BAX (BCL2-associated X protein)

2009-05-01 Hellinida Thomadaki , Andreas Scorilas Affiliation

Department of Biochemistry, Molecular Biology, University of Athens, 157 01, Panepistimiopolis, Athens, Greece

Identity

HGNC

BAX

LOCATION

19q13.33

LOCUSID

581

ALIAS

BCL2L4

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

The BAX gene, with 6.939 bases in length, consists of 6 exons and 5 intervening introns.

Transcription

The BAX gene is characterized by 5 protein coding transcripts (alpha/psi, beta, delta, epsilon, sigma). Bax-beta encodes the longest isoform (891 bp) of the gene. BAX-alpha/Bax-psi variant is 888 bp in length and codes for a protein isoform that possesses a shorter and different C terminus, as compared with the isoform BAX-beta. The third variant (BAX-delta), which is 741 bp in length, lacks exon 3, whereas it retains the functionally critical C-terminal membrane anchorage region, as well as the BCL2 homology 1 and 2 (BH1 and BH2) domains, although it has a shorter and different C terminus, in comparison with BAX-beta. The fourth identified variant of BAX, which is designated as BAX-epsilon, is 986 bp in length because it contains an extra fragment within the coding region, as well as a distinct 3 coding region and 3 UTR, resulting in a distinct BAX isoform with a shorter and distinct C terminus, as compared with BAX-beta. The fifth identified variant of BAX, BAX-sigma, is 849 bp in length and has also a shorter and different C terminus, when compared with the isoform beta.

Pseudogene

Not identified so far.

Proteins

Note

The BAX gene encodes for a 21 kDa protein, named BAX-alpha. It was the first death-inducing member of the BCL2 family to be identified, and it was detected as a protein co-purified with BCL2 in immunoprecipitation studies. The BH3 domain of BAX is essential for its homodimerization and its heterodimerization with BCL2 and BCL-XL. Furthermore, the protein contains a hydrophobic C-terminal region essential for membrane targeting, while BH1 and BH2 domains show homology to pore-forming proteins that contribute to apoptosis. In addition to BAX-alpha, which is the major protein product of the whole gene, BAX undergoes alternative splicing, resulting in the production of distinct protein isoforms. The tumour suppressor p53 is a transcriptional regulator of BAX, since the promoter of the BAX gene possesses four regions with high homology to the consensus p53 binding sites.

Description

The BAX belongs to the BCL2 family of proteins. It is composed of 192 amino acids (21184 kDa), with a calculated molecular mass of 21.184 kDa. The BAX protein exists as a monomer, a homodimer, or as a heterodimer with BCL2, E1B 19K protein, BCL2L1 isoform Bcl-X(L), MCL1 and BCL2A1/A1. It also interacts with SH3GLB1 and HN. It contains one BH3 homology domain.

Localisation

BAX protein has been reported to be localized in the mitochondria, mitochondrial permeability transition pore complex, mitochondrial outer membrane, endoplasmic reticulum membrane and cytoplasm.

Function

BAX protein heterodimerizes either with members of the BCL2 family of proteins or with tyrosine kinases enabling them it to display its proapoptotic function within the cell. It is also implicated in the loss of mitochondrial membrane potential and the release of cytochrome c.

Homology

Human BAX shares 99.5% amino acid identity with Pan troglodytes, 97.4% identity with Canis lupus familiaris, 96.4% identity with Bos Taurus, 92.2% identity with Mus musculus, 91.2% identity with Rattus norvegicus and 52.7% identity with Danio rerio. In addition, BAX protein presents high homology to the BCL2 protein, containing the conserved regions BH1, BH2 and BH3.

