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HGNC Approved Gene Symbol: BAK1
Cytogenetic location: 6p21.31 Genomic coordinates (GRCh38): 6:33,572,552-33,580,276 (from NCBI)
The BCL2 oncogene (151430), which is activated in follicular lymphomas, functions as a potent suppressor of apoptosis under diverse conditions. Chittenden et al. (1995) and Kiefer et al. (1995) described the cDNA cloning of a novel BCL2 homolog, BAK.
Kim et al. (2004) identified a 101-amino acid splice variant of BAK1, which they called BAK-like, that contains BH1, BH2, and TM domains, but lacks a BH3 domain. Northern blot analysis detected a 2.4-kb transcript in most human tissues and cell lines examined. Confocal microscopy studies localized the variant to a diffuse cytosolic pattern that redistributed to a mitochondrial staining pattern upon apoptosis.
Herberg et al. (1998) found that the BAK1 gene spans 7.6 kb and contains 6 exons. The first exon is noncoding, and most of the largest, final exon is untranslated.
By Southern blot analysis of genomic DNA from human/rodent somatic cell hybrids, Kiefer et al. (1995) localized the BAK gene to chromosome 6. Ulrich et al. (1997) mapped the mouse homolog of BAK1 to chromosome 17 in region B by fluorescence in situ hybridization (FISH). Because of the location of the bak gene on mouse chromosome 17, the human BAK1 gene was expected to be located on 6p. By FISH, Herberg et al. (1998) mapped the BAK1 gene to 6p21.3.
Chittenden et al. (1995) and Kiefer et al. (1995) described the functional analysis of BAK, which promotes cell death and counteracts the protection from apoptosis provided by BCL2. Chittenden et al. (1995) found that enforced expression of BAK induced rapid and extensive apoptosis of serum-deprived fibroblasts. This suggested that BAK may be directly involved in activating the cell death machinery. Kiefer et al. (1995) pointed out that, like BAX (600040), the BAK gene product primarily enhances apoptotic cell death following an appropriate stimulus. Unlike BAX, however, BAK can inhibit cell death in an Epstein-Barr virus-transformed cell line.
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 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.
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.
Cheng et al. (2003) found that in viable cells, BAK complexed with the mitochondrial outer membrane protein VDAC2 (193245), a VDAC isoform present in low abundance that interacts specifically with the inactive conformer of BAK. Cells deficient in VDAC2, but not cells lacking the more abundant VDAC1, exhibited enhanced BAK oligomerization and were more susceptible to apoptotic death. Conversely, overexpression of VDAC2 selectively prevented BAK activation and inhibited the mitochondrial apoptotic pathway. Death signals activate 'BH3-only' molecules such as tBID, BIM (603827), or BAD (603167), which displace VDAC2 from BAK, enabling homooligomerization of BAK and apoptosis. Thus, Cheng et al. (2003) concluded that VDAC2, an isoform restricted to mammals, regulates the activity of BAK and provides a connection between mitochondrial physiology and the core apoptotic pathway.
Fannjiang et al. (2003) examined the ability of Bak1-null and Bak1-overexpressing mice to resist various neuronal injuries, including neuronotropic Sindbis virus infection, Parkinson disease, ischemia/stroke, and seizure. The results showed that Bak1 could promote or inhibit neuronal death depending on the specific death stimulus and the maturity of the animal. Bak1 protected immature mice and neurons from Sindbis virus and excitotoxic stimuli. Deletion of the hydrophobic C terminus converted Bak1 from an antiapoptotic to a proapoptotic protein. In older mice, Bak1 could be anti- or proapoptotic depending on the neuronal subtype and the neuronal injury. Bak1 protected older mice from excitotoxic cell death and seizure, but it promoted Sindbis virus toxicity. Bak1-deficient adult mice showed enhanced sensitivity to kainate-induced seizures, and this increased sensitivity was associated with reduced neurotransmitter release from inhibitory GABAergic nerve terminals and increased release from excitatory glutamatergic neurons, indicating that BAK1 modifies synaptic activity of hippocampal neurons.
The p53 protein (191170) is an important proapoptotic regulator. Leu et al. (2004) found that after cell stress, p53 interacted with BAK. This interaction caused oligomerization of BAK and release of cytochrome c from mitochondria. Formation of the p53-BAK complex coincided with loss of an interaction between BAK and the antiapoptotic protein MCL1 (159552). Leu et al. (2004) suggested that p53 and MCL1 have opposing effects on mitochondrial apoptosis by modulating BAK activity.
Hetz et al. (2006) investigated the unfolded protein response signaling events in mice in the absence of proapoptotic BCL2 family members Bax (600040) and Bak 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, 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.
Liver is generally refractory to apoptosis induced by p53. Leu and George (2007) found that p53 activation led to enhanced expression of IGFBP1 (146730) in human hepatoma cells. A portion of intracellular IGFBP1 localized to mitochondria, where it bound the proapoptotic protein BAK. Binding of IGFBP1 to BAK impaired formation of the proapoptotic p53/BAK complex and induction of apoptosis in cultured human and mouse cells and in mouse liver. In contrast, livers of Igfbp1-deficient mice exhibited spontaneous apoptosis accompanied by p53 mitochondrial accumulation and evidence of Bak oligomerization. Leu and George (2007) concluded that IGFBP1 is a negative regulator of the p53/BAK-dependent pathway of apoptosis.
