Trends in Pharmacological Sciences
Tumour necrosis factor α and interleukin 1 signalling: do MAPKK kinases connect it all?
Section snippets
Nuclear factor κB and activating protein 1
The two most prominent transcription factors responsible for the effects of TNF-α and IL-1 are nuclear factor κB (NF-κB) and activating protein 1 (AP-1). These factors mediate the induction of many proteins central to inflammatory processes and immune responses, such as cytokines, cell-adhesion molecules, growth factors, metalloproteinases and other proteins that participate in the production of prostaglandins, leukotrienes and NO (5, 6). Interestingly, glucocorticoids, which are potent
Link between NF-κB and AP-1 signal transduction pathways
Tumour necrosis factor α- and IL-1-like stimuli (such as UV irradiation, osmotic stress and lipopolysaccharide) induce the simultaneous activation of NF-κB, JNK and p38 kinase, and a connection between these MAP kinase pathways and NF-κB activation has now been established at the molecular level. The foundation for these discoveries was laid by D. Goeddel and co-workers studying the early events in TNF receptor signalling which led to the identification of a new family of proteins, termed
What the future might hold
At present, the TRAF–MAPKKK signal transduction level is one of the least-defined steps in TNF-α and IL-1 signalling. So far, direct binding of TRAFs to MAPKKs has only been demonstrated in one case: the TRAF2–NIK interaction, and it will be crucial to learn whether or not binding of TRAFs to MAPKKKs is indeed a general principle. Given that a catalytically inactive NIK mutant protein can block TNF-α- as well as IL-1-induced NF-κB activation, and that an inactive MEKK1 variant can inhibit
Acknowledgements
I am grateful to Max Schreier for many stimulating discussions and for his constant support for and interest in my work. I also thank Ralf Heilker and Hermann Gram for their critical reading of the manuscript.
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