmic Ku70 in human LAMA2-deficient myotubes was both reduced in
amount and more highly acetylated than in normal myotubes. Vishnudas and
Miller (2009) concluded that increased susceptibility to cell death
appears to be an intrinsic property of human LAMA2-deficient myotubes
and that Ku70 is a regulator of Bax-mediated pathogenesis.

BIOCHEMICAL FEATURES

Apoptosis is stimulated by the insertion of BAX from the cytosol into
mitochondrial membranes. Suzuki et al. (2000) determined the solution
structure of BAX, including the putative transmembrane domain at the C
terminus, in order to understand the regulation of its subcellular
location. BAX consists of 9 alpha helices, and the assembly of helices
alpha-1 through -8 resembles that of BCLXL. The C-terminal alpha-9 helix
occupies the hydrophobic pocket proposed to mediate heterodimer
formation and bioactivity of opposing members of the BCL2 family. The
authors concluded that the BAX structure shows that the orientation of
helix alpha-9 provides simultaneous control over its mitochondrial
targeting and dimer formation.

Gavathiotis et al. (2008) demonstrated by nuclear magnetic resonance
(NMR) analysis that the BIM stabilized alpha-helix of BCL2 (SAHB) domain
binds BAX at an interaction site that is distinct from the canonic
binding groove characterized for antiapoptotic proteins. The specificity
of the human BIM-SAHB-BAX interaction was highlighted by point
mutagenesis that disrupts functional activity, confirming that BAX
activation is initiated at this novel structural location. The BAX
binding site is defined by lysine at position 21 (K21), glutamine at
positions 28 and 32 (Q28, Q32), arginine at position 134 (R134), and
glutamic acid at position 131 (E131).

MAPPING

Through analysis of human/hamster somatic cell hybrid DNA and by
isotopic in situ hybridization, Apte et al. (1995) determined that the
BAX gene is located on 19q13.3-q13.4. By fluorescence in situ
hybridization, Matsuda et al. (1996) showed that the Bax gene is located
on mouse chromosome 7 and rat chromosome 1q31.2 in a region of conserved
linkage homology between the 2 species. The gene was also mapped by
molecular linkage analysis using interspecific backcross mice.

MOLECULAR GENETICS

Cancers of the microsatellite mutator phenotype (MMP) show exaggerated
genomic instability at simple repeat sequences. The human BAX gene
contains a tract of 8 consecutive deoxyguanosines in the third coding
exon, spanning codons 38 to 41. To determine whether this sequence is a
mutational target in MMP(+) tumor cells, Rampino et al. (1997) amplified
by PCR the region containing the (G)8 tract from various MMP(+) tumor
cell lines. This analysis revealed band shifts, suggestive of 1-bp
insertions (600040.0001) and deletions (600040.0002) in some of these
tumor cells. These mutations were somatic. Homozygous (or hemizygous)
frameshift insertion or deletion mutations in BAX were found in multiple
primary colorectal cancers as well as colorectal cancer cell lines. The
resulting frameshift was thought to interfere with the suppressor role
of the wildtype BAX gene. Rampino et al. (1997) noted that colon tumors
of the MMP type typically do not contain p53 mutations, in contrast with
those of the suppressor pathway. Once the MMP is manifested (after the
occurrence of mutator mutations in, for example, mismatch repair genes),
mutations at the BAX (G)8 hotspot would be more likely to occur than
other frameshift or missense mutations in p53. In tumor cells with
frameshift BAX mutations, transcriptional activation of BAX by wildtype
p53 would be irrelevant. In cancer of the MMP, the generation of
thousands of DNA mismatches during every replication of each MMP(+)
tumor cell may trigger the p53-mediated apoptotic response to DNA
damage. But the response would be futile because the chain leading to
apoptosis is broken in a downstream link. Therefore, Rampino et al.
(1997) speculated that BAX mutations eliminate the selective pressure
for p53 mutations during colorectal tumorigenesis.

ANIMAL MODEL

Knudson et al. (1995) found that Bax knockout mice were viable but
displayed lineage-specific aberrations in cell death. Thymocytes and B
cells displayed hyperplasia, and Bax-deficient ovaries contained unusual
atretic follicles with excess granulosa cells. In contrast,
Bax-deficient males were infertile as a result of disordered
seminiferous tubules with an accumulation of atypical premeiotic germ
cells, but no mature haploid sperm. Multinucleated giant cells and
dysplastic cells accompanied massive cell death. Knudson et al. (1995)
concluded that the loss of Bax resulted in hyperplasia or hypoplasia,
depending on the cellular context.