Mutations

Note

One regulatory type of mutation has been identified according to which a guanine substituting adenosine substitution at position 125 (G125A) in the BAX promoter is associated with higher stage of chronic lymphocytic leukemia (CLL) and failure to respond to treatment in CLL patients. Additionally, 110 SNPs, with uknown clinical association and the following IDs, have been reported in Entrez SNP database: rs62125987, rs62125961, rs61473366, rs61415800, rs60900019, rs59878749, rs59152877, rs57453473, rs57028628, rs56251427, rs56251427, rs55692456, rs55692456, rs36101119, rs36096807, rs36017265, rs35946201, rs35630245, rs35475300, rs35258702, rs34873472, rs34124134, rs34043541, rs28624947, rs28450536, rs12983717, rs12976339, rs12976283, rs12975003, rs11671610, rs11669164, rs11669162, rs11668424, rs11668008, rs11667351, rs11400412, rs11358529, rs11302449, rs10644606, rs7508566, rs7259013, rs7255991, rs7255559, rs4645904, rs4645903, rs4645902, rs4645903, rs4645902, rs4645901, rs4645900, rs4645899, rs4645898, rs4645897, rs4645896, rs4645895, rs4645894, rs4645893, rs4645891, rs4645890, rs4645889, rs4645888, rs4645887, rs4645886, rs4645885, rs4645884, rs4645883, rs4645882, rs4645881, rs4645880, rs4645879, rs4645878, rs4309503, rs3817074, rs3817073, rs2387583, rs1985882, rs1974820, rs1805419, rs1805418, rs1805417, rs1805416, rs1075531, rs1057369, rs1010104, rs1010103, rs1009316, rs1009315, rs905238, rs704243.

Implicated in

Entity name

Various cancers and diseases

Disease

Colorectal cancer, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), B cell chronic lymphocytic leukemia, osteomyelitis.

Prognosis

BAX mutations have been found to be associated with positive prognosis in Dukes B2 patients, concerning survival.
The G(-248)A polymorphism in the promoter region of the BAX gene has been associated with reduced BAX expression, advanced disease stage, reduced treatment response and short overall survival in B-cell chronic lymphocytic leukemia (CLL).
Polymorphisms were found for BAX, caused by variation in nucleotide A repeat number at position 360 in the 5-region of BAX gene. These allelic frequencies of BAX polymorphism were significantly different between males and females and therefore associated with gender-based heamatocrite (HCT) differences.
Substitution of the nucleotide G-->A at position -248 in the BAX gene was more frequent in patients with osteomyelitis and was associated with a longer lifespan of their peripheral blood neutrophils, probably possessing a significant role in the pathogenesis of osteomyelitis.
In cases of malignancies, the concentration of BAX protein in cancer cells is reduced. In addition, p53- deficient mice show reduced BAX levels, ultimately developing T-cell lymphoma.
Reduction of BAX expression levels is negatively associated with many cancers outcome. It is associated with a variety of adverse prognostic factors such as poor response to radio- and chemotherapy, advanced stage, lymph node metastasis, and reduced disease-free and overall survival in variety cancer types, such as colorectal, pancreatic, breast, head and neck, prostate, small cell lung cancer and gynecological (ovarian) malignancies. More specifically, the enhanced expression of BAX protein is a positive prognostic factor for pancreatic cancer and sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents. In the case of stage II colon cancer, treated only with surgery, BAX protein expression may be a predictor for prognosis. In ovarian cancer, BAX protein may have a predictive potential in taxane-platinum-treated patients. Moreover, in resected non-small cell lung cancer, low expression of BAX implies poor prognosis. In addition, in patients with advanced esophageal cancer, treated with chemoradiotherapy, reduced expression levels of BAX predict poor prognosis. Low expression of BAX was also significantly associated with poor PFS and OS in nasopharyngeal cancer patients.
In lung cancer, BAX is translocated to the nucleus, enhancing tumour development. Furthermore, mutational analysis of the gene in cases of lung cancer patients revealed the presence of a silent point mutation in codon 184 (TCG>TCA), as well as intronic mutations.
In T cells and endometrium of patients with acute lymphoblastic leukaemia, frameshift mutations have been detected in the BAX gene.
It is a common observation in cases of gastrointestinal cancer, the detection of two specific missense mutations of the BAX gene in codon 169 (Thr > Ala or Thr > Met), which cause inhibition of the proapoptotic activity of the protein and enhance the development of cancer.
Various chemotherapeutic treatments act via up-regulation of the BAX gene to block tumour progression.
BAX is highly expressed in HL-60 but it was found to be hardly expressed in HL-CR cells, a C2-ceramide-resistant HL-60 subline, which has been recently established. These cells showed reduced response to a variety of anticancer drugs including ceramide, doxorubicin, etoposide and cytosine arabinoside.

Hybrid gene

Not identified so far.

