Disease relevance of Bcl3

• Knockout of the B cell lymphoma 3 (Bcl3) gene also showed an inhibition of fiber atrophy and an abolition of NF-kappaB reporter activity [1].
• We demonstrate that Bcl-3(-/-) mice are highly susceptible to Listeria monocytogenes infection [2].
• Our finding on Bcl-3 overexpression in late papillomas and SCC could explain the selective increase of p50-related kappaB-binding in mouse skin tumors [3].
• Bcl-3-deficient mice are also impaired in germinal center reactions and T-dependent antibody responses to influenza virus [4].
• A potential involvement of Bcl-3 in oncogenesis is highlighted by the fact that it was cloned due to its location at a breakpoint junction in some cases of human B-cell chronic lymphocytic leukemia and that it is highly expressed in human breast tumor tissue [5].

High impact information on Bcl3

• Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling [6].
• Expression of the Bcl-3 proto-oncogene suppresses p53 activation [7].
• While Bcl-3 expression in cancer was originally thought to be limited to B-cell lymphomas with a 14;19 chromosomal translocation, more recent evidence indicates that expression of this presumptive oncoprotein is significantly more widespread in cancer [7].
• The Bcl-3 protein is known to interact specifically with the p50 and p52 subunits of NFkappaB [8].
• Additionally, spleens from Bcl-3(-/-) mice are abnormal and void of germinal centers [8].

Chemical compound and disease context of Bcl3

• We propose that E2 withdrawal may initiate selection for hormone independence in breast cancer cells by activation of NF-kappaB and Bcl-3, which could then supplant E2 by providing both survival and growth signals [9].
• No changes in the levels of nuclear I kappa B alpha or Bcl-3 occurred after hemorrhage when xanthine oxidase activity was inhibited [10].

Biological context of Bcl3

• Thus both the Nfkb1 and the Bcl3 genes are necessary for unloading-induced atrophy and the associated phenotype transition [1].
• METHODS: NF-kappaB1-, NF-kappaB2-, and Bcl-3-deficient mouse lines were established, and their role in organogenesis of Peyer's patches (PP) was investigated [11].
• Furthermore, constitutive expression of Bcl-3 suppresses DNA damage-induced p53 activation and inhibits p53-induced apoptosis through a mechanism that is at least partly dependent on the up-regulation of Hdm2 [7].
• Since Bcl-3 is required for germinal center formation, these results suggest functional similarities with the unrelated Bcl-6 oncoprotein in suppressing potential p53-dependent cell cycle arrest and apoptosis in response to somatic hypermutation and class switch recombination [7].
• Experiments presented here indicate that Bcl-3 is inducible by DNA damage and is required for the induction of Hdm2 gene expression and the suppression of persistent p53 activity [7].

Anatomical context of Bcl3

• Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy [1].
• Thus, these data establish Bcl-3 as an inhibitor of IL-10 expression in macrophages [2].
• Isolated peritoneal macrophages from Bcl-3(-/-) mice also produce elevated amounts of IL-10, which inhibit IL-12 p70 synthesis in an autocrine fashion [2].
• Abnormal organogenesis of Peyer's patches in mice deficient for NF-kappaB1, NF-kappaB2, and Bcl-3 [11].
• Bcl-3 overexpression increased survival, and activated bcl-3-/- T cells died abnormally rapidly [12].

Associations of Bcl3 with chemical compounds

• Nuclear localization of Bcl-3 was associated with inhibition of LPS-induced TNF-alpha production [13].
• Tumors derived from MCF-7 cells ectopically expressing Bcl-3 remain E2 dependent but display a markedly higher tumor establishment and growth rate compared to controls [9].
• Transfer of the N-terminal domain of IkappaB alpha to the ankyrin domain of the related oncoprotein Bcl-3 or to the unrelated protein glutathione S-transferase confers signal-induced phosphorylation on the resulting chimeric proteins [14].
• Estrogen withdrawal increases both NF-kappaB DNA binding activity and expression of Bcl-3 in MCF-7 and LCC1 cells in vitro and in vivo [9].
• These results demonstrate that blood loss, at least partly through xanthine oxidase-dependent mechanisms, produces alterations in the levels of both I kappa B alpha and Bcl-3 in lung mononuclear cell populations [10].
• Platelets from wild-type mice synthesize Bcl-3 in response to activation, as do human platelets, and platelets from mice with targeted deletion of Bcl-3 have defective retraction of fibrin in platelet-fibrin clots mimicking treatment of human platelets with rapamycin [15].

Physical interactions of Bcl3

• Remarkably, constitutive expression of Bcl-3 in these cells augments the DNA binding activity of p52 homodimers [16].

Regulatory relationships of Bcl3

• The IkappaB protein Bcl-3 negatively regulates transcription of the IL-10 gene in macrophages [2].
• The putative oncoprotein Bcl-3 induces cyclin D1 to stimulate G(1) transition [5].
• Analysis of the Bcl-3-expressing cells suggests that these cells have a shortened G(1) phase of the cell cycle as well as a significant increase in hyperphosphorylation of the retinoblastoma protein [5].

Other interactions of Bcl3

• The results indicate that Bcl-3 is associated with endogenous p50 and p52 in nuclear extracts from transgenic animals [16].
• These genes included nuclear IkappaB proteins such as Bcl-3 and IkappaBNS [17].
• Overexpression of Jun family proteins transactivates the promoter and restores Bcl-3 expression in the absence of IL-4 stimulation [18].
• To characterize the IL-4-induced regulation of murine Bcl-3 expression, we cloned the promoter of this gene [18].
• The time courses of expression suggest that Bcl-2 and Bcl-x(L) promote survival early in the response, whereas Bcl-3 acts later in the response [19].

Analytical, diagnostic and therapeutic context of Bcl3

• In this study, the role of Bcl-3 in an innate immune response was examined by gene targeting [2].
• Here, we performed a microarray analysis and identified Bcl-3 as an IL-10-inducible gene in macrophages [13].
• We have confirmed these increases in Bcl-3 transcription levels using reverse transcription-PCR and S1 nuclease protection assays [20].
• The content of Bcl-3 was about 20-fold higher in platelet from CD18 -/-, than in those from +/+ or CD54 -/- donors, as seen on Western blots or by immunofluorescence and flow cytometry, while the amount of pro-caspase-3 was decreased [21].

References