Deckwerth et al. (1996) reported that sympathetic neurons from Bax -/-
mice were independent of nerve growth factor (NGF; 162030) for survival
and that neonatal motor neurons survived disconnection from their
targets by axotomy. The trophic factor-independent neurons showed
reduced neurite outgrowth and had atrophic somas. However, they
responded to trophic factor addition with enhanced neurite outgrowth and
soma hypertrophy. Developmental sympathetic and motor neuronal death was
reduced in Bax-deficient mice. Deckwerth et al. (1996) concluded that
BAX is required for neuronal death after deprivation of neurotrophic
factors and that the consequences of altering BCL2 family members can
depend on the context in which they interact.

The proapoptotic BAX protein induces cell death by acting on the
mitochondria. BAX binds to the permeability transition pore complex
(PTPC), a composite proteaceous channel that is involved in the
regulation of mitochondrial membrane permeability. Marzo et al. (1998)
found that immunodepletion of Bax from PTPC or purification of PTPC from
Bax-deficient mice yielded a PTPC that could not permeabilize membranes
in response to atractyloside, a proapoptotic ligand of the adenine
nucleotide translocator (ANT; 103220). Bax and ANT coimmunoprecipitated
and interacted in the yeast 2-hybrid system. Ectopic expression of Bax
induced cell death in wildtype but not in ANT-deficient yeast.
Recombinant Bax and purified ANT, but neither of them alone, efficiently
formed atractyloside-responsive channels in artificial membranes. Hence,
the proapoptotic molecule Bax and the constitutive mitochondrial protein
ANT cooperate within the PTPC to increase mitochondrial membrane
permeability and to trigger cell death.

Female mammals are endowed with a finite number of oocytes at birth,
each enclosed by a single layer of somatic (granulosa) cells in a
primordial follicle. The fate of most follicles is atretic degeneration,
a process that culminates in near exhaustion of the oocyte reserve at
approximately the fifth decade of life in women, leading to menopause.
Apoptosis has a fundamental role in follicular atresia, and several
studies had indicated that BAX, which is expressed in both granulosa
cells and oocytes, may be central to ovarian cell death. Perez et al.
(1999) showed that young adult female mice homozygous for disruption of
the Bax gene, (Bax -/-), possessed 3-fold more primordial follicles in
their ovarian reserve than their wildtype sisters, and that this surfeit
of follicles was maintained in advanced chronologic age, such that 20-
to 22-month-old female Bax -/- mice possessed hundreds of follicles at
all developmental stages and exhibited ovarian steroid-driven uterine
hypertrophy. These observations contrasted with the ovarian and uterine
atrophy seen in aged wildtype female mice. Aged female Bax -/- mice
failed to become pregnant when housed with young adult males; however,
metaphase II oocytes could be retrieved from, and corpora lutea formed
in, ovaries of aged Bax -/- females following superovulation with
exogenous gonadotropins, and some oocytes were competent for in vitro
fertilization and early embryogenesis. Therefore, ovarian life span
could be extended by selectively disrupting Bax function, but other
aspects of normal reproductive performance remained defective in aged
Bax -/- female mice.

The central nervous system (CNS) of Atm (607585)-null mice shows a
pronounced defect in apoptosis induced by genotoxic stress, suggesting
that ATM functions to eliminate neurons with excessive genomic damage.
Chong et al. (2000) reported that the death effector Bax is required for
a large proportion of Atm-dependent apoptosis in the developing CNS
after ionizing radiation (IR). Although many of the same regions of the
CNS in both Bax -/- and Atm -/- mice were radioresistant, mice
nullizygous for both Bax and Atm showed additional reduction in
IR-induced apoptosis in the CNS. Therefore, although the major
IR-induced apoptotic pathway in the CNS requires Atm and Bax, a
p53-dependent collateral pathway exists that has both Atm- and
Bax-independent branches. Furthermore, Atm- and Bax-dependent apoptosis
in the CNS also required caspase-3 (600636) activation. These data
implicated Bax and caspase-3 as death effectors in neurodegenerative
pathways.

Proapoptotic Bcl2 family members have been proposed to play a central
role in regulating apoptosis, yet mice lacking Bax display limited
phenotypic abnormalities. Lindsten et al. (2000) found that Bak -/- mice
were developmentally normal and reproductively fit and failed to develop
any age-related disorders. However, when Bak-deficient mice were mated
to Bax-deficient mice to create mice lacking both genes, the majority of
Bax-/- Bak-/- animals died perinatally, with fewer than 10% surviving
into adulthood. Bax-/- Bak-/- mice displayed multiple developmental
defects, including persistence of interdigital webs, an imperforate
vaginal canal, and accumulation of excess cells within both the central
nervous and hematopoietic systems. Thus, the authors concluded that Bax
and Bak have overlapping roles in the regulation of apoptosis during
mammalian development and tissue homeostasis.

