-
Journal of Musculoskeletal & Neuronal... Dec 2021This research aims to analyze the expression of pro-apoptotic proteins (Bax, p53) and anti-apoptotic protein (Bcl-2) in the nerve roots of the brachial plexus following...
OBJECTIVES
This research aims to analyze the expression of pro-apoptotic proteins (Bax, p53) and anti-apoptotic protein (Bcl-2) in the nerve roots of the brachial plexus following traumatic brachial plexus injury (TBPI) in the early and late stage.
METHODS
A total of 30 biopsy samples were taken from the proximal stump of the postganglionic nerve roots of the TBPI patients' brachial plexus from January 2018 until September 2019. The samples were taken from patients within six months of trauma (early stage, group A) and more than six months following trauma (late stage, group B). Bcl-2, Bax, and p53 expressions in each group were measured and compared.
RESULTS
We found significant differences in the Bcl-2 (p=0.04), Bax (p<0.0001), p53 (p<0.0001) expressions between group A and B. The Bcl-2/Bax expression ratio in group A and B was 2.26 and 0.22, respectively. Meanwhile, the Bcl-2/p53 expression ratio in group A and B was 1.64 and 0.23, respectively.
CONCLUSION
Apoptosis is inhibited by Bcl-2 activities in the early stage following trauma. In the late stage, a significant decrease of Bcl-2 coupled with a substantial increase of Bax and p53 indicates a continuation of the apoptotic process.
Topics: Apoptosis; Brachial Plexus; Humans; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53; bcl-2-Associated X Protein
PubMed: 34854392
DOI: No ID Found -
Biomolecules Dec 2020BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has... (Review)
Review
BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has traditionally been classified as a BAX-like pro-apoptotic protein. However, the mechanism of action and cellular functions of BOK remains controversial. While some studies propose that BOK could replace BAK and BAX to elicit apoptosis, others attribute to this protein an indirect way of apoptosis regulation. Adding to the debate, BOK has been associated with a plethora of non-apoptotic functions that makes this protein unpredictable when dictating cell fate. Here, we compile the current knowledge and open questions about this paradoxical protein with a special focus on its structural features as the key aspect to understand BOK biological functions.
Topics: Amino Acid Sequence; Animals; Apoptosis; Calcium; Eukaryotic Cells; Gene Expression Regulation; Humans; Mitochondria; Mitochondrial Membranes; Models, Molecular; Permeability; Protein Conformation; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Uridine; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 33291826
DOI: 10.3390/biom10121638 -
The Journal of Biological Chemistry Oct 2020Previously we reported that adipocyte SNAP23 (synaptosome-associated protein of 23 kDa) deficiency blocks the activation of macroautophagy, leading to an increased...
Previously we reported that adipocyte SNAP23 (synaptosome-associated protein of 23 kDa) deficiency blocks the activation of macroautophagy, leading to an increased abundance of BAX, a pro-death Bcl-2 family member, and activation and adipocyte cell death both and Here, we found that knockdown of SNAP23 inhibited the association of the autophagosome regulators ATG16L1 and ATG9 compartments by nutrient depletion and reduced the formation of ATG16L1 membrane puncta. ATG16L1 knockdown inhibited autophagy flux and increased BAX protein levels by suppressing BAX degradation. The elevation in BAX protein had no effect on BAX activation or cell death in the nutrient-replete state. However, following nutrient depletion, BAX was activated with a concomitant induction of cell death. Co-immunoprecipitation analyses demonstrated that SNAP23 and ATG16L1 proteins form a stable complex independent of nutrient condition, whereas in the nutrient-depleted state, BAX binds to SNAP23 to form a ternary BAX-SNAP23-ATG16L1 protein complex. Taken together, these data support a model in which SNAP23 plays a crucial function as a scaffold for ATG16L1 necessary for the suppression of BAX activation and induction of the intrinsic cell death program.
Topics: Animals; Apoptosis; Autophagy; Autophagy-Related Proteins; Mice; NIH 3T3 Cells; Protein Binding; Qb-SNARE Proteins; Qc-SNARE Proteins; Subcellular Fractions; bcl-2-Associated X Protein
PubMed: 32848017
DOI: 10.1074/jbc.RA120.013999 -
Biomolecules May 2023The antiapoptotic protein Bcl-xL is a major regulator of cell death and survival, but many aspects of its functions remain elusive. It is mostly localized in the...
