Abstract
The early response gene IEX-1 is involved in the regulation of cellular growth and survival, and its expression is related to stress-, growth- and death-inducing signals. Addressing the role of IEX-1 in the promotion of apoptosis, we investigated the effect of IEX-1 on nuclear factor-κB (NF-κB) activation. Stably transfected HEK-293 cells conditionally overexpressing IEX-1 exhibit decreased levels of NF-κB activity, either basal or TNFα induced, as shown by gel-shift and luciferase reporter gene assay. Furthermore, activated p65 accumulated in the nuclei of 293 cells to a lower degree, if IEX-1 expression was increased. This inhibited NF-κB activation was preceded by an altered turnover of IκBα and phospho-IκBα. In addition, IEX-1 expression also inhibited the activity of the 26S-proteasome, as shown by a fluorometric proteasome assay. Conversely, disruption of IEX-1 expression in 293 cells by stable transfection with specific anti-IEX-1 hammerhead ribozymes increased NF-κB activity, and accelerated the degradation of IκBα. Along with these opposite effects of IEX-1 expression and IEX-1 disruption on NF-κB activation, the sensitivity of 293 cells towards various apoptotic stimuli also changed. In contrast to ribozyme-transduced 293 cells that were significantly less sensitive to apoptosis, this sensitivity was enhanced if IEX-1 expression was increased. Our data suggest that IEX-1 – itself an NF-κB target gene – inhibits the activation of this transcription factor, and hereby may counteract the antiapoptotic potential of NF-κB.
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Abbreviations
- NF-κB:
-
nuclear factor-κB
- IκB:
-
inhibitor κB
- IKK:
-
IκB kinase
- Suc-LLVY-AMC:
-
N-succinyl-L-leucyl-L-leucyl-L-valyl-L-tyrosyl-7-amido-4-methylcumarin
- Tet:
-
tetracycline
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Acknowledgements
We thank Mr Hermann and Ms Wenzel for preparation of the illustrations. This study was supported by a grant of the German Research Society (DFG/SFB415-A13).
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Arlt, A., Kruse, ML., Breitenbroich, M. et al. The early response gene IEX-1 attenuates NF-κB activation in 293 cells, a possible counter-regulatory process leading to enhanced cell death. Oncogene 22, 3343–3351 (2003). https://doi.org/10.1038/sj.onc.1206524
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DOI: https://doi.org/10.1038/sj.onc.1206524
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