Since IL7 (146660) is required for normal T-cell development, Khaled et
al. (2002) evaluated the role of BAX in vivo by generating mice
deficient in both Bax and Il7r (146661). Bax deficiency protected cells
from death due to the absence of Il7 signaling up to 4 weeks of age. By
12 weeks of age, Bax- and Il7r-deficient mice exhibited a loss of thymic
cellularity comparable to that observed in mice deficient in Il7r alone.
Khaled et al. (2002) determined that Bad (603167) and Bim (BCL2L11;
603827) were also part of the death pathway repressed by Il7. Khaled et
al. (2002) concluded that, in young mice, Bax is an essential protein in
the death pathway induced by Il7 deficiency.

Scorrano et al. (2003) found that mouse embryonic fibroblasts deficient
for Bax and Bak (600516) had a reduced resting concentration of calcium
in the endoplasmic reticulum (ER) that resulted in decreased uptake of
calcium by mitochondria after calcium release from the ER. Expression of
SERCA (sarcoplasmic-endoplasmic reticulum calcium adenosine
triphosphatase; see 108740) corrected ER calcium concentration and
mitochondrial calcium uptake in double knockout cells, restoring
apoptotic death in response to agents that release calcium from
intracellular stores, such as arachidonic acid, C2-ceramide, and
oxidative stress. In contrast, targeting of Bax to mitochondria
selectively restored apoptosis to 'BH3-only' signals. A third set of
stimuli, including many intrinsic signals, required both ER-released
calcium and the presence of mitochondrial Bax or Bak to fully restore
apoptosis. Scorrano et al. (2003) concluded that BAX and BAK operate in
both the ER and the mitochondria as an essential gateway for selected
apoptotic signals.

Garcia-Barros et al. (2003) investigated the hypothesis that tumor
response to radiation is determined not only by tumor cell type but also
by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas
grown in apoptosis-resistant 'acid sphingomyelinase' (asmase)-deficient
or Bax-deficient mice displayed markedly reduced baseline microvascular
endothelial apoptosis and grew 200 to 400% faster than tumors on
wildtype microvasculature. Thus, Garcia-Barros et al. (2003) concluded
that endothelial apoptosis is a homeostatic factor regulating
angiogenesis-dependent tumor growth. Moreover, these tumors exhibited
reduced endothelial apoptosis upon irradiation and, unlike tumors in
wildtype mice, they were resistant to single-dose radiation up to 20 Gy.
Garcia-Barros et al. (2003) concluded that microvascular damage
regulates tumor cell response to radiation at the clinically relevant
dose range.

Takeuchi et al. (2005) generated mice conditionally deficient in both
Bax and Bak in B cells, but not T cells, and compared them with Bim -/-
mice. Deletion of Bak and Bax in B cells caused accumulation of immature
and mature follicular B cells and abrogation of apoptosis, whereas Bim
deficiency caused accumulation of mature splenic B cells only and
partial resistance to apoptosis. B cells from the Bax- and Bak-deficient
mice were also defective in cell cycling in response to B-cell receptor
crosslinking and lipopolysaccharide. Induced Bax and Bak deficiency in
adult mice resulted in development of severe autoimmune glomerular
nephritis. Takeuchi et al. (2005) concluded that BAX and BAK are
essential for apoptosis and maintenance of B-cell homeostasis.

Ren et al. (2010) provided in vivo evidence demonstrating an essential
role of the proteins BID (601997), BIM (603827), and PUMA (605854) in
activating BAX and BAK. Bid, Bim, and Puma triple-knockout mice showed
the same developmental defects that are associated with deficiency of
Bax and Bak, including persistent interdigital webs and imperforate
vaginas. Genetic deletion of Bid, Bim, and Puma prevented the
homooligomerization of Bax and Bak, and thereby cytochrome c
(123970)-mediated activation of caspases in response to diverse death
signals in neurons and T lymphocytes, despite the presence of other
BH3-only molecules. Thus, Ren et al. (2010) concluded that many forms of
apoptosis require direct activation of BAX and BAK at the mitochondria
by a member of the BID, BIM, or PUMA family of proteins.

*FIELD* AV
.0001
COLORECTAL CANCER, SOMATIC
BAX, 1-BP INS, G, CODON 38-41

Rampino et al. (1997) found that more than 50% (21 of 41) of human
MMP(+) colorectal carcinomas (see 114500) that they examined had
frameshift mutations in a tract of 8 deoxyguanosines within the BAX gene
in the third coding exon, spanning codons 38 to 41. These mutations were
absent in MMP(-) tumors and were significantly less frequent in G8
tracts from other genes. Frameshift mutations were present in both BAX
alleles and some MMP(+) colon tumor cell lines and in primary tumors.
These results suggested to Rampino et al. (1997) that inactivating BAX
mutations are selected for during the progression of colorectal MMP(+)
tumors and that the wildtype BAX gene plays a suppressor role in a
p53-independent pathway for colorectal carcinogenesis.