The antiapoptotic protein Bcl-xL is a major regulator of cell death and survival, but many aspects of its functions remain elusive. It is mostly localized in the mitochondrial outer membrane (MOM) owing to its C-terminal hydrophobic α-helix. In order to gain further information about its membrane organization, we set up a model system combining cell-free protein synthesis and nanodisc insertion. We found that, contrary to its proapoptotic partner Bax, neosynthesized Bcl-xL was spontaneously inserted into nanodiscs. The deletion of the C-terminal α-helix of Bcl-xL prevented nanodisc insertion. We also found that nanodisc insertion protected Bcl-xL against the proteolysis of the 13 C-terminal residues that occurs during expression of Bcl-xL as a soluble protein in . Interestingly, we observed that Bcl-xL increased the insertion of Bax into nanodiscs, in a similar way to that which occurs in mitochondria. Cell-free synthesis in the presence of nanodiscs is, thus, a suitable model system to study the molecular aspects of the interaction between Bcl-xL and Bax during their membrane insertion.
Topics: bcl-2-Associated X Protein; bcl-X Protein; Escherichia coli; Apoptosis; Apoptosis Regulatory Proteins
PubMed: 37371456
DOI: 10.3390/biom13060876 -
Nature Chemical Biology Apr 2019BAX is a critical effector of the mitochondrial cell death pathway in response to a diverse range of stimuli in physiological and disease contexts. Upon binding by...
BAX is a critical effector of the mitochondrial cell death pathway in response to a diverse range of stimuli in physiological and disease contexts. Upon binding by BH3-only proteins, cytosolic BAX undergoes conformational activation and translocation, resulting in mitochondrial outer-membrane permeabilization. Efforts to rationally target BAX and develop inhibitors have been elusive, despite the clear therapeutic potential of inhibiting BAX-mediated cell death in a host of diseases. Here, we describe a class of small-molecule BAX inhibitors, termed BAIs, that bind directly to a previously unrecognized pocket and allosterically inhibit BAX activation. BAI binding around the hydrophobic helix α5 using hydrophobic and hydrogen bonding interactions stabilizes key areas of the hydrophobic core. BAIs inhibit conformational events in BAX activation that prevent BAX mitochondrial translocation and oligomerization. Our data highlight a novel paradigm for effective and selective pharmacological targeting of BAX to enable rational development of inhibitors of BAX-mediated cell death.
Topics: Amino Acid Sequence; Apoptosis; Binding Sites; Gas Chromatography-Mass Spectrometry; Humans; Mitochondria; Models, Molecular; Peptide Fragments; Permeability; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; bcl-2-Associated X Protein
PubMed: 30718816
DOI: 10.1038/s41589-018-0223-0 -
Medicine Jul 2018BCL-2 Associated X (BAX) is an important modulator of apoptosis. The associations between BAX gene polymorphism and cancer susceptibility and prognosis in different... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
BCL-2 Associated X (BAX) is an important modulator of apoptosis. The associations between BAX gene polymorphism and cancer susceptibility and prognosis in different ethnic groups and types of cancer have yielded controversial results. To reconcile the results, a systematic review followed by meta-analysis was performed to assess the associations.
METHODS
A systematic search of Medline database (PubMed), EMBASE, China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang databases for publications on BAX polymorphisms, and susceptibility and prognosis was carried out until July 2017. Retrieved 14 articles met the inclusions. Summary odds ratios (ORs) and hazard ratios (HRs) with their 95% confidence intervals (CIs) were harnessed to determine the strength of correlation between BAX polymorphisms and cancer susceptibility and prognosis, which were combined using fixed- or random-effects models as appropriate.
RESULTS
A total of 12 trials involving 3321 cases and 3209 controls were included in our pooled analysis regarding the polymorphisms and the susceptibility of cancers. Overall, results of the present meta-analysis demonstrated that there was no significant association between BAX polymorphisms and susceptibility of cancers (OR = 1.052, 95% CI: 0.827-1.339, P = .679, A vs G). Even in a stratified analysis by ethnicity and the sources of control groups, the results were consistent. Four retrospective studies of 549 cases qualified for meta-analysis were identified to set forth the associations of the polymorphisms with cancer prognosis. Our results suggested that BAX gene polymorphisms were significantly associated with unfavorable prognosis (HR = 1.735, 95% CI: 1.368-2.202, P = .000, GG vs GA/AA).
CONCLUSION
There is no significant association between BAX gene polymorphism and cancer susceptibility, but it probably contributes to increased adverse prognosis to cancer.
Topics: Genetic Predisposition to Disease; Humans; Neoplasms; Polymorphism, Genetic; Prognosis; bcl-2-Associated X Protein
PubMed: 30024563
DOI: 10.1097/MD.0000000000011591 -
Philosophical Transactions of the Royal... Aug 2017Apoptotic cell death via the mitochondrial pathway occurs in all vertebrate cells and requires the formation of pores in the mitochondrial outer membrane. Two Bcl-2... (Review)
Review
Apoptotic cell death via the mitochondrial pathway occurs in all vertebrate cells and requires the formation of pores in the mitochondrial outer membrane. Two Bcl-2 protein family members, Bak and Bax, form these pores during apoptosis, and how they do so has been investigated for the last two decades. Many of the conformation changes that occur during their transition to pore-forming proteins have now been delineated. Notably, biochemical, biophysical and structural studies indicate that symmetric homodimers are the basic unit of pore formation. Each dimer contains an extended hydrophobic surface that lies on the outer membrane, and is anchored at either end by a transmembrane domain. Membrane-remodelling events such as positive membrane curvature have been reported to accompany apoptotic pore formation, suggesting Bak and Bax form lipidic pores rather than proteinaceous pores. However, it remains unclear how symmetric dimers assemble to porate the membrane. Here, we review how clusters of dimers and their lipid-mediated interactions provide a molecular explanation for the heterogeneous assemblies of Bak and Bax observed during apoptosis.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'.