Fusion protein

Not identified so far.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
11136736	2001	Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells.	Antonsson B et al
7607685	1995	Mapping of the human BAX gene to chromosome 19q13.3-q13.4 and isolation of a novel alternatively spliced transcript, BAX delta.	Apte SS et al
11376125	2001	Signalling pathways involved in antiproliferative effects of IGFBP-3: a review.	Baxter RC et al
11032947	2000	Microsatellite alterations and K-ras, TGFbetaRII, IGFRII and bax mutations in sporadic cancers of the gastrointestinal tract.	Caligo MA et al
11912183	2002	The expression of a new variant of the pro-apoptotic molecule Bax, Baxpsi, is correlated with an increased survival of glioblastoma multiforme patients.	Cartron PF et al
14553942	2003	Changes in apoptosis-related pathways in acute myelocytic leukemia.	Casas S et al
14963330	2004	Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis.	Chipuk JE et al
8640722	1996	The BAX gene maps to the glioma candidate region at 19q13.3, but is not altered in human gliomas.	Chou D et al
12424199	2003	Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML).	Del Poeta G et al
15676142	2005	Significance of mutations in TGFBR2 and BAX in neoplastic progression and patient outcome in sporadic colorectal tumors with high-frequency microsatellite instability.	Fernández-Peralta AM et al
17384250	2006	Alterations in mRNA expression of apoptosis-related genes BCL2, BAX, FAS, caspase-3, and the novel member BCL2L12 after treatment of human leukemic cell line HL60 with the antineoplastic agent etoposide.	Floros KV et al
9863489	1998	bax, but not bcl-2, influences the prognosis of human pancreatic cancer.	Friess H et al
19150424	2009	Baxbeta: a constitutively active human Bax isoform that is under tight regulatory control by the proteasomal degradation mechanism.	Fu NY et al
12750523	2003	Tumor response to radiotherapy regulated by endothelial cell apoptosis.	Garcia-Barros M et al
19056676	2008	BAX and BAK proteins are required for cyclin-dependent kinase inhibitory drugs to cause apoptosis.	Garrofé-Ochoa X et al
18948948	2008	BAX activation is initiated at a novel interaction site.	Gavathiotis E et al
18772168	2008	Low expression of Bax predicts poor prognosis in resected non-small cell lung cancer patients with non-squamous histology.	Jeong SH et al
16380996	2006	Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers.	Jung B et al
17634542	2007	Low expression of Bax predicts poor prognosis in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy.	Kang SY et al
17013542	2006	Concurrent chemoradiotherapy in patients with nasopharyngeal cancer: prognostic significance of low expression of bax.	Kang SY et al
17035996	2006	Role of Bax and Bak in mitochondrial morphogenesis.	Karbowski M et al
12433363	2002	Bax deficiency partially corrects interleukin-7 receptor alpha deficiency.	Khaled AR et al
19141860	2009	Genetic variants in the candidate genes of the apoptosis pathway and susceptibility to chronic myeloid leukemia.	Kim DH et al
8142617	1993	Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death.	Korsmeyer SJ et al
12161031	2002	Investigation of bax, bcl-2, bcl-x and p53 gene polymorphisms in multiple sclerosis.	Kuhlmann T et al
17981213	2007	p53 pathway gene single nucleotide polymorphisms and chronic lymphocytic leukemia.	Lahiri O et al
11875499	2002	Tumor-cell resistance to death receptor--induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax.	LeBlanc H et al
19101510	2009	RhoE enhances multidrug resistance of gastric cancer cells by suppressing Bax.	Li K et al
