Disease relevance of Tnfaip3

• Mice deficient for A20 develop severe inflammation and cachexia, are hypersensitive to both lipopolysaccharide and TNF, and die prematurely [1].
• For the first time we report that A20 expression blocks OxLDL-mediated cell toxicity and apoptosis [2].
• Here, using the murine B-cell lymphoma cell line A20, we show that the TNF-alpha gene is regulated in a cell-type-specific manner [3].
• Here, we have examined the role of A20 in influenza virus infection-induced NF-kappaB promoter activation in human bronchial epithelial cells [4].
• These results indicate that A20 may function as a negative regulator of NF-kappaB-mediated lung inflammation and injury upon influenza virus infection, thereby protecting the host against inflammatory response to influenza virus infection [4].

High impact information on Tnfaip3

• The phenomenon proved reproducible with two antibodies against CD40 (3/23 and FGK-45) in three CD40+ lymphomas (A20, A31 and BCL1) and gave partial protection in one of two CD40- lymphomas (EL4 and Ten1) [5].
• A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor kappaB (NF-kappaB) activity and tumor necrosis factor (TNF)-mediated programmed cell death (PCD) [1].
• Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice [1].
• TNF dramatically increases A20 messenger RNA expression in all tissues [1].
• The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses [6].

Chemical compound and disease context of Tnfaip3

• Adenoviral mediated hepatic expression of A20 in BALB/c mice yields an 85% survival rate in the D-galactosamine (D-gal)/lipolysaccharide (LPS) model of acute toxic hepatitis compared with 15% to 20 % in control mice [7].
• Intratumoral inoculation of VSV-C:U in the presence of the systemically administered prodrug 5-fluorocytosine produced statistically significant reductions in the malignant growth of syngeneic lymphoma (A20) or mammary carcinoma (TSA) in BALB/c mice compared with rVSV treatments or with control 5-FU alone [8].
• To identify other molecules that may be involved in proximal BCR signaling, we examined the substrates that were tyrosine phosphorylated following stimulation with either anti-IgG Abs or pervanadate in the murine B cell lymphoma A20 IIA1.6 and in resting splenic B cells [9].
• Cyclosporine (CsA) was tested for its ability to inhibit antigen presentation by spleen cells or the B lymphoma line A20 to T cell hybridomas specific for hen egg-white lysozyme (HEL) [10].
• Northern blot analysis showed comparable amounts of A alpha mRNA in 2PK3 as compared to another Iad expressing B cell lymphoma, A20, which predominantly expresses I-A and I-E [11].

Biological context of Tnfaip3

• This mutation introduces a putative casein kinase 2 phosphorylation site in C57BL/6J-A20 not present in FVB/N-A20 [12].
• We sequenced the A20 gene coding region from the parental strains and found a single-nucleotide polymorphism resulting in a single amino acid exchange, Glu627Ala (C57BL/6J vs. FVB/N) [12].
• NFkappaB reporter gene assays showed that this amino acid change results in less effective termination of TNFalpha-stimulated NFkappaB activation by C57BL/6J-A20 [12].
• A20 overexpression under control of mouse osteocalcin promoter in MC3T3-E1 cells inhibited tumor necrosis factor-alpha-induced apoptosis [13].
• Activation leads to a down-regulation of A20 expression in both mature thymocytes and peripheral T cells [14].

Anatomical context of Tnfaip3

• In accordance, the TNFalpha-induced expression of NFkappaB target genes (A20, IkappaBalpha) in vascular smooth muscle cells was prolonged in cells isolated from C57BL/6J compared with FVB/N mice [12].
• We further found that the induction of the negative regulators of TLR signaling IL-1R-associated kinase-M, Toll-interacting protein, and A20 by intratracheal LPS in vivo and in macrophages in vitro was significantly reduced in CD44(-/-) mice [15].
• Then the mouse MC3T3-E1 cell line, stably transfected by A20, was established [13].
• CONCLUSION: We constructed an osteoblast-specific expression vector that expressed A20 protein in MC3T3-E1 cells and confirmed that A20 protects osteoblast against TNF-alpha-induced apoptosis [13].
• In conclusion, A20 provides a proliferative advantage to hepatocytes [16].

Associations of Tnfaip3 with chemical compounds

• A20 expression in the liver limits hepatocellular damage hence maintains bilirubin clearance and the liver synthetic function [16].
• This new site plays a critical role in the calcium-mediated, cyclosporin A-sensitive induction of TNF-alpha in both A20 B cells and Ar-5 cells [3].
• 2. After fixation with glutaraldehyde, Daudi and A20/2J continued to stimulate this gamma delta T-cell line [17].
• A20 protects mice from D-galactosamine/lipopolysaccharide acute toxic lethal hepatitis [7].
• The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation [18].

Enzymatic interactions of Tnfaip3

• We show that IKKbeta phosphorylates A20 in vitro and in vivo at serine 381, and we further show that this phosphorylation event increases the ability of A20 to inhibit the NF-kappaB signaling pathway [19].

Other interactions of Tnfaip3

• In addition, A20 confers a proliferative advantage to hepatocytes via decreased expression of the cyclin-dependent kinase inhibitor p21(waf1) [16].
• We cloned and characterized a murine A20 cDNA and mapped the gene to mouse chromosome 10, 3.5 centimorgans proximal to the c-myb locus [14].
• A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6 [6].
• A20 protects hepatocytes from apoptosis and ongoing inflammation by inhibiting NF-kappaB [16].
• MOPC 315 tumor expressed the most IL-10 mRNA (23.2 pg/micrograms of poly(A)+ RNA), whereas 2PK-3, A20, and RAW 8.1 tumors expressed 7.4, 2.6, and 0.6 pg/micrograms of poly(A)+ RNA, respectively [20].

Analytical, diagnostic and therapeutic context of Tnfaip3

• The expression of A20 mRNA and A20 protein in the cells were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively [13].
• The anti-apoptotic role of A20 in MC3T3-E1 cells was determined by Flow cytometric analysis (FACS), terminal dUTP nick endo-labeling (TUNEL) and DNA gel electrophoresis analysis (DNA Ladder), respectively [13].
• In particular, A20 is significantly upregulated in the liver following partial hepatectomy [16].
• Using the murine cDNA, we conducted in situ hybridization studies to examine patterns of A20 expression in mouse embryos and postnatal tissues [14].
• However, in the A20 B cell lymphoma-transferred tumor model, TRAIL/Apo2L(-/-) mice are clearly more susceptible to death from overwhelming tumor burden, due to increased lymphoma load in the liver [21].

References