Apoptosis regulator BAX

Last updated

BAX
BAX protein 1F16.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases BAX , BCL2L4, BCL2 associated X protein, BCL2 associated X, apoptosis regulator
External IDs OMIM: 600040; MGI: 99702; HomoloGene: 7242; GeneCards: BAX; OMA:BAX - orthologs
Orthologs
SpeciesHumanMouse
Entrez

581

12028

Ensembl

ENSG00000087088

ENSMUSG00000003873

UniProt

Q07812
Q5ZPJ0

Q07813

RefSeq (mRNA)

NM_007527

RefSeq (protein)

NP_031553

Location (UCSC) Chr 19: 48.95 – 48.96 Mb Chr 7: 45.11 – 45.12 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. [5] BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis. [6]

Structure

The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family. [7] Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4), and can form hetero- or homodimers. [7] [8] These domains are composed of nine α-helices, with a hydrophobic α-helix core surrounded by amphipathic helices and a transmembrane C-terminal α-helix anchored to the mitochondrial outer membrane (MOM). A hydrophobic groove formed along the C-terminal of α2 to the N-terminal of α5, and some residues from α8, binds the BH3 domain of other BAX or BCL-2 proteins in its active form. In the protein's inactive form, the groove binds its transmembrane domain, transitioning it from a membrane-bound to a cytosolic protein. A smaller hydrophobic groove formed by the α1 and α6 helices is located on the opposite side of the protein from the major groove, and may serve as a BAX activation site. [9]

Orthologs of the BAX gene have been identified in most mammals for which complete genome data are available. [10]

Function

In healthy mammalian cells, the majority of BAX is found in the cytosol, but upon initiation of apoptotic signaling, Bax undergoes a conformational shift. Upon induction of apoptosis, BAX becomes organelle membrane-associated, and in particular, mitochondrial membrane associated. [11] [12] [13] [14] [15]

BAX is believed to interact with, and induce the opening of the mitochondrial voltage-dependent anion channel, VDAC. [16] Alternatively, growing evidence also suggests that activated BAX and/or Bak form an oligomeric pore, MAC in the MOM (mitochondrial outer membrane). [17] [18] This results in the release of cytochrome c and other pro-apoptotic factors from the mitochondria, often referred to as mitochondrial outer membrane permeabilization, leading to activation of caspases. [19] This defines a direct role for BAX in mitochondrial outer membrane permeabilization. BAX activation is stimulated by various abiotic factors, including heat, hydrogen peroxide, low or high pH, and mitochondrial membrane remodeling. In addition, it can become activated by binding BCL-2, as well as non-BCL-2 proteins such as p53 and Bif-1. Conversely, BAX can become inactivated by interacting with VDAC2, Pin1, and IBRDC2. [9]

Clinical significance

The expression of BAX is upregulated by the tumor suppressor protein p53, and BAX has been shown to be involved in p53-mediated apoptosis. The p53 protein is a transcription factor that, when activated as part of the cell's response to stress, regulates many downstream target genes, including BAX. Wild-type p53 has been demonstrated to upregulate the transcription of a chimeric reporter plasmid utilizing the consensus promoter sequence of BAX approximately 50-fold over mutant p53. Thus it is likely that p53 promotes BAX's apoptotic faculties in vivo as a primary transcription factor. However, p53 also has a transcription-independent role in apoptosis. In particular, p53 interacts with BAX, promoting its activation as well as its insertion into the mitochondrial membrane. [20] [21] [22]

Drugs that activate BAX, such as ABT-737, a BH3 mimetic, hold promise as anticancer treatments by inducing apoptosis in cancer cells. [9] For instance, binding of HA-BAD to BCL-xL and concomitant disruption of BAX:BCL-xL interaction was found to partly reverse paclitaxel resistance in human ovarian cancer cells. [23] Meanwhile, excessive apoptosis in such conditions as ischemia reperfusion injury and amyotrophic lateral sclerosis may benefit from drug inhibitors of BAX. [9]

Interactions

Overview of signal transduction pathways involved with apoptosis. Signal transduction pathways.svg
Overview of signal transduction pathways involved with apoptosis.

Bcl-2-associated X protein has been shown to interact with:

See also

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Type of programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Bcl-2</span> Protein found in humans

Bcl-2, encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first apoptosis regulator identified in any organism.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

p53 upregulated modulator of apoptosis Protein-coding gene in the species Homo sapiens

The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. The expression of PUMA is regulated by the tumor suppressor p53. PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.

<span class="mw-page-title-main">Phorbol-12-myristate-13-acetate-induced protein 1</span> Protein-coding gene in the species Homo sapiens

Phorbol-12-myristate-13-acetate-induced protein 1 is a protein that in humans is encoded by the PMAIP1 gene, and is also known as Noxa.

<span class="mw-page-title-main">Bcl-2 homologous antagonist killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2 homologous antagonist/killer is a protein which in humans is encoded by the BAK1 gene on chromosome 6. It belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.

<span class="mw-page-title-main">Bcl-2-associated death promoter</span> Mammalian protein found in Homo sapiens

The BCL2 associated agonist of cell death (BAD) protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family, a subfamily of the Bcl-2 family. It does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2 family. After activation, it is able to form a heterodimer with anti-apoptotic proteins and prevent them from stopping apoptosis.

<span class="mw-page-title-main">Bcl-xL</span> Transmembrane molecule in the mitochondria

B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as cytochrome c, which leads to caspase activation and ultimately, programmed cell death.