11163212	2000	The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.	Lindsten T et al
11455387	2001	Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals.	Matikainen T et al
9531611	1998	Hematopoietic malignancies demonstrate loss-of-function mutations of BAX.	Meijerink JP et al
7834749	1995	Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.	Miyashita T et al
15688029	2005	G125A single-nucleotide polymorphism in the human BAX promoter affects gene expression.	Moshynska O et al
9843949	1998	Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria.	Narita M et al
19221769	2009	Prognostic implications of BAX protein expression and microsatellite instability in all non-metastatic stages of primary colon cancer treated by surgery alone.	Nehls O et al
17438390	2007	Bax gene G(-248)A promoter polymorphism is associated with increased lifespan of the neutrophils of patients with osteomyelitis.	Ocaña MG et al
9777952	1998	The clinicopathological features of gastric carcinomas with microsatellite instability may be mediated by mutations of different "target genes": a study of the TGFbeta RII, IGFII R, and BAX genes.	Oliveira C et al
8358790	1993	Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.	Oltvai ZN et al
16424160	2006	The endoplasmic reticulum is a key component of the plasma cell death pathway.	Pelletier N et al
9988273	1999	Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency.	Perez GI et al
9020077	1997	Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype.	Rampino N et al
12359369	2002	Association of a novel single nucleotide polymorphism, G(-248)A, in the 5'-UTR of BAX gene in chronic lymphocytic leukemia with disease progression and treatment resistance.	Saxena A et al
19125733	2009	Bif-1 and Bax expression in cutaneous Merkel cell carcinoma.	Schlauder SM et al
12624178	2003	BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis.	Scorrano L et al
10365962	1999	Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC.	Shimizu S et al
10589765	1999	Apoptosis and expression of apoptosis regulating proteins bcl-2, mcl-1, bcl-X, and bax in malignant mesothelioma.	Soini Y et al
15735127	2005	Common polymorphism G(-248)A in the promoter region of the bax gene results in significantly shorter survival in patients with chronic lymphocytic Leukemia once treatment is initiated.	Starczynski J et al
11106734	2000	Structure of Bax: coregulation of dimer formation and intracellular localization.	Suzuki M et al
18783338	2008	Molecular profile of breast versus ovarian cancer cells in response to treatment with the anticancer drugs cisplatin, carboplatin, doxorubicin, etoposide and taxol.	Thomadaki H et al
11326099	2001	Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.	Wei MC et al
17289999	2007	Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.	Willis SN et al
17404017	2007	Significant coexpression of GLUT-1, Bcl-xL, and Bax in colorectal cancer.	Wincewicz A et al
16059649	2005	Abnormalities of the P53, MDM2, BCL2 and BAX genes in acute leukemias.	Wojcik I et al
12107556	2002	Overexpression of Bax sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents.	Xu ZW et al
8183370	1994	BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax.	Yin XM et al
14714449	2003	Sequence-based polymorphisms in members of the apoptosis Bcl-2 gene family and their association with hematocrit level.	Zeng SM et al
16113678	2005	Clusterin inhibits apoptosis by interacting with activated Bax.	Zhang H et al
11062132	2000	Role of BAX in the apoptotic response to anticancer agents.	Zhang L et al
18937971	2009	TP53, BCL-2 and BAX analysis in 199 ovarian cancer patients treated with taxane-platinum regimens.	Ziółkowska-Seta I et al

