Disease relevance of TNFAIP3

• Furthermore, cells stably expressing the active form of RIG-I induced an antiviral state that interfered with replication of vesicular stomatitis virus, an effect that was reversed by stable co-expression of A20 [1].
• Cytokine induction of A20 mRNA in primary islets and insulinoma cells was rapid and observed within 1 h, consistent with A20 being an immediate early response gene in beta-cells [2].
• Finally, expression of A20 could be induced at protein level by Sendai virus infection [3].
• This effect is specific, as A20 does not block a noninducible, constitutively expressed reporter, Rous sarcoma virus-luciferase (RSV-LUC); nor does it block the c-Tat-inducible, NF-kappaB-independent reporter, human immunodeficiency virus-chloramphenicol acetyltransferase (HIV-CAT) [4].
• A20 gene expression is regulated by TNF, Vitamin D and androgen in prostate cancer cells [5].
• High A20 expression levels were observed in more aggressive breast tumors (ER-negative, progesterone receptor-negative and high histological grade) [6].
• We also found evidence of two independent signals near TNFAIP3 associated with SLE, including one previously associated with rheumatoid arthritis (RA) [7].
• We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry [8].

High impact information on TNFAIP3

• It also induces binding of NEMO to the signaling inhibitor A20, and recruitment of A20 to the receptor [9].
• The cytoprotective effect of A20 against apoptosis correlates with and is dependent on the abrogation of cytokine-induced NO production [10].
• Stimulation of a B lymphoma cell line, A20, with intact anti-IgG antibody induced a direct, SH2-mediated association between Csk and a 62-kD phosphotyrosine-containing protein that was identified as RasGTPase-activating protein-associated p62 (GAP-A.p62) [11].
• One of these is an A20 zinc finger that binds to a polar interaction interface of ubiquitin centered on Asp58 [12].
• Recently, the underlying mechanism by which A20 downregulates NF-kappaB activation in response to the pro-inflammatory cytokine tumor necrosis factor (TNF) has been described [13].

Chemical compound and disease context of TNFAIP3

• Identification of a novel mechanism of NF-kappaB inactivation by progesterone through progesterone receptors in Hec50co poorly differentiated endometrial cancer cells: induction of A20 and ABIN-2 [14].
• Twenty-nine type 2 diabetic patients with dyslipidemia were enrolled and randomly assigned to receive atorvastatin orally at 10 mg (A10; n = 10), 20 mg (A20; n = 10), or 40 mg (A40; n = 9) daily for 12 weeks [15].

Biological context of TNFAIP3

• The ability of A20 to block NF-kappaB activation was mapped to its C-terminal zinc finger domain [16].
• Our findings suggest that ZNF216 and A20 have redundant and distinct roles in regulating NFkappaB activation and apoptosis [17].
• Deletion of the N-terminal de-ubiquitination domain had no significant effect on the inhibitory effect of A20, whereas deletion or mutation of zinc finger motif 7 ablated the inhibitory function of A20 on IRF- or NF-kappaB-mediated gene expression [1].
• We showed that PML inhibits A20 transactivation through the NF kappa B site by interfering with its binding to the promoter [18].
• Expression of A20 completely blocked CARD domain containing DeltaRIG-I-induced IRF-3 Ser-396 phosphorylation, homodimerization, and DNA binding [1].

Anatomical context of TNFAIP3

• A20 is a stress response gene in endothelial cells (ECs) [19].
• Our data demonstrate that A20 targets the TNF apoptotic pathway by inhibiting proteolytic cleavage of apical caspases 8 and 2, executioner caspases 3 and 6, Bid cleavage, and release of cytochrome c, thus preserving mitochondrion integrity [19].
• Combined expression of A1 and A20 achieves optimal protection of renal proximal tubular epithelial cells [20].
• TNF induced A20 gene expression in both cell lines, but with different effect [5].
• Tag Polymorphisms at the A20 (TNFAIP3) Locus Are Associated With Lower Gene Expression and Increased Risk of Coronary Artery Disease in Type 2 Diabetes [21].

Associations of TNFAIP3 with chemical compounds

• Finally, A20 expression was sufficient to protect beta-cells from TNF-induced apoptosis [2].
• We have previously identified in endothelial cells a gene product designated A20, that is rapidly and profoundly induced by tumor necrosis factor alpha (Dixit, V. M., Green, S., Sarma, V., Holzman, L. B., Wolf, F. W., O'Rourke, K., Ward, P. A., Prochownik, E. V., and Marks, R. M. (1990) J. Biol. Chem. 265, 2973-2978) [22].
• Stimulation with LPS and PGN resulted in a significant increase in the level of A20 mRNA in primary cultured AECs and in NCI-H292 AECs [23].
• A20 mRNA expression was down-regulated by 10nM calcitriol within 3-9h after treatment and up-regulated by androgen reaching maximal values by 6h after stimulation in LNCaP cells [5].
• Enforced overexpression of either A1 or A20 inhibits LPS and cycloheximide-initiated apoptosis [24].

Physical interactions of TNFAIP3

• The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation [16].
• Moreover, A20 interacted with TRIF in co-immunoprecipitation experiments [3].
• A20 has been shown to bind to TNF-receptor-associated factor 2 (TRAF2) and 14-3-3 chaperone proteins [25].
• Moreover, A20 was shown to directly interact with TRAF6 [26].
• Overexpression of A20 does not affect the binding of TNF to its cell surface receptors [27].

Regulatory relationships of TNFAIP3

• A20 also inhibited TNF and IL-1-induced NF-kappaB activation, suggesting that it may inhibit NF-kappaB activation signaled by diverse stimuli [16].
• The promyelocytic leukemia protein represses A20-mediated transcription [18].
• Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20 [1].
• A20 inhibits NF-kappa B activation downstream of multiple Map3 kinases and interacts with the I kappa B signalosome [28].
• ABIN-2 inhibits nuclear factor-kappaB (NF-kappaB) activity and is a possible effector of A20 regulation of NF-kappaB [29].

Other interactions of TNFAIP3

• We also showed that stable overexpression of A20 inhibits apoptosis and caspase activation induced by PML/TNF alpha [18].
• Domain mapping experiments indicated that the ZnF-A20 domain was responsible for interacting with IKKgamma and RIP, whereas the ZnF-AN1 domain interacted with TRAF6 [17].
• Similarly, the NF-kappa B inducing activity of TAX, an activator of the I kappa B kinase complex, is also abrogated by A20 [28].
• ZNF216 Is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB activation [17].
• These results suggest that A20 and ABIN-1 probably act independently of their mutual interaction [30].

Analytical, diagnostic and therapeutic context of TNFAIP3

• Using oligonucleotide microarrays and real-time PCR, we identified TNFAIP3/A20 as the most highly regulated antiapoptotic gene expressed in cytokine-stimulated human and mouse islets [2].
• Similar to A20, ZNF216 interacted with IKKgamma, RIP, and TRAF6 in co-immunoprecipitation experiments [17].
• Site-specific mutagenesis of this region abolished the NF-kappa B inhibiting function of ABIN-1, without affecting the interaction with A20 [30].
• Transplantation of 250 islets overexpressing A20 resulted in a cure rate of 75% with a mean time to cure of 5.2 days, comparable to that achieved with 500 islets [31].
• These data demonstrate that A20 is an ideal cytoprotective gene therapy candidate for islet transplantation [31].

References