Disease relevance of Bax

• Bax inactivation also improved postnatal growth rate and myofiber histology and decreased fixed contractures of Lama2(-/-) mice [1].
• Taken together, these results provide unprecedented evidence that the membrane-associated anti-apoptotic CD19-Lyn complex may be at least as important as Bcl-2/Bax ratio for survival of lymphoma cells [2].
• We previously showed that overexpression of Bax restores the chemosensitivity of Bax-deficient breast cancer cell lines [3].
• Adenovirus E1B 19-kDa death suppressor protein interacts with Bax but not with Bad [4].
• Using murine lung endothelial cells as a model, we found that the induction of apoptosis by hypoxia/reoxygenation involved the activation of both Bax-dependent and death receptor-mediated pathways [5].

High impact information on Bax

• Although its ability to activate various p53 target genes is largely compromised, the p53(QS) protein retains the ability to transactivate the gene Bax [6].
• However, using growth factor-dependent cells from Bax/Bak-deficient mice, we demonstrate that apoptosis is not essential to limit cell autonomous survival [7].
• Thus, Ahr-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsible for environmental toxicant-induced ovarian failure [8].
• Oocytes in human ovarian biopsies grafted into immunodeficient mice also accumulate Bax and undergo apoptosis after PAH exposure in vivo [8].
• Mice lacking either Ahr or the pro-apoptotic protein Bax have an increased number of primordial follicles, and these mutant oocytes are resistant to PAH toxicity [9].

Chemical compound and disease context of Bax

• Caspase-2 triggers Bax-Bak-dependent and -independent cell death in colon cancer cells treated with resveratrol [10].
• The impact of Bax/Bcl-xL expression on gemcitabine-sensitivity in vivo was evaluated in orthotopic Colo357 tumors in SCID mice [11].
• To determine whether the stress kinase JNK was an upstream regulator of Bax activation, MLE-12 cells were exposed to bleomycin in the presence of an adenovirus encoding a dominant negative JNK [12].
• Taken together, genistein-induced apoptosis of p815 mastocytoma cells is at least in part mediated by proteasome, Bax, apoptosis-inducing factor, and caspase and augmented by cotreatment with a proteasome inhibitor, lactacystin [13].
• Genistein-induced apoptosis of p815 mastocytoma cells is mediated by Bax and augmented by a proteasome inhibitor, lactacystin [13].

Biological context of Bax

• When Bad dimerized with Bcl-xL, Bax was displaced and apoptosis was restored [14].
• Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death [14].
• Mouse embryonic fibroblasts deficient in Noxa [Noxa(-/-) mouse embryonic fibroblasts (MEFs)] showed notable resistance to oncogene-dependent apoptosis in response to DNA damage, which was further increased by introducing an additional null zygosity for Bax [15].
• Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis [16].
• Combined loss of proapoptotic genes Bak or Bax with Bim synergizes to cause defects in hematopoiesis and in thymocyte apoptosis [17].

Anatomical context of Bax

• Furthermore, whereas mouse embryo fibroblasts (MEF) expressing only Bax or Bak displayed resistance to transformation, bax(-/-)bak(-/-) MEF were nearly as prone to oncogenic transformation as p53(-/-) MEF [18].
• Our results suggest a way in which both Bim and Bax/Bak might be required for activated T cell apoptosis [19].
• Agents that initiate ER stress responses can induce conformational changes and oligomerization of Bax on the ER as well as on mitochondria [20].
• As shown here, freshly generated tetraploid cells arising due to mitotic slippage or failed cytokinesis are prone to undergo Bax-dependent mitochondrial membrane permeabilization and subsequent apoptosis [21].
• Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis [20].

Associations of Bax with chemical compounds

• Peptide mass fingerprinting identified this protein as Bid, a BH3 domain-containing protein known to interact with both Bcl2 and Bax [22].
• Thus, in young mice, Bax emerges as an essential protein in the death pathway induced by IL-7 deficiency [23].
• One potential target of JNK is Bax translocation, which was enhanced by APAP and blocked by the JNK inhibitor [24].
• These data show that Bik/Nbk, which, unlike Bax, carries only a BH3 but no BH1 or BH2 domain may be a target to enhance chemosensitivity [3].
• The levels of Bax and Bad proteins remained relatively constant during DMSO-induced differentiation [25].
• Specific depletion of PKCzeta by RNA interference blocks nicotine-stimulated Bax phosphorylation and enhances apoptotic cell death [26].
• The subcellular distribution of Proline 13 mutant Bax was identical to wild-type Bax in both healthy and apoptotic cells [27].

Physical interactions of Bax

• The repression is direct and depends on several Gfi-1-binding sites in the p53-inducible Bax promoter [28].
• Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria [29].

Enzymatic interactions of Bax

• However, Bax with BH3 deleted did not form heterodimers with Bcl-XL, but retained its ability to counter the death repressor activity of Bcl-XL [30].
• Moreover, in the absence of the putative transmembrane C-terminal domain, Bax does not form ionic channels in the presence of cut Bid [31].

Regulatory relationships of Bax

• BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak [18].
• In addition, we show that enforced expression of AIF can induce neuronal cell death in a Bax- and caspase-independent manner [32].
• Jak3-deficient thymocytes express elevated levels of Bax and reduced levels of Bcl-2 relative to those in wild-type littermates [33].
• Overexpression of N-Bak promotes Bax translocation in HeLa cells and induces neuronal cell death in cortical, hippocampal, and cerebellar granule neurons in a Bax-dependent manner [34].
• Mammalian prion protein suppresses Bax-induced cell death in yeast [35].
• In the diencephalon regions of the forebrain (thalamus), Bax deficiency blocks c-Jun activation, indicating that a Bax-JNK pathway of death is more relevant [36].

Other interactions of Bax

• Tumor-cell resistance to death receptor--induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax [37].
• Thus, the function of either Bax or Bak appears required to initiate most forms of apoptosis and to suppress oncogenic transformation [18].
• Consistent with this prediction, truncation of this short helix was required for Bim/Bax interaction and led to spontaneous activation of Bax [19].
• Bax deficiency partially corrects interleukin-7 receptor alpha deficiency [23].
• NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax [38].
• They demonstrate that Bax, Bid, and MMP-12 play similar roles in bleomycin-induced fibrosis, thereby highlighting the importance of this Bid-activated, Bax-mediated pathway and downstream MMP-12 in a variety of fibrogenic settings [39].

Analytical, diagnostic and therapeutic context of Bax

• Thus, Bax mutation in mismatch repair--deficient tumors can cause resistance to death receptor--targeted therapy, but pre-exposure to chemotherapy rescues tumor sensitivity [37].
• Animal models suggest that Bax and Bak play an essential role in the implementation of apoptosis and as a result can hinder tumorigenesis [40].
• However, whereas combination treatment applied to in vitro cell culture was characterized by a significant up-regulation and activation of Bax and down-regulation of Bcl-xL, the treatment applied to tumors induced Bak and Bcl-xS, whereas Bcl-omega and Bcl-xL were down-regulated [41].
• Western blot analysis revealed that the expression of Bcl-xL, Bax, and Apaf-1 was not affected in cells transfected with sense or antisense AP-4 genes [42].
• Furthermore, using immunocytochemistry as well as chemical blocking of putative apical pathways we could demonstrate that Bak is activated prior to Bax [43].

References