Disruption of I kappa B alpha regulation by antisense RNA expression leads to malignant transformation

Oncogene. 1994 Nov;9(11):3189-97.


NF-kappa B transcription factors regulate the expression of a variety of genes involved in immune regulation and cell growth. In most cell types NF-kappa B proteins are localized in an inactive form in the cytoplasm coupled to the inhibitory I kappa B proteins. Viruses, cytokines, lipopolysaccharides and other stimulating agents promote the dissociation of the cytosolic NF-kappa B/I kappa B complexes, via phosphorylation and degradation of I kappa B, resulting in the translocation of DNA binding, NF-kappa B complexes to the nucleus. To further understand the association of I kappa B with cell growth regulation, the effect of ectopic expression of sense and antisense I kappa B genes was examined in NIH3T3 cells. Overexpression of I kappa B alpha antisense RNA but not I kappa B gamma antisense RNA decreased the steady state levels of I kappa B alpha protein, altered NF-kappa B DNA binding and gene activity and, most importantly, induced malignant transformation as measured by saturation density, growth in soft agar and tumorigenicity in nude mice. In contrast, overexpression of I kappa B alpha resulted in decreased saturation density, a flattened cellular morphology and decreased NF-kappa B dependent reporter gene activity. These results indicate that overexpression of an I kappa B alpha antisense RNA may disrupt the NF-kappa B/I kappa B autoregulatory loop, leading to cellular transformation. Our results raise the interesting possibility that I kappa B alpha represents a potential tumor suppressor activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Base Sequence
  • Cell Transformation, Neoplastic*
  • Clone Cells / metabolism
  • DNA-Binding Proteins / genetics*
  • Gene Expression
  • Humans
  • I-kappa B Proteins*
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology*
  • NF-kappa B p50 Subunit
  • Oligodeoxyribonucleotides
  • Protein Binding
  • RNA, Antisense / biosynthesis*
  • RNA, Antisense / genetics
  • Transcription Factors / genetics


  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Oligodeoxyribonucleotides
  • RNA, Antisense
  • Transcription Factors
  • NF-KappaB Inhibitor alpha
  • Nfkb1 protein, mouse