Disease relevance of Bcl2a1a

• Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury [1].
• Interestingly, a correlation was noted between the expression level of Bfl-1 gene and the development of stomach cancer in eight sets of clinical samples [2].
• Although the TLR-9-mediated death of Nfkb1(-/-)C-Rel(-/-) pDCs, which coincided with a failure to up-regulate the prosurvival proteins B-cell lymphoma apoptosis regulator xL (Bcl-x(L)) and A1, was blocked by Bcl-2 transgene expression, this inhibition of apoptosis still failed to rescue the differentiation defects [3].
• In contrast to Emu-Bcl-2 transgenes, A1 expression in pro-B cells did not rescue pre-B-cell development in SCID mice [4].
• This study uncovers the importance of A1 for mast cell survival in allergic reactions, and it proposes A1 as a potential target for the treatment of allergic diseases [5].

High impact information on Bcl2a1a

• These mechanisms are distinct from those involving upregulation of the genes encoding the anti-apoptotic Bcl-2 homolog A1 and inhibitor of apoptosis protein-1 (IAP-1) by APC in umbilical vein endothelial cells [6].
• Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis [7].
• Strikingly, Noxa bound only Mcl-1 and A1 [8].
• Essential role of the prosurvival bcl-2 homologue A1 in mast cell survival after allergic activation [5].
• Activation of mast cells through FcepsilonRI resulted in degranulation, strong induction of A1 mRNA and protein, and cell survival [5].

Chemical compound and disease context of Bcl2a1a

• By contrast, murine S49 lymphoma cells were able to generate the A1 subunit with a time course that closely resembled the kinetics of toxin-mediated cyclic AMP accumulation in these cells [9].

Biological context of Bcl2a1a

• It is conceivable that Bfl-1 is involved in the promotion of the cell survival in the stomach cancer development or progression [2].
• A new cDNA clone which is homologous to Bcl-2, named as Bfl-1 were isolated from a human fetal liver at 22 week of gestation [2].
• The absence of mature B cells was associated with impaired survival that coincided with reduced expression of bcl-2 and A1. bcl-2 transgene expression not only prevented apoptosis and increased peripheral B-cell numbers, but also induced further maturation to an IgM(lo)IgD(hi) phenotype [10].
• Bcl-2, Bcl-xL, and A1 are differentially expressed during B- and T-cell development, and they have shared and distinct roles in regulating cell death [4].
• A1 gene expression was strongly but transiently induced during the first day of activation, with a peak at 2 to 6 hours, whereas Bcl-2 mRNA was simultaneously transiently down-regulated [11].

Anatomical context of Bcl2a1a

• In vitro hyperoxia also stimulated A1, and A1 overexpression inhibited oxidant-induced epithelial cell apoptosis and necrosis [1].
• We analyzed regulation of the prosurvival Bcl-2 homologue A1, following T-cell receptor (TCR) or cytokine receptor engagement [12].
• Bfl-1 is abundantly expressed in the bone marrow and at a low level in some other tissues [2].
• Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene [13].
• These studies indicate that A1 protects lymphocytes from apoptosis in vitro but that it has lineage- and stage-specific effects on lymphoid development [4].

Associations of Bcl2a1a with chemical compounds

• In vitro studies suggest that calpain-mediated cleavage of Bfl-1 occurs between its Bcl-2 homology (BH)4 and BH3 domains [14].
• Moreover, while Bfl-1 suppresses apoptosis induced by staurosporine or cytokine withdrawal, it is proapoptotic in response to tumor necrosis factor (TNF) receptor activation in FL5.12 pro-B cells [14].
• The homology to the BH1 and BH2 domains of Bcl-2 was especially significant, suggesting that Bfl-1 is a new member of the Bcl-2-related genes [2].
• Unlike other Bcl-2 family members, Bfl-1 contains a GIn-rich NH2-terminal region and lacks an NH (19K homology) domain 1 [15].
• The RXR agonist 9-cis-retinoic acid also increased Bcl2a1 expression, although all-trans-retinoic acid and ligands for other RXR partner receptors did not [16].

Physical interactions of Bcl2a1a

• However, Bfl-1 remains tightly and selectively bound to tBid and blocks collaboration between tBid and Bax or Bak in the plane of the mitochondrial membrane, thereby preventing mitochondrial apoptotic activation [17].

Regulatory relationships of Bcl2a1a

• In contrast, IL-11 stimulated A1, diminished the toxic effects of hyperoxia, stimulated Bcl-2 and Bcl-xl, and enhanced murine survival in 100% O(2) [1].
• In murine bone marrow-derived macrophages, A1 gene expression is rapidly and transiently induced by GM-CSF, and the induction was independent of de novo protein synthesis [18].
• 4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1 [19].

Other interactions of Bcl2a1a

• To test this, we characterized the expression of A1 and the oxygen susceptibility of WT and IL-11 Tg(+) mice with normal and null A1 loci [1].
• We show that Bfl-1 undergoes constitutive ubiquitin/proteasome-mediated turnover [14].
• The decreased expression observed with A1, a bcl-2 like gene, may account in part for the suppression of growth in cells from the null mice [20].
• In addition to GM-CSF, a transient induction of A1 mRNA accumulation was observed in response to LPS in macrophages [18].
• This induction is not mediated by IL-1 alpha or IL-6, neither of which stimulate A1 [18].

Analytical, diagnostic and therapeutic context of Bcl2a1a

• In B-cell lines derived from c-rel-/- mice, which like primary cells lacking Rel undergo apoptosis in response to antigen receptor ligation, constitutive expression of an A1 transgene inhibits this pathway to cell death [7].
• Confocal microscopy showed that the A1 protein was localized to the cytoplasm in a pattern similar to that of Bcl-2 [21].
• A1 protein levels were also increased as determined by Western blot analysis and immunohistochemical studies [22].
• Quantitative real-time PCR analysis confirmed this finding and demonstrated that Bcl2a1 mRNA expression was significantly greater in nonapoptotic than in apoptotic T lymphocytes [16].
• Exudate macrophages and granulocytes that were apoptotic by TUNEL staining occasionally appeared to display A1 throughout the cell nucleus [22].

References