BHRF1 is a prosurvival molecule from Epstein-Barr virus that is homologous to BCL2. Desbien et al. (2009) showed that, in mouse T cells, BHRF1 bound Bak, and that in cell cultures without cytokines, BHRF1 associated with Bim. BHRF1 with a point mutation in its BH3-binding groove that eliminated binding to Bak retained its ability to bind Bim and to protect cells. Desbien et al. (2009) concluded that binding of BHRF1 to BIM, rather than BAK, provides protection.
For discussion of a possible association between variation in the BAK1 gene and testicular germ cell tumors, see 273300.
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.
Scorrano et al. (2003) found that mouse embryonic fibroblasts deficient for Bax (600040) and Bak 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.
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.
The C57BL/6J mouse strain shows a classic pattern of age-related hearing loss (612448) by 12 to 15 months of age. Someya et al. (2009) found that mice with deletion in the Bak gene had significantly less age-related hearing loss compared to wildtype mice. Preservation of hearing was associated with reduced oxidative stress-induced apoptosis of spiral ganglion cells and cochlear hair cells. Bax-null mice did not show such resistance to hearing loss. In vitro studies on primary cochlear cells showed that oxidative stress was associated with overexpression of Bak and apoptosis. Oral supplementation of wildtype mice with the mitochondrial antioxidants alpha-lipoic acid and coenzyme Q10 suppressed Bak expression in the cochlea, reduced cochlear cell death, and prevented age-related hearing loss. Someya et al. (2009) suggested that BAK is required for the development of age-related hearing loss, and that induction of a BAK-dependent mitochondrial apoptosis program in response to oxidative stress is a key pathogenic mechanism.
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.
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Herberg, J. A., Phillips, S., Beck, S., Jones, T., Sheer, D., Wu, J. J., Prochazka, V., Barr, P. J., Kiefer, M. C., Trowsdale, J. Genomic structure and domain organisation of the human Bak gene. Gene 211: 87-94, 1998. [PubMed: 9573342] [Full Text: https://doi.org/10.1016/s0378-1119(98)00101-2]
Hetz, C., Bernasconi, P., Fisher, J., Lee, A.-H., Bassik, M. C., Antonsson, B., Brandt, G. S., Iwakoshi, N. N., Schinzel, A., Glimcher, L. H., Korsmeyer, S. J. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1-alpha. Science 312: 572-576, 2006. [PubMed: 16645094] [Full Text: https://doi.org/10.1126/science.1123480]
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Kim, J. K., Kim, K. S., Ahn, J. Y., Kim, N. K., Chung, H. M., Yun, H. J., Cha, K. Y. Enhanced apoptosis by a novel gene, Bak-like, that lacks the BH3 domain. Biochem. Biophys. Res. Commun. 316: 18-23, 2004. [PubMed: 15003505] [Full Text: https://doi.org/10.1016/j.bbrc.2004.01.173]
Leu, J. I.-J., Dumont, P., Hafey, M., Murphy, M. E., George, D. L. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nature Cell Biol. 6: 443-450, 2004. [PubMed: 15077116] [Full Text: https://doi.org/10.1038/ncb1123]
Leu, J. I.-J., George, D. L. Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria. Genes Dev. 21: 3095-3109, 2007. [PubMed: 18056423] [Full Text: https://doi.org/10.1101/gad.1567107]
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Ren, D., Tu, H.-C., Kim, H., Wang, G. X., Bean, G. R., Takeuchi, O., Jeffers, J. R., Zambetti, G. P., Hsieh, J. J.-D., Cheng, E. H.-Y. BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330: 1390-1393, 2010. [PubMed: 21127253] [Full Text: https://doi.org/10.1126/science.1190217]
Scorrano, L., Oakes, S. A., Opferman, J. T., Cheng, E. H., Sorcinelli, M. D., Pozzan, T., Korsmeyer, S. J. BAX and BAK regulation of endoplasmic reticulum Ca(2+): a control point for apoptosis. Science 300: 135-139, 2003. [PubMed: 12624178] [Full Text: https://doi.org/10.1126/science.1081208]
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Someya, S., Xu, J., Kondo, K., Ding, D., Salvi, R. J., Yamasoba, T., Rabinovitch, P. S., Weindruch, R., Leeuwenburgh, C., Tanokura, M., Prolla, T. A. Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proc. Nat. Acad. Sci. 106: 19432-19437, 2009. [PubMed: 19901338] [Full Text: https://doi.org/10.1073/pnas.0908786106]
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Willis, S. N., Fletcher, J. I., Kaufmann, T., van Delft, M. F., Chen, L., Czabotar, P. E., Ierino, H., Lee, E. F., Fairlie, W. D., Bouillet, P., Strasser, A., Kluck, R. M., Adams, J. M., Huang, D. C. S. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315: 856-859, 2007. [PubMed: 17289999] [Full Text: https://doi.org/10.1126/science.1133289]