A20 and A20-binding proteins as cellular inhibitors of nuclear factor-κB-dependent gene expression and apoptosis
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.
References (77)
Cytokine regulation of cellular adhesion molecule expression in inflammation
Cytokine Growth Factor Rev
(1999)- et al.
New insights into the roles of ReL/NF-κB transcription factors in immune function, hemopoiesis and human disease
Int J Biochem Cell Biol
(1999) - et al.
Activate NF-κB or die?
Curr Biol
(1997) - et al.
NF-κB and the innate immune response
Curr Opin Immunol
(2000) Toll signaling pathways in the innate immune response
Curr Opin Immunol
(2000)- et al.
TRAF2 plays a dual role in NF-κB-dependent gene activation by mediating the TNF-induced activation of p38 MAPK and IκB kinase pathways
FEBS Lett
(1998) - et al.
p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-κB p65 transactivation mediated by tumor necrosis factor
J Biol Chem
(1998) IκB–NF-κB structuresAt the interface of inflammation control
Cell
(1998)- et al.
Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by κB elements
J Biol Chem
(1992) - et al.
Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin
J Biol Chem
(1990)