The early response gene IEX-1 attenuates NF-kappaB activation in 293 cells, a possible counter-regulatory process leading to enhanced cell death

Oncogene. 2003 May 22;22(21):3343-51. doi: 10.1038/sj.onc.1206524.


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-kappaB (NF-kappaB) activation. Stably transfected HEK-293 cells conditionally overexpressing IEX-1 exhibit decreased levels of NF-kappaB activity, either basal or TNFalpha 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-kappaB activation was preceded by an altered turnover of IkappaBalpha and phospho-IkappaBalpha. 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-kappaB activity, and accelerated the degradation of IkappaBalpha. Along with these opposite effects of IEX-1 expression and IEX-1 disruption on NF-kappaB 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-kappaB target gene - inhibits the activation of this transcription factor, and hereby may counteract the antiapoptotic potential of NF-kappaB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Cell Line
  • Cell Nucleus / chemistry
  • Cysteine Endopeptidases / metabolism
  • Humans
  • I-kappa B Proteins / metabolism
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / physiology*
  • Kinetics
  • Membrane Proteins
  • Multienzyme Complexes / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / analysis
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Proteasome Endopeptidase Complex
  • RNA, Catalytic / genetics
  • RNA, Catalytic / metabolism
  • Transcription Factor RelA
  • Transfection


  • Apoptosis Regulatory Proteins
  • I-kappa B Proteins
  • IER3 protein, human
  • Immediate-Early Proteins
  • Membrane Proteins
  • Multienzyme Complexes
  • NF-kappa B
  • NFKBIA protein, human
  • Neoplasm Proteins
  • RNA, Catalytic
  • Transcription Factor RelA
  • hammerhead ribozyme
  • NF-KappaB Inhibitor alpha
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex