Inducible phosphorylation of I kappa B alpha is not sufficient for its dissociation from NF-kappa B and is inhibited by protease inhibitors

Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11884-8. doi: 10.1073/pnas.91.25.11884.


The ubiquitous transcription factor NF-kappa B is regulated by its cytoplasmic inhibitor I kappa B. A variety of cellular stimuli cause the dissociation of NF-kappa B from I kappa B, allowing NF-kappa B to translocate to the nucleus and regulate gene expression. Although the activation of NF-kappa B in vivo is associated with the phosphorylation and degradation of I kappa B alpha, it has remained unclear how each of these events contributes to this process. Recently, studies utilizing protease inhibitors have suggested that the proteolysis of I kappa B alpha is a necessary event in the activation of NF-kappa B. We demonstrate in this study that these and an additional protease inhibitor also completely repress inducible phosphorylation of I kappa B alpha. This surprising result suggests a more complex role of proteases in NF-kappa B activation. In addition, data presented here indicate that many of these inhibitors also directly modify NF-kappa B and inhibit its DNA binding activity. Due to the pleiotropic effects of these protease inhibitors, it is difficult to conclude from their use how I kappa B alpha phosphorylation and degradation contribute to NF-kappa B activation. In the present study, a more direct approach demonstrates that phosphorylation of I kappa B alpha alone is not sufficient for NF-kappa B activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • DNA, Neoplasm / metabolism*
  • DNA-Binding Proteins / metabolism*
  • HeLa Cells
  • Humans
  • I-kappa B Proteins*
  • Molecular Sequence Data
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Oligonucleotide Probes
  • Phosphorylation
  • Protease Inhibitors / pharmacology*
  • Protein Binding
  • T-Lymphocytes
  • Tumor Cells, Cultured


  • DNA, Neoplasm
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Oligonucleotide Probes
  • Protease Inhibitors
  • NF-KappaB Inhibitor alpha