HGNC Approved Gene Symbol: BAX
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:48,954,875-48,961,798 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | Colorectal cancer, somatic | 114500 | 3 | |
| T-cell acute lymphoblastic leukemia, somatic | 613065 | 3 |
The proapoptotic BAX protein induces cell death by acting on mitochondria.
Oltvai et al. (1993) identified BAX as a protein partner of BCL2 (151430).
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 (HN; 561010), 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 discernible 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.
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).
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.
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.
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.
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.
See 600040.0001 and Rampino et al. (1997).
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.
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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