Abstract
Although nuclear factor-κB (NF-κB) usually exerts anti-apoptotic activity, upon activation by interleukin-1 (IL-1) it enhances ultraviolet-B radiation (UVB)-induced apoptosis. This paradoxical effect is associated with NF-κB-dependent pronounced secretion of tumour necrosis factor-α (TNF) which activates TNF-R1 in an autocrine fashion to enhance UVB-induced apoptosis. We demonstrate that sustained TNF transcription in UVB+IL-1-treated cells involves complete abrogation of the negative feedback loop of NF-κB preventing IκBα resynthesis, hence allowing uncontrolled NF-κB activity. We show that IκBα is not transcriptionally inhibited but resynthesized protein is immediately marked for degradation due to persistent inhibitor of κB kinaseβ (IKKβ) activity. Continuous IKKβ phosphorylation and activation is caused by UVB-mediated inhibition of the phosphatase PP2A. This study demonstrates that the cellular response to different NF-κB activators may be converted to the opposite reaction when both stimuli act in concert. Our data shed new light on the significance of negative feedback regulation of NF-κB and identifies PP2A as the key regulator of this process.
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Abbreviations
- UVB:
-
ultraviolet-B light
- TNF:
-
tumour necrosis factor-α
- IL-1:
-
interleukin-1
- NF-κB:
-
nuclear factor-κB
- IκBα:
-
inhibitor of κBα
- IKKβ:
-
inhibitor of κB kinaseβ
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Acknowledgements
We are grateful to T Schwarz, University of Kiel, and K Pfizenmaier, University of Stuttgart, for help with the paper. We also thank P Scheurich and A Hausser, University of Stuttgart, for supplying reagents. This work was funded by the German Research Foundation (DFG, KU 1981/1-1).
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Barisic, S., Strozyk, E., Peters, N. et al. Identification of PP2A as a crucial regulator of the NF-κB feedback loop: its inhibition by UVB turns NF-κB into a pro-apoptotic factor. Cell Death Differ 15, 1681–1690 (2008). https://doi.org/10.1038/cdd.2008.98
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DOI: https://doi.org/10.1038/cdd.2008.98
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