Other Information

Locus ID:

NCBI: 581
MIM: 600040
HGNC: 959
Ensembl: ENSG00000087088

Variants:

dbSNP: 581
ClinVar: 581
TCGA: ENSG00000087088
COSMIC: BAX

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000087088	ENST00000293288	Q07812
ENSG00000087088	ENST00000345358	Q07812
ENSG00000087088	ENST00000354470	Q07812
ENSG00000087088	ENST00000356483	Q07812
ENSG00000087088	ENST00000391871	K4JQN1
ENSG00000087088	ENST00000415969	Q07812
ENSG00000087088	ENST00000506183	H0YA56
ENSG00000087088	ENST00000515540	Q07812
ENSG00000087088	ENST00000539787	I6LPK7

Expression (GTEx)

100

150

200

250

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
p53 signaling pathway	KEGG	ko04115
Apoptosis	KEGG	ko04210
Amyotrophic lateral sclerosis (ALS)	KEGG	ko05014
Huntington's disease	KEGG	ko05016
Colorectal cancer	KEGG	ko05210
p53 signaling pathway	KEGG	hsa04115
Apoptosis	KEGG	hsa04210
Amyotrophic lateral sclerosis (ALS)	KEGG	hsa05014
Huntington's disease	KEGG	hsa05016
Pathways in cancer	KEGG	hsa05200
Colorectal cancer	KEGG	hsa05210
Neurotrophin signaling pathway	KEGG	ko04722
Prion diseases	KEGG	ko05020
Neurotrophin signaling pathway	KEGG	hsa04722
Prion diseases	KEGG	hsa05020
Protein processing in endoplasmic reticulum	KEGG	ko04141
Protein processing in endoplasmic reticulum	KEGG	hsa04141
Tuberculosis	KEGG	ko05152
Tuberculosis	KEGG	hsa05152
HTLV-I infection	KEGG	ko05166
HTLV-I infection	KEGG	hsa05166
Viral carcinogenesis	KEGG	hsa05203
Viral carcinogenesis	KEGG	ko05203
Hepatitis B	KEGG	hsa05161
Non-alcoholic fatty liver disease (NAFLD)	KEGG	hsa04932
Non-alcoholic fatty liver disease (NAFLD)	KEGG	ko04932
Sphingolipid signaling pathway	KEGG	hsa04071
Sphingolipid signaling pathway	KEGG	ko04071
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Transcriptional Regulation by TP53	REACTOME	R-HSA-3700989
Programmed Cell Death	REACTOME	R-HSA-5357801
Apoptosis	REACTOME	R-HSA-109581
Intrinsic Pathway for Apoptosis	REACTOME	R-HSA-109606
Activation, translocation and oligomerization of BAX	REACTOME	R-HSA-114294
AGE-RAGE signaling pathway in diabetic complications	KEGG	ko04933
AGE-RAGE signaling pathway in diabetic complications	KEGG	hsa04933
Longevity regulating pathway	KEGG	hsa04211
TP53 Regulates Transcription of Cell Death Genes	REACTOME	R-HSA-5633008
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	REACTOME	R-HSA-6803204
TP53 Regulates Transcription of Cell Cycle Genes	REACTOME	R-HSA-6791312
TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest	REACTOME	R-HSA-6804114
Apoptosis - multiple species	KEGG	ko04215
Apoptosis - multiple species	KEGG	hsa04215
EGFR tyrosine kinase inhibitor resistance	KEGG	ko01521
Platinum drug resistance	KEGG	ko01524
Endocrine resistance	KEGG	ko01522
Platinum drug resistance	KEGG	hsa01524
EGFR tyrosine kinase inhibitor resistance	KEGG	hsa01521
Endocrine resistance	KEGG	hsa01522

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38001340	2024	Cell-specific modulation of mitochondrial respiration and metabolism by the pro-apoptotic Bcl-2 family members Bax and Bak.	0
38241555	2024	Value of Bax and Bcl2 expression in peripheral blood mononuclear cells for clinical prognosis of patients with chronic heart failure.	0
38342602	2024	Splicing Factor PQBP1 Curtails BAX Expression to Promote Ovarian Cancer Progression.	1
38503846	2024	Endogenous BAX and BAK form mosaic rings of variable size and composition on apoptotic mitochondria.	0
38001340	2024	Cell-specific modulation of mitochondrial respiration and metabolism by the pro-apoptotic Bcl-2 family members Bax and Bak.	0
38241555	2024	Value of Bax and Bcl2 expression in peripheral blood mononuclear cells for clinical prognosis of patients with chronic heart failure.	0
38342602	2024	Splicing Factor PQBP1 Curtails BAX Expression to Promote Ovarian Cancer Progression.	1
38503846	2024	Endogenous BAX and BAK form mosaic rings of variable size and composition on apoptotic mitochondria.	0
35951115	2023	Expression profile of the proapoptotic protein Bax in the human brain.	1
36219880	2023	Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia.	22
36705418	2023	By modulating miR-525-5p/Bax axis, LINC00659 promotes vascular endothelial cell apoptosis.	1
36918717	2023	Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer.	6
37202188	2023	[Overexpression of miR-431-5p impairs mitochondrial function and induces apoptosis in gastric cancer cells via the Bax/Bcl-2/caspase3 pathway].	0
38003498	2023	Analysis of the Polymorphisms and Expression Levels of the BCL2, BAX and c-MYC Genes in Patients with Ovarian Cancer.	2
35951115	2023	Expression profile of the proapoptotic protein Bax in the human brain.	1

Citation

Hellinida Thomadaki ; Andreas Scorilas

BAX (BCL2-associated X protein)

Atlas Genet Cytogenet Oncol Haematol. 2009-05-01

Online version: http://atlasgeneticsoncology.org/gene/128/bax-(bcl2-associated-x-protein)