.0002
COLORECTAL CANCER, SOMATIC
BAX, 1-BP DEL, G, CODON 38-41

See 600040.0001 and Rampino et al. (1997).

.0003
LEUKEMIA, T-CELL ACUTE LYMPHOBLASTIC, SOMATIC
BAX, GLY67ARG

In a T-cell acute lymphoblastic leukemia (see 613065) cell line,
Meijerink et al. (1998) found a somatic gly67-to-arg (G67R) missense
mutation of the BAX gene.

.0004
LEUKEMIA, T-CELL ACUTE LYMPHOBLASTIC, SOMATIC
BAX, 7-BP DEL, 114-121G

In several cell lines from patients with T-cell acute lymphoblastic
leukemia (see 613065), Meijerink et al. (1998) found a somatic deletion
of 7 guanine residues from a simple tract of 8 such residues
encompassing codons 38 to 41 of the BAX gene.

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*FIELD* CN
Ada Hamosh - updated: 12/28/2010
George E. Tiller - updated: 10/28/2010
Ada Hamosh - updated: 11/26/2008
Ada Hamosh - updated: 4/17/2007
Ada Hamosh - updated: 10/24/2006
Ada Hamosh - updated: 8/1/2006
Paul J. Converse - updated: 6/21/2006
Paul J. Converse - updated: 4/21/2006
Cassandra L. Kniffin - updated: 1/11/2006
Patricia A. Hartz - updated: 12/19/2005
Ada Hamosh - updated: 3/10/2004
Cassandra L. Kniffin - updated: 6/13/2003
Ada Hamosh - updated: 4/15/2003
George E. Tiller - updated: 10/17/2002
Paul J. Converse - updated: 4/24/2002
Ada Hamosh - updated: 4/2/2002
John A. Phillips, III - updated: 3/12/2002
Jane Kelly - updated: 12/13/2001
John A. Phillips, III - updated: 8/8/2001
Ada Hamosh - updated: 7/13/2001
Ada Hamosh - updated: 5/7/2001
Stylianos E. Antonarakis - updated: 1/11/2001
Stylianos E. Antonarakis - updated: 11/21/2000
Ada Hamosh - updated: 11/14/2000
Victor A. McKusick - updated: 3/2/2000
Ada Hamosh - updated: 6/23/1999
Victor A. McKusick - updated: 1/29/1999
Victor A. McKusick - updated: 9/24/1998
Victor A. McKusick - updated: 7/1/1998
Victor A. McKusick - updated: 2/13/1997

*FIELD* CD
Victor A. McKusick: 7/18/1994

*FIELD* ED
carol: 12/06/2013
terry: 10/3/2012
carol: 4/26/2011
alopez: 1/3/2011
terry: 12/28/2010
ckniffin: 11/17/2010
wwang: 11/5/2010
terry: 10/28/2010
wwang: 10/13/2009
ckniffin: 10/5/2009
alopez: 12/9/2008
terry: 11/26/2008
alopez: 4/19/2007
terry: 4/17/2007
alopez: 11/6/2006
terry: 10/24/2006
alopez: 8/1/2006
mgross: 6/21/2006
carol: 6/5/2006
mgross: 4/21/2006
wwang: 1/31/2006
ckniffin: 1/11/2006
wwang: 12/19/2005
terry: 10/12/2005
terry: 4/4/2005
alopez: 3/12/2004
terry: 3/10/2004
carol: 6/13/2003
ckniffin: 6/13/2003
alopez: 6/11/2003
terry: 6/10/2003
alopez: 4/17/2003
terry: 4/15/2003
ckniffin: 3/11/2003
cwells: 10/17/2002
mgross: 4/24/2002
alopez: 4/4/2002
terry: 4/2/2002
alopez: 3/12/2002
alopez: 12/13/2001
joanna: 10/17/2001
alopez: 9/24/2001
alopez: 8/8/2001
alopez: 8/2/2001
alopez: 7/16/2001
terry: 7/13/2001
alopez: 5/8/2001
terry: 5/7/2001
mgross: 1/11/2001
mgross: 11/21/2000
mgross: 11/16/2000
terry: 11/14/2000
mgross: 3/2/2000
alopez: 2/2/2000
alopez: 6/23/1999
alopez: 2/2/1999
terry: 1/29/1999
alopez: 9/24/1998
carol: 9/24/1998
carol: 7/14/1998
terry: 7/1/1998
alopez: 5/21/1998
joanna: 1/15/1998
mark: 2/13/1997
terry: 2/13/1997
jenny: 12/17/1996
terry: 12/9/1996
jamie: 12/4/1996
terry: 11/8/1996
mark: 2/13/1996
terry: 2/7/1996
mark: 5/16/1995
carol: 2/9/1995
mimadm: 7/30/1994
jason: 7/18/1994