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

<span class="mw-page-title-main">Bcl-2-like protein 1</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 1 is a protein encoded in humans by the BCL2L1 gene. Through alternative splicing, the gene encodes both of the human proteins Bcl-xL and Bcl-xS.

<span class="mw-page-title-main">MCL1</span> Protein-coding gene in the species Homo sapiens

Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the MCL1 gene.

<span class="mw-page-title-main">BNIP3</span> Protein-coding gene in the species Homo sapiens

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 is a protein found in humans that is encoded by the BNIP3 gene.

<span class="mw-page-title-main">BCL2L11</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 11, commonly called BIM, is a protein that in humans is encoded by the BCL2L11 gene.

<span class="mw-page-title-main">BCL2-related protein A1</span> Protein-coding gene in the species Homo sapiens

Bcl-2-related protein A1 is a protein in humans which is encoded by the BCL2A1 gene.

<span class="mw-page-title-main">Bcl-2-interacting killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2-interacting killer is a protein that in humans is encoded by the BIK gene.

<span class="mw-page-title-main">SH3GLB1</span> Protein-coding gene in the species Homo sapiens

Endophilin-B1 is a protein that in humans is encoded by the SH3GLB1 gene. Endophilin-B1 belongs to the Bin/Amphiphysin/Rvs167 (BAR) family of proteins and plays a critical role in mitochondrial fission and fusion, as well as in autophagy and apoptosis. Loss of functional endophilin-B1 is seen in many different forms of cancer. The link between carcinogenesis and dysregulation of cell death pathways suggests that endophilin-B1 serves a critical tumor suppressor role in the cell, although the underlying mechanisms are not known.

<span class="mw-page-title-main">HRK (gene)</span>

Activator of apoptosis harakiri is a protein that in humans is encoded by the HRK gene.

<span class="mw-page-title-main">BMF (gene)</span> Protein-coding gene in the species Homo sapiens

Bcl-2-modifying factor is a protein that in humans is encoded by the BMF gene.

<span class="mw-page-title-main">BOK (gene)</span> Protein-coding gene in the species Homo sapiens

Bok is a protein-coding gene of the Bcl-2 family that is found in many invertebrates and vertebrates. It induces apoptosis, a special type of cell death. Currently, the precise function of Bok in this process is unknown.

<span class="mw-page-title-main">Bcl-2 family</span>

The Bcl-2 family consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion. The Bcl-2 family proteins consists of members that either promote or inhibit apoptosis, and control apoptosis by governing mitochondrial outer membrane permeabilization (MOMP), which is a key step in the intrinsic pathway of apoptosis. A total of 25 genes in the Bcl-2 family were identified by 2008.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000087088 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000003873 – Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "UniProt". www.uniprot.org. Retrieved 30 April 2023.
  6. ↑ "Entrez Gene: BCL2-associated X protein".
  7. 1 2 3 Oltvai ZN, Milliman CL, Korsmeyer SJ (August 1993). "Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death". Cell. 74 (4): 609–619. doi:10.1016/0092-8674(93)90509-O. PMID   8358790. S2CID   31151334.
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  22. ↑ Miyashita T, Reed JC (January 1995). "Tumor suppressor p53 is a direct transcriptional activator of the human bax gene". Cell. 80 (2): 293–299. doi: 10.1016/0092-8674(95)90412-3 . PMID   7834749. S2CID   14495370.
  23. 1 2 Strobel T, Tai YT, Korsmeyer S, Cannistra SA (November 1998). "BAD partly reverses paclitaxel resistance in human ovarian cancer cells". Oncogene. 17 (19): 2419–2427. doi:10.1038/sj.onc.1202180. PMID   9824152. S2CID   44240363.
  24. ↑ Hoetelmans RW (June 2004). "Nuclear partners of Bcl-2: Bax and PML". DNA and Cell Biology. 23 (6): 351–354. doi:10.1089/104454904323145236. PMID   15231068.
  25. ↑ Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, et al. (February 2004). "Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3". Cell. 116 (4): 527–540. doi: 10.1016/S0092-8674(04)00162-X . PMID   14980220. S2CID   17808479.
  26. ↑ Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, et al. (January 2000). "Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis". Nature Cell Biology. 2 (1): 1–6. doi:10.1038/71316. PMID   10620799. S2CID   52847351.
  27. ↑ Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M (August 2002). "Development of a high-throughput fluorescence polarization assay for Bcl-x(L)". Analytical Biochemistry. 307 (1): 70–75. doi:10.1016/S0003-2697(02)00028-3. PMID   12137781.
  28. ↑ Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken B, et al. (July 2003). "Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway". The EMBO Journal. 22 (14): 3580–3590. doi:10.1093/emboj/cdg343. PMC   165613 . PMID   12853473.
  29. ↑ Zhang H, Cowan-Jacob SW, Simonen M, Greenhalf W, Heim J, Meyhack B (April 2000). "Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells". The Journal of Biological Chemistry. 275 (15): 11092–11099. doi: 10.1074/jbc.275.15.11092 . PMID   10753914.
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  32. ↑ Susini L, Besse S, Duflaut D, Lespagnol A, Beekman C, Fiucci G, et al. (August 2008). "TCTP protects from apoptotic cell death by antagonizing bax function". Cell Death and Differentiation. 15 (8): 1211–1220. doi: 10.1038/cdd.2008.18 . PMID   18274553.
  33. ↑ Nomura M, Shimizu S, Sugiyama T, Narita M, Ito T, Matsuda H, et al. (January 2003). "14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax". The Journal of Biological Chemistry. 278 (3): 2058–2065. doi: 10.1074/jbc.M207880200 . PMID   12426317.
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