BAX (BCL2-associated X protein)
2009-05-01 Hellinida Thomadaki , Andreas Scorilas AffiliationDepartment of Biochemistry, Molecular Biology, University of Athens, 157 01, Panepistimiopolis, Athens, Greece
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.
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
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
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-%28bcl2-associated-x-protein%29
