Elsevier

Biochemical Pharmacology

Volume 60, Issue 8, 15 October 2000, Pages 1143-1151
Biochemical Pharmacology

A20 and A20-binding proteins as cellular inhibitors of nuclear factor-κB-dependent gene expression and apoptosis

https://doi.org/10.1016/S0006-2952(00)00404-4Get rights and content

Abstract

Proper gene expression and cell growth are critical for the survival of all organisms. Nuclear factor-kappaB (NF-κB)-dependent gene expression and apoptosis play crucial roles in numerous cellular processes, and defects in their regulation may contribute to a variety of diseases including inflammation and cancer. Although there has recently been tremendous progress in our understanding of the signaling pathways that lead to NF-κB activation and apoptosis, signaling mechanisms that negatively regulate these processes are only partially understood. This review deals with the zinc finger protein A20, which has been characterized as a dual inhibitor of NF-κB activation and apoptosis. Its inducible expression by a wide variety of stimuli, including cytokines such as tumor necrosis factor, interleukin-1, and CD40, as well as bacterial and viral products such as lipopolysaccharide, Epstein–Barr virus latent membrane protein 1, and human T-cell leukemia virus type I Tax, suggests that it is involved in the negative feedback regulation of signaling. We will discuss the possible underlying mechanisms, placing emphasis on the role of several A20-binding proteins that have recently been described. Moreover, evidence is presented that A20 and A20-binding proteins are potential novel therapeutic tools in the treatment of a variety of diseases.

Section snippets

A20: structure and expression

A20 is encoded by a primary response gene originally identified as a TNF-inducible gene in human umbilical vein endothelial cells [16]. The induction of A20 by TNF is transient, being detectable after 15 min, and is maximal after 1-hr stimulation. Costimulation with cycloheximide results in stabilization of the A20 mRNA, consistent with the fact that the 3′-untranslated region of A20 mRNA contains four copies of the canonical sequence ATTTA, which is known to confer instability on a number of

Function of A20

A20 was initially characterized as an inhibitor of TNF-induced apoptosis [27]. Stable overexpression of A20 in a number of cell lines was shown to result in partial resistance to TNF-induced apoptosis. It should be noted that A20-mediated inhibition of apoptosis has not been observed in all cell lines studied. Hence, protection against TNF cytotoxicity exists for human breast carcinoma MCF7 cells, murine fibrosarcoma WEHI164 cells, murine embryonic fibroblast NIH3T3 cells, and human umbilical

A20

A20 has been shown to self-associate via its zinc finger domain [48]. Whether A20 forms homodimers or multimers is still not known. As well, the functional significance of A20 oligomerization is still unclear.

TRAFs

A20 has been shown to interact via its N-terminal domain with TRAF1 and TRAF2, which are part of the NF-κB activation cascade initiated by TNF [40], as well as with TRAF6 [49], which is part of the IL-1- and LPS-induced signaling pathway to NF-κB. At the moment, six members of the TRAF

A20: mechanism of action

As A20 is capable of inhibiting both TNF-induced cell death and NF-κB activation, it is tempting to speculate that it may interfere with TRADD binding to the TNF-R1. However, it should be mentioned that in contrast to the NF-κB modulatory effect of A20, its antiapoptotic activity can only be observed in a limited number of cell lines 31, 33, suggesting at least two different targets for A20. Alternatively, one cannot exclude the cell line-specific existence of different proapoptotic signaling

Therapeutic implications

The increased understanding of the activation and regulation of NF-κB has opened the way for the development of new treatments for inflammatory diseases in the future. Several synthetic and naturally occurring inhibitors of NF-κB-dependent gene expression have been described [64]. Some of these have recently been shown to directly target the IKK complex 65, 66, while many others are certainly in the pipeline. Antisense oligonucleotides against the p65 subunit of NF-κB have been evaluated

Concluding remarks

Over the last 2–3 years, our understanding of the signaling pathways involved in the regulation of NF-κB-dependent gene expression and apoptosis in response to diverse stimuli has increased enormously. A20 promises to be an interesting molecule because of its dual activity on NF-κB activation and cell death. Nevertheless, intriguing questions regarding the mechanism of action, regulation, and function of A20 and A20-binding proteins remain to be answered:

  • 1.

    What is the molecular basis for the

Acknowledgements

R.B. is a Research Associate with the Fund for Scientific Research-Flanders. Supported in part by the IUAP, FWO, and EC-TMR.

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