Epidermal growth factor activation of NF-kappaB is mediated through IkappaBalpha degradation and intracellular free calcium

Oncogene. 1998 Apr 23;16(16):2095-102. doi: 10.1038/sj.onc.1201731.


The transcription factor NF-kappa-B is normally sequestered in the cytoplasm by its inhibitory subunit IkappaB. Most extracellular signals activate NF-kappa-B through a mechanism involving the phosphorylation and proteasome-dependent degradation of IkappaB. EGF activates NF-kappaB in A-431 carcinoma cells, which overexpress EGF receptors and in mouse embryo fibroblasts, which have a normal complement of receptors. Supershift experiments indicate that the NF-kappa-B complexes induced by EGF are composed of p50/p50 homodimers and p65/p50 heterodimers, but not c-rel. EGF stimulation enhances the degradation of IkappaBalpha, but not IkappaBbeta nor an N-terminal deletion mutant of IkappaBalpha. Treatment of cells with a proteasome inhibitor, such as ALLN or MG132, blocks EGF-mediated NF-kappaB activation, indicating that EGF-induced NF-kappa-B activation requires proteasome-dependent IkappaB degradation. Also, Bapta A/M (a cell-permeable chelator of intracellular calcium) blocks EGF-induced NF-kappa-B activation and IkappaBalpha degradation, suggesting a requirement of intracellular free Ca2+ for this growth factor response. Protein kinase C inhibition, in contrast, did not influence EGF activation of NF-kappaB.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cell Communication
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Epidermal Growth Factor / pharmacology*
  • Humans
  • I-kappa B Proteins*
  • Intracellular Fluid
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Tumor Cells, Cultured


  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • NF-KappaB Inhibitor alpha
  • Epidermal Growth Factor
  • Calcium