Topics: Apoptosis; Mitochondrial Membranes; Protein Multimerization; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 28630157
DOI: 10.1098/rstb.2016.0218 -
Nature Communications Feb 2021The BCL-2 family protein BAX has essential activity in mitochondrial regulation of cell death. While BAX activity ensures tissue homeostasis, when dysregulated it...
The BCL-2 family protein BAX has essential activity in mitochondrial regulation of cell death. While BAX activity ensures tissue homeostasis, when dysregulated it contributes to aberrant cell death in several diseases. During cellular stress BAX is transformed from an inactive cytosolic conformation to a toxic mitochondrial oligomer. Although the BAX transformation process is not well understood, drugs that interfere with this process are useful research tools and potential therapeutics. Here, we show that Eltrombopag, an FDA-approved drug, is a direct inhibitor of BAX. Eltrombopag binds the BAX trigger site distinctly from BAX activators, preventing them from triggering BAX conformational transformation and simultaneously promoting stabilization of the inactive BAX structure. Accordingly, Eltrombopag is capable of inhibiting BAX-mediated apoptosis induced by cytotoxic stimuli. Our data demonstrate structure-function insights into a mechanism of BAX inhibition and reveal a mechanism for Eltrombopag that may expand its use in diseases of uncontrolled cell death.
Topics: 3T3 Cells; Animals; Apoptosis; Benzoates; Cell Death; Humans; Hydrazines; Magnetic Resonance Spectroscopy; Mice; Models, Biological; Models, Molecular; Protein Stability; Pyrazoles; bcl-2-Associated X Protein
PubMed: 33602934
DOI: 10.1038/s41467-021-21224-1 -
Biochimica Et Biophysica Acta Apr 2011Bax and Bak are two nuclear-encoded proteins present in higher eukaryotes that are able to pierce the mitochondrial outer membrane to mediate cell death by apoptosis.... (Review)
Review
Bax and Bak are two nuclear-encoded proteins present in higher eukaryotes that are able to pierce the mitochondrial outer membrane to mediate cell death by apoptosis. Thus, organelles recruited by nucleated cells to supply energy can be recruited by Bax and Bak to kill cells. The two proteins lie in wait in healthy cells where they adopt a globular α-helical structure, seemingly as monomers. Following a variety of stress signals, they convert into pore-forming proteins by changing conformation and assembling into oligomeric complexes in the mitochondrial outer membrane. Proteins from the mitochondrial intermembrane space then empty into the cytosol to activate proteases that dismantle the cell. The arrangement of Bax and Bak in membrane-bound complexes, and how the complexes porate the membrane, is far from being understood. However, recent data indicate that they first form symmetric BH3:groove dimers which can be linked via an interface between the α6-helices to form high order oligomers. Here, we review how Bax and Bak change conformation and oligomerize, as well as how oligomers might form a pore. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.
Topics: Animals; Apoptosis; Humans; Mitochondria; Molecular Biology; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 21195116
DOI: 10.1016/j.bbamcr.2010.12.019 -
Cell Death & Disease Jul 2023Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor...
Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor agonist eltrombopag (Eltro) inhibits BAX activation and BAX-mediated apoptosis. Here we report that, in contrast to its function as a BAX inhibitor, Eltro directly binds BAK but induces its activation in vitro. Moreover, Eltro induces or sensitizes BAK-dependent cell death in mouse embryonic fibroblasts (MEFs) and Jurkat cells. Chemical shift perturbation analysis by NMR indicates that Eltro binds to the BAK α4/α6/α7 groove to initiate BAK activation. Further molecular docking by HADDOCK suggests that several BAK residues, including R156, F157, and H164, play an important role in the interaction with Eltro. The introduction of an R156E mutation in the BAK α4/α6/α7 groove not only decreases Eltro binding and Eltro-induced BAK activation in vitro but also diminishes Eltro-induced apoptosis. Thus, our data suggest that Eltro directly induces BAK activation and BAK-dependent apoptosis, providing a starting point for the future development of more potent and selective direct BAK activators.
Topics: Animals; Mice; Molecular Docking Simulation; bcl-2-Associated X Protein; Fibroblasts; Apoptosis
PubMed: 37393297
DOI: 10.1038/s41419